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Welc SS, Brotto M, White KE, Bonewald LF. Aging: A struggle for beneficial to overcome negative factors made by muscle and bone. Mech Ageing Dev 2025; 224:112039. [PMID: 39952614 PMCID: PMC11893237 DOI: 10.1016/j.mad.2025.112039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/15/2024] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
Musculoskeletal health is strongly influenced by regulatory interactions of bone and muscle. Recent discoveries have identified a number of key mechanisms through which soluble factors released during exercise by bone exert positive effects on muscle and by muscle on bone. Although exercise can delay the negative effects of aging, these beneficial effects are diminished with aging. The limited response of aged muscle and bone tissue to exercise are accompanied by a failure in bone and muscle communication. Here, we propose that exercise induced beneficial factors must battle changes in circulating endocrine and inflammatory factors that occur with aging. Furthermore, sedentary behavior results in the release of negative factors impacting the ability of bone and muscle to respond to physical activity especially with aging. In this review we report on exercise responsive factors and evidence of modification occurring with aging.
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Affiliation(s)
- Steven S Welc
- Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
| | - Marco Brotto
- Bone-Muscle Research Center, College of Nursing & Health Innovation, University of Texas-Arlington, Arlington, TX 76019, USA.
| | - Kenneth E White
- Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Department of Molecular and Medical Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
| | - Lynda F Bonewald
- Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
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Azhdari M, Zur Hausen A. Wnt/β-catenin and notch signaling pathways in cardiovascular disease: Mechanisms and therapeutics approaches. Pharmacol Res 2025; 211:107565. [PMID: 39725339 DOI: 10.1016/j.phrs.2024.107565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/30/2024] [Accepted: 12/23/2024] [Indexed: 12/28/2024]
Abstract
Wnt and Notch signaling pathways play crucial roles in the development and homeostasis of the cardiovascular system. These pathways regulate important cellular processes in cardiomyocytes, endothelial cells, and smooth muscle cells, which are the key cell types involved in the structure and function of the heart and vasculature. During embryonic development, Wnt and Notch signaling coordinate cell fate specification, proliferation, differentiation, and morphogenesis of the heart and blood vessels. In the adult cardiovascular system, these pathways continue to maintain tissue homeostasis and arrange adaptive responses to various physiological and pathological stimuli. Dysregulation of Wnt and Notch signaling has been involved in the pathogenesis of numerous cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and heart failure. Abnormal activation or suppression of these pathways in specific cell types can contribute to endothelial dysfunction, vascular remodeling, cardiomyocyte hypertrophy, impaired cardiac contractility and dead. Understanding the complex interplay between Wnt and Notch signaling in the cardiovascular system has led to the investigation of these pathways as potential therapeutic targets in clinical trials. In conclusion, this review summarizes the current knowledge on the roles of Wnt and Notch signaling in the development and homeostasis of cardiomyocytes, endothelial cells, and smooth muscle cells. It further discusses the dysregulation of these pathways in the context of major cardiovascular diseases and the ongoing clinical investigations targeting Wnt and Notch signaling for therapeutic intervention.
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Affiliation(s)
- Manizheh Azhdari
- Pathologie, School for Cardiovascular Diseases, Fac. Health, Medicine and Life Sciences, Maastricht university, MUMC, the Netherland.
| | - Axel Zur Hausen
- Pathologie, School for Cardiovascular Diseases, Fac. Health, Medicine and Life Sciences, Maastricht university, MUMC, the Netherland.
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Zhang H, Hao J, Hong H, Gu W, Li Z, Sun J, Zhan H, Wei X, Zhou L. Redox signaling regulates the skeletal tissue development and regeneration. Biotechnol Genet Eng Rev 2024; 40:2308-2331. [PMID: 37043672 DOI: 10.1080/02648725.2023.2199244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/30/2023] [Indexed: 04/14/2023]
Abstract
Skeletal tissue development and regeneration in mammals are intricate, multistep, and highly regulated processes. Various signaling pathways have been implicated in the regulation of these processes, including redox. Redox signaling is the signal transduction by electron transfer reactions involving free radicals or related species. Redox homeostasis is essential to cell metabolic states, as the ROS not only regulates cell biological processes but also mediates physiological processes. Following a bone fracture, redox signaling is also triggered to regulate bone healing and regeneration by targeting resident stromal cells, osteoblasts, osteoclasts and endothelial cells. This review will focus on how the redox signaling impact the bone development and bone regeneration.
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Affiliation(s)
- Hao Zhang
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, East China, Shanghai, China
| | - Jin Hao
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, East China, Shanghai, China
| | - HaiPing Hong
- FangTa Hospital of Traditional Chinese Medicine, Songjiang Branch, Shanghai, East China, China
| | - Wei Gu
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, East China, Shanghai, China
| | | | - Jun Sun
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, East China, Shanghai, China
| | - Hongsheng Zhan
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, East China, Shanghai, China
| | - Xiaoen Wei
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, East China, Shanghai, China
| | - Lin Zhou
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, East China, Shanghai, China
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Sandhu S, Keyworth M, Karimi-Jashni S, Alomar D, Smith BJ, Kozbenko T, Doty S, Hocking R, Hamada N, Reynolds RJ, Scott RT, Costes SV, Beheshti A, Yauk C, Wilkins RC, Chauhan V. AOP Report: Development of an adverse outcome pathway for deposition of energy leading to bone loss. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2024; 65 Suppl 3:85-111. [PMID: 39387375 DOI: 10.1002/em.22631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 08/27/2024] [Indexed: 10/15/2024]
Abstract
Bone loss, commonly seen in osteoporosis, is a condition that entails a progressive decline of bone mineral density and microarchitecture, often seen in post-menopausal women. Bone loss has also been widely reported in astronauts exposed to a plethora of stressors and in patients with osteoporosis following radiotherapy for cancer. Studies on mechanisms are well documented but the causal connectivity of events to bone loss development remains incompletely understood. Herein, the adverse outcome pathway (AOP) framework was used to organize data and develop a qualitative AOP beginning from deposition of energy (the molecular initiating event) to bone loss (the adverse outcome). This qualitative AOP was developed in collaboration with bone loss research experts to aggregate relevant findings, supporting ongoing efforts to understand and mitigate human system risks associated with radiation exposures. A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 2029 studies, an empirically supported AOP was developed, showing the progression to bone loss through many factors affecting the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The structural, functional, and quantitative basis of each proposed relationship was defined, for inference of causal changes between key events. Current knowledge and its gaps relating to dose-, time- and incidence-concordance across the key events were identified, as well as modulating factors that influence linkages. The new priorities for research informed by the AOP highlight areas for improvement to enable development of a quantitative AOP used to support risk assessment strategies for space travel or cancer radiotherapy.
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Affiliation(s)
- Snehpal Sandhu
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Mitchell Keyworth
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Syna Karimi-Jashni
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Dalya Alomar
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Benjamin J Smith
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Tatiana Kozbenko
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Stephen Doty
- Hospital for Special Surgery Research Institute, New York City, New York, USA
| | - Robyn Hocking
- Learning and Knowledge and Library Services, Health Canada, Ottawa, Ontario, Canada
| | - Nobuyuki Hamada
- Biology and Environmental Chemistry Division, Substantiable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Chiba, Japan
| | | | - Ryan T Scott
- KBR, NASA Ames Research Center, Moffett Field, California, USA
| | - Sylvain V Costes
- NASA Ames Research Center, Space Biosciences Research Branch, Mountain View, California, USA
| | - Afshin Beheshti
- McGowan Institute for Regenerative Medicine - Center for Space Biomedicine, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Carole Yauk
- Department of Biology, University of Ottawa, Ottawa, Ontario, Canada
| | - Ruth C Wilkins
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Vinita Chauhan
- Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, Ontario, Canada
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Anagnostis P, Lallas K, Pappa A, Avgeris G, Beta K, Damakis D, Fountoukidou E, Zidrou M, Lambrinoudaki I, Goulis DG. The association of vasomotor symptoms with fracture risk and bone mineral density in postmenopausal women: a systematic review and meta-analysis of observational studies. Osteoporos Int 2024; 35:1329-1336. [PMID: 38563960 PMCID: PMC11281950 DOI: 10.1007/s00198-024-07075-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND/AIMS Vasomotor symptoms (VMS) adversely affect postmenopausal quality of life. However, their association with bone health has not been elucidated. This study aimed to systematically review and meta-analyze the evidence regarding the association of VMS with fracture risk and bone mineral density (BMD) in peri- and postmenopausal women. METHODS A literature search was conducted in PubMed, Scopus and Cochrane databases until 31 August 2023. Fracture, low BMD (osteoporosis/osteopenia) and mean change in lumbar spine (LS) and femoral neck (FN) BMD were assessed. The results are presented as odds ratio (OR) and mean difference (MD), respectively, with a 95% confidence interval (95% CI). The I2 index quantified heterogeneity. RESULTS Twenty studies were included in the qualitative and 12 in the quantitative analysis (n=49,659). No difference in fractures between women with and without VMS was found (n=5, OR 1.04, 95% CI 0.93-1.16, I2 16%). However, VMS were associated with low BMD (n=5, OR 1.54, 95% CI 1.42-1.67, I2 0%). This difference was evident for LS (MD -0.019 g/cm2, 95% CI -0.03 to -0.008, I2 85.2%), but not for FN BMD (MD -0.010 g/cm2, 95% CI -0.021 to 0.001, I2 78.2%). These results were independent of VMS severity, age and study design. When the analysis was confined to studies that excluded menopausal hormone therapy use, the association with BMD remained significant. CONCLUSIONS The presence of VMS is associated with low BMD in postmenopausal women, although it does not seem to increase fracture risk.
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Affiliation(s)
- Panagiotis Anagnostis
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Konstantinos Lallas
- Department of Medical Oncology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Anna Pappa
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios Avgeris
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kristina Beta
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Damakis
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eirini Fountoukidou
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Zidrou
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Irene Lambrinoudaki
- 2nd Department of Obstetrics and Gynecology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios G Goulis
- 1st Department of Obstetrics and Gynecology, Medical School, Unit of Reproductive Endocrinology, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Chen X, Yao N, Mao Y, Xiao D, Huang Y, Zhang X, Wang Y. Activation of the Wnt/β-catenin/CYP1B1 pathway alleviates oxidative stress and protects the blood-brain barrier under cerebral ischemia/reperfusion conditions. Neural Regen Res 2024; 19:1541-1547. [PMID: 38051897 PMCID: PMC10883507 DOI: 10.4103/1673-5374.386398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 06/20/2023] [Indexed: 12/07/2023] Open
Abstract
Abstract
JOURNAL/nrgr/04.03/01300535-202407000-00033/figure1/v/2023-11-20T171125Z/r/image-tiff
Accumulating evidence suggests that oxidative stress and the Wnt/β-catenin pathway participate in stroke-induced disruption of the blood-brain barrier. However, the potential links between them following ischemic stroke remain largely unknown. The present study found that cerebral ischemia leads to oxidative stress and repression of the Wnt/β-catenin pathway. Meanwhile, Wnt/β-catenin pathway activation by the pharmacological inhibitor, TWS119, relieved oxidative stress, increased the levels of cytochrome P450 1B1 (CYP1B1) and tight junction-associated proteins (zonula occludens-1 [ZO-1], occludin and claudin-5), as well as brain microvascular density in cerebral ischemia rats. Moreover, rat brain microvascular endothelial cells that underwent oxygen glucose deprivation/reoxygenation displayed intense oxidative stress, suppression of the Wnt/β-catenin pathway, aggravated cell apoptosis, downregulated CYP1B1 and tight junction protein levels, and inhibited cell proliferation and migration. Overexpression of β-catenin or knockdown of β-catenin and CYP1B1 genes in rat brain microvascular endothelial cells at least partly ameliorated or exacerbated these effects, respectively. In addition, small interfering RNA-mediated β-catenin silencing decreased CYP1B1 expression, whereas CYP1B1 knockdown did not change the levels of glycogen synthase kinase 3β, Wnt-3a, and β-catenin proteins in rat brain microvascular endothelial cells after oxygen glucose deprivation/reoxygenation. Thus, the data suggest that CYP1B1 can be regulated by Wnt/β-catenin signaling, and activation of the Wnt/β-catenin/CYP1B1 pathway contributes to alleviation of oxidative stress, increased tight junction levels, and protection of the blood-brain barrier against ischemia/hypoxia-induced injury.
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Affiliation(s)
- Xingyong Chen
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Nannan Yao
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
- Department of Neurology, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Yanguang Mao
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Dongyun Xiao
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yiyi Huang
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xu Zhang
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yinzhou Wang
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Academy of Medical Science, Fuzhou, Fujian Province, China
- Key Testing Laboratory of Fujian Province, Fuzhou, Fujian Province, China
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Zhang L, Wang Z, Zhang Y, Ji R, Li Z, Zou J, Gao B. Regulatory cellular and molecular networks in the bone microenvironment during aging. LIFE MEDICINE 2024; 3:lnae019. [PMID: 39871887 PMCID: PMC11749081 DOI: 10.1093/lifemedi/lnae019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/30/2024] [Indexed: 01/29/2025]
Abstract
Age-induced abnormalities in bone metabolism disrupt the equilibrium between bone resorption and formation. This largely stems from disturbances in bone homeostasis, in which signaling pathways exert a significant regulatory influence. Aging compromises the functionality of the bone marrow mesenchymal stem cells (BMSCs), ultimately resulting in tissue dysfunction and pathological aging. Age-related bone degradation primarily manifests as reduced bone formation and the increased accumulation of bone marrow fat. Cellular senescence diminishes bone cell vitality, thereby disrupting the balance of bone remodeling. Intensive osteoclast differentiation leads to the generation of more osteoclasts and increased bone resorption. This review provides insight into the impact of aging on bone, encompassing bone cell states during the aging process and bone signaling pathway transformations. It primarily delves into aging-related signaling pathways, such as the bone morphogenetic protein/Smad, Wnt/β-catenin, osteoprotegerin/receptor activator of NF-κB ligand/receptor activator of NF-κB, connexin43/miR21, and nuclear factor erythroid 2-related factor 2/antioxidant response element pathways, seeking to enhance our comprehension of crucial bone cells and their secretory phenotypes during aging. Furthermore, the precise molecular regulatory mechanisms underlying the interactions between bone signaling pathways and aging are investigated.
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Affiliation(s)
- Lingli Zhang
- School of Athletic Performance, Shanghai University of Sport, Shanghai 200438, China
| | - Zhikun Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Yuan Zhang
- School of Athletic Performance, Shanghai University of Sport, Shanghai 200438, China
| | - Rui Ji
- Department of Orthopedic Surgery, Xijing Hospital, Airforce Medical University, Xi'an 710032, China
| | - Zhiben Li
- Department of Orthopedic Surgery, Xijing Hospital, Airforce Medical University, Xi'an 710032, China
| | - Jun Zou
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Bo Gao
- Department of Orthopedic Surgery, Xijing Hospital, Airforce Medical University, Xi'an 710032, China
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Belenkov YN, Iusupova AO, Slepova OA, Pakhtusov NN, Popova LV, Lishuta AS, Krivova AV, Khabarova NV, Abidaev MY, Privalova EV. WNT Signaling Cascade Proteins and LRP6 in the Formation of Various Types of Coronary Lesions in Patients With Coronary Artery Disease. KARDIOLOGIIA 2024; 64:3-10. [PMID: 38841783 DOI: 10.18087/cardio.2024.5.n2626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 06/07/2024]
Abstract
AIM Assessment of WNT1, WNT3a, and LRP6 concentrations in patients with ischemic heart disease (IHD) and obstructive and non-obstructive coronary artery (CA) disease. MATERIAL AND METHODS This cross-sectional observational study included 50 IHD patients (verified by coronary angiography, CAG), of which 25 (50%) were men, mean age 64.9±8.1 years; 20 patients had non-obstructive CA disease (stenosis <50%), and 30 patients had hemodynamically significant stenosis. Concentrations of WNT1, WNT3a and LRP6 were measured in all patients. RESULTS The concentrations of WNT1 and WNT3a proteins were significantly higher in patients with IHD and obstructive CA disease (p < 0.001), while the concentration of LRP6 was higher in the group with non-obstructive CA disease (p = 0.016). Data analysis of the group with obstructive CA disease showed a moderate correlation between WNT1 and LRP6 (ρ=0.374; p=0.042). Correlation analysis of all groups of patients with CA disease revealed a moderate association between the concentrations of WNT1 and uric acid (ρ=0.416; p=0.007). Regression analysis showed that risk factors for the development of IHD, such as increased body mass index, age, smoking, dyslipidemia, and hypertension, did not significantly influence the type of CA disease in IHD patients. According to ROC analysis, the obstructive form of IHD was predicted by a WNT3a concentration higher than 0.155 ng/ml and a LRP6 concentration lower than 12.94 ng/ml. CONCLUSION IHD patients with non-obstructive CA disease had the greatest increase in LRP6, while patients with obstructive CA disease had significantly higher concentrations of the canonical WNT cascade proteins, WNT1 and WNT3a. According to the ROC analysis, a WNT3a concentration >0.155 ng/ml can serve as a predictor for the presence of hemodynamically significant CA stenosis in IHD patients (sensitivity 96.7%; specificity 70%), whereas a LRP6 concentration >12.94 ng/ml can predict the development of non-obstructive CA disease (sensitivity 76.7%; specificity 65%).
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Affiliation(s)
- Yu N Belenkov
- Sechenov First Moscow State Medical University, Moscow
| | - A O Iusupova
- Sechenov First Moscow State Medical University, Moscow
| | - O A Slepova
- Sechenov First Moscow State Medical University, Moscow
| | - N N Pakhtusov
- Sechenov First Moscow State Medical University, Moscow
| | - L V Popova
- Sechenov First Moscow State Medical University, Moscow
| | - A S Lishuta
- Sechenov First Moscow State Medical University, Moscow
| | - A V Krivova
- Sechenov First Moscow State Medical University, Moscow
| | - N V Khabarova
- Sechenov First Moscow State Medical University, Moscow
| | - M Yu Abidaev
- Sechenov First Moscow State Medical University, Moscow
| | - E V Privalova
- Sechenov First Moscow State Medical University, Moscow
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Yu S, Huang W, Zhang H, Guo Y, Zhang B, Zhang G, Lei J. Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design. Eur J Med Chem 2024; 271:116414. [PMID: 38677061 DOI: 10.1016/j.ejmech.2024.116414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 04/11/2024] [Accepted: 04/11/2024] [Indexed: 04/29/2024]
Abstract
Sclerostin is a secreted glycoprotein that expresses predominantly in osteocytes and inhibits bone formation by antagonizing the Wnt/β-catenin signaling pathway, and the loop3 region of sclerostin has recently discovered as a novel therapeutic target for bone anabolic treatment without increasing cardiovascular risk. Herein, we used a structural based virtual screening to search for small molecular inhibitors selectively targeting sclerostin loop3. A novel natural product hit ZINC4228235 (THFA) was identified as the sclerostin loop3-selective inhibitor with a Kd value of 42.43 nM against sclerostin loop3. The simplification and derivation of THFA using molecular modeling-guided modification allowed the discovery of an effective and loop3-selective small molecular inhibitor, compound (4-(3-acetamidoprop-1-yn-1-yl)benzoyl)glycine (AACA), with improved binding affinity (Kd = 15.4 nM) compared to the hit THFA. Further in-vitro experiment revealed that compound AACA could attenuate the suppressive effect of transfected sclerostin on Wnt signaling and bone formation. These results make AACA as a potential candidate for development of anti-osteoporosis agents without increasing cardiovascular risk.
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Affiliation(s)
- Sifan Yu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, China.
| | - Weifeng Huang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Hao Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Yinfeng Guo
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Baoting Zhang
- School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, China.
| | - Jinping Lei
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
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10
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Gumede DB, Abrahamse H, Houreld NN. Targeting Wnt/β-catenin signaling and its interplay with TGF-β and Notch signaling pathways for the treatment of chronic wounds. Cell Commun Signal 2024; 22:244. [PMID: 38671406 PMCID: PMC11046856 DOI: 10.1186/s12964-024-01623-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 04/20/2024] [Indexed: 04/28/2024] Open
Abstract
Wound healing is a tightly regulated process that ensures tissue repair and normal function following injury. It is modulated by activation of pathways such as the transforming growth factor-beta (TGF-β), Notch, and Wnt/β-catenin signaling pathways. Dysregulation of this process causes poor wound healing, which leads to tissue fibrosis and ulcerative wounds. The Wnt/β-catenin pathway is involved in all phases of wound healing, primarily in the proliferative phase for formation of granulation tissue. This review focuses on the role of the Wnt/β-catenin signaling pathway in wound healing, and its transcriptional regulation of target genes. The crosstalk between Wnt/β-catenin, Notch, and the TGF-β signaling pathways, as well as the deregulation of Wnt/β-catenin signaling in chronic wounds are also considered, with a special focus on diabetic ulcers. Lastly, we discuss current and prospective therapies for chronic wounds, with a primary focus on strategies that target the Wnt/β-catenin signaling pathway such as photobiomodulation for healing diabetic ulcers.
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Affiliation(s)
- Dimakatso B Gumede
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa
| | - Nicolette N Houreld
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa.
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11
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Wang B, Huang Y, Cai Q, Du Z, Li X. Biomaterials for diabetic bone repair: Influencing mechanisms, multi-aspect progress and future prospects. COMPOSITES PART B: ENGINEERING 2024; 274:111282. [DOI: 10.1016/j.compositesb.2024.111282] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2025]
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Walle M, Duseja A, Whittier DE, Vilaca T, Paggiosi M, Eastell R, Müller R, Collins CJ. Bone remodeling and responsiveness to mechanical stimuli in individuals with type 1 diabetes mellitus. J Bone Miner Res 2024; 39:85-94. [PMID: 38477745 PMCID: PMC11340785 DOI: 10.1093/jbmr/zjad014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/24/2023] [Accepted: 12/01/2023] [Indexed: 03/14/2024]
Abstract
Type 1 diabetes mellitus (T1DM) has been linked to increased osteocyte apoptosis, local accumulation of mineralized lacunar spaces, and microdamage suggesting an impairment of the mechanoregulation network in affected individuals. Diabetic neuropathy might exacerbate this dysfunction through direct effects on bone turnover, and indirect effects on balance, muscle strength, and gait. However, the in vivo effects of impaired bone mechanoregulation on bone remodeling in humans remain underexplored. This longitudinal cohort study assessed consenting participants with T1DM and varying degree of distal symmetric sensorimotor polyneuropathy (T1DM, n = 20, median age 46.5 yr, eight female) and controls (CTRL; n = 9, median age 59.0 yr, four female) at baseline and 4-yr follow-up. Nerve conduction in participants with T1DM was tested using DPNCheck and bone remodeling was quantified with longitudinal high-resolution peripheral quantitative-computed tomography (HR-pQCT, 82 μm) at the standard distal sites. Local trabecular bone formation (Tb.F) and resorption (Tb.R) sites were captured by implementing 3D rigid image registration of HR-pQCT images, and the mechanical environment across the bone microarchitecture at these sites was simulated using micro-finite element analysis. We calculated odds ratios to determine the likelihood of bone formation (ORF) and resorption (ORR) with increasing/decreasing strain in percent as markers for mechanoregulation. At the distal radius, Tb.F was 47% lower and Tb.R was 59% lower in T1DM participants compared with CTRL (P < .05). Tb.F correlated positively with nerve conduction amplitude (R = 0.69, P < .05) in participants with T1DM and negatively with glycated hemoglobin (HbA1c) (R = -0.45, P < .05). Additionally, ORF was 34% lower and ORR was 18% lower in T1DM compared with CTRL (P < .05). Our findings represent in vivo evidence suggesting that bone remodeling in individuals with T1DM is in a state of low responsiveness to mechanical stimuli, resulting in impaired bone formation and resorption rates; these correlate to the degree of neuropathy and level of diabetes control.
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Affiliation(s)
- Matthias Walle
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Ankita Duseja
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Danielle E Whittier
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Department of Osteoporosis, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Tatiane Vilaca
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Margaret Paggiosi
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Richard Eastell
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Ralph Müller
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Caitlyn J Collins
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, United States
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Iusupova AO, Pakhtusov NN, Slepova OA, Belenkov YN, Privalova EV, Bure IV, Vetchinkina EA, Nemtsova MV. MiRNA-21a, miRNA-145, and miRNA-221 Expression and Their Correlations with WNT Proteins in Patients with Obstructive and Non-Obstructive Coronary Artery Disease. Int J Mol Sci 2023; 24:17613. [PMID: 38139440 PMCID: PMC10744268 DOI: 10.3390/ijms242417613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/08/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023] Open
Abstract
MicroRNAs and the WNT signaling cascade regulate the pathogenetic mechanisms of atherosclerotic coronary artery disease (CAD) development. OBJECTIVE To evaluate the expression of microRNAs (miR-21a, miR-145, and miR-221) and the role of the WNT signaling cascade (WNT1, WNT3a, WNT4, and WNT5a) in obstructive CAD and ischemia with no obstructive coronary arteries (INOCA). METHOD The cross-sectional observational study comprised 94 subjects. The expression of miR-21a, miR-145, miR-221 (RT-PCR) and the protein levels of WNT1, WNT3a, WNT4, WNT5a, LRP6, and SIRT1 (ELISA) were estimated in the plasma of 20 patients with INOCA (66.5 [62.8; 71.2] years; 25% men), 44 patients with obstructive CAD (64.0 [56.5; 71,0] years; 63.6% men), and 30 healthy volunteers without risk factors for cardiovascular diseases (CVD). RESULTS Higher levels of WNT1 (0.189 [0.184; 0.193] ng/mL vs. 0.15 [0.15-0.16] ng/mL, p < 0.001) and WNT3a (0.227 [0.181; 0.252] vs. 0.115 [0.07; 0.16] p < 0.001) were found in plasma samples from patients with obstructive CAD, whereas the INOCA group was characterized by higher concentrations of WNT4 (0.345 [0.278; 0.492] ng/mL vs. 0.203 [0.112; 0.378] ng/mL, p = 0.025) and WNT5a (0.17 [0.16; 0.17] ng/mL vs. 0.01 [0.007; 0.018] ng/mL, p < 0.001). MiR-221 expression level was higher in all CAD groups compared to the control group (p < 0.001), whereas miR-21a was more highly expressed in the control group than in the obstructive (p = 0.012) and INOCA (p = 0.003) groups. Correlation analysis revealed associations of miR-21a expression with WNT1 (r = -0.32; p = 0.028) and SIRT1 (r = 0.399; p = 0.005) protein levels in all CAD groups. A positive correlation between miR-145 expression and the WNT4 protein level was observed in patients with obstructive CAD (r = 0.436; p = 0.016). Based on multivariate regression analysis, a mathematical model was constructed that predicts the type of coronary lesion. WNT3a and LRP6 were the independent predictors of INOCA (p < 0.001 and p = 0.002, respectively). CONCLUSIONS Activation of the canonical cascade of WNT-β-catenin prevailed in patients with obstructive CAD, whereas in the INOCA and control groups, the activity of the non-canonical pathway was higher. It can be assumed that miR-21a has a negative effect on the formation of atherosclerotic CAD. Alternatively, miR-145 could be involved in the development of coronary artery obstruction, presumably through the regulation of the WNT4 protein. A mathematical model with WNT3a and LRP6 as predictors allows for the prediction of the type of coronary artery lesion.
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Affiliation(s)
- Alfiya Oskarovna Iusupova
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Nikolay Nikolaevich Pakhtusov
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Olga Alexandrovna Slepova
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Yuri Nikitich Belenkov
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Elena Vitalievna Privalova
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Irina Vladimirovna Bure
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (I.V.B.); (E.A.V.); (M.V.N.)
- Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, 125445 Moscow, Russia
| | - Ekaterina Alexandrovna Vetchinkina
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (I.V.B.); (E.A.V.); (M.V.N.)
| | - Marina Vyacheslavovna Nemtsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (I.V.B.); (E.A.V.); (M.V.N.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
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14
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Meczekalski B, Niwczyk O, Bala G, Szeliga A. Managing Early Onset Osteoporosis: The Impact of Premature Ovarian Insufficiency on Bone Health. J Clin Med 2023; 12:4042. [PMID: 37373735 DOI: 10.3390/jcm12124042] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/21/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Premature ovarian insufficiency is a reproductive endocrine disorder characterized by the cessation of ovarian function before the age of 40 years. Although the etiopathology of POI remains largely unknown, certain causative factors have been identified. Individuals affected by POI are at an increased risk of experiencing bone mineral density (BMD) loss. Hormonal replacement therapy (HRT) is recommended for patients with POI to mitigate the risk of decreased BMD, starting from the time of diagnosis until reaching the average age of natural menopause. Various studies have compared the dose-effect relationship of estradiol supplementation, as well as different HRT formulations on BMD. The impact of oral contraception on reduced BMD or the potential benefits of adding testosterone to estrogen replacement therapy are still subjects of ongoing discussion. This review provides an overview of the latest advancements in the diagnosis, evaluation, and treatment of POI as it relates to BMD loss.
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Affiliation(s)
- Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Olga Niwczyk
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Gregory Bala
- UCD School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Anna Szeliga
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
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Abdul Rahim M, Khan K, Chrcanovic BR. Influence of Crown-Implant Ratio and Implant Inclination on Marginal Bone Loss around Dental Implants Supporting Single Crowns in the Posterior Region: A Retrospective Clinical Study. J Clin Med 2023; 12:3219. [PMID: 37176659 PMCID: PMC10179148 DOI: 10.3390/jcm12093219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
The aim of this present record-based retrospective study was to investigate the influence of the crown-implant ratio (CIR) and implant inclination in relation to the occlusal plane on the marginal bone loss (MBL) around dental implants supporting single crowns in the posterior region of the jaws. All the cases of implant-supported single crowns in the premolar and molar regions were initially considered for inclusion. Only implants not lost, with baseline radiographs taken within 12 months after implant placement and with a minimum of 36 months of radiological follow-up, were considered for the analysis of MBL. Univariate linear regression models were used to compare MBL over time between 12 clinical covariates, after which a linear mixed-effects model was built. After the exclusion of 49 cases, a total of 316 implant-supported single crowns in 234 patients were included. The results from the statistical models suggested that implant inclination and anatomical- and clinical CIR (the main related factors investigated in the study) were not statistically significantly related to MBL over time. Age (older people), tooth region (premolar), and bruxism (bruxers) had a statistically significant influence on MBL over time.
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Affiliation(s)
- Maha Abdul Rahim
- Faculty of Odontology, Malmö University, 214 21 Malmö, Sweden; (M.A.R.); (K.K.)
| | - Kashmala Khan
- Faculty of Odontology, Malmö University, 214 21 Malmö, Sweden; (M.A.R.); (K.K.)
| | - Bruno Ramos Chrcanovic
- Department of Prosthodontics, Faculty of Odontology, Malmö University, 214 21 Malmö, Sweden
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Hu L, Cheng Z, Wu L, Luo L, Pan P, Li S, Jia Q, Yang N, Xu B. Histone methyltransferase SETDB1 promotes osteogenic differentiation in osteoporosis by activating OTX2-mediated BMP-Smad and Wnt/β-catenin pathways. Hum Cell 2023:10.1007/s13577-023-00902-w. [PMID: 37074626 DOI: 10.1007/s13577-023-00902-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 03/24/2023] [Indexed: 04/20/2023]
Abstract
Osteogenic differentiation plays important roles in the pathogenesis of osteoporosis. In this study, we explored the regulatory mechanism of histone methyltransferase SET domain bifurcated 1 (SETDB1) underlying the osteogenic differentiation in osteoporosis. The common osteoporosis-related genes were retrieved from the GeneCards, CTD, and Phenolyzer databases. The enrichment analysis was conducted on the candidate osteoporosis-related genes using the PANTHER software, and the binding site between transcription factors and target genes predicted by hTFtarget. The bioinformatics analyses suggested 6 osteoporosis-related chromatin/chromatin binding protein or regulatory proteins (HDAC4, SIRT1, SETDB1, MECP2, CHD7, and DKC1). Normal and osteoporosis tissues were collected from osteoporosis patients to examine the expression of SETDB1. It was found that SETDB1 was poorly expressed in osteoporotic femoral tissues, indicating that SETDB1 might be involved in the development of osteoporosis. We induced SETDB1 overexpression/knockdown, orthodenticle homeobox 2 (OTX2) overexpression, activation of Wnt/β-catenin or BMP-Smad pathways alone or in combination in osteoblasts or ovariectomized mice. The data indicated that SETDB1 methylation regulated H3K9me3 in the OTX2 promoter region and inhibited the expression of OTX2. Besides, the BMP-Smad and Wnt/β-catenin pathways were inhibited by OTX2, thereby resulting in inhibited osteogenic differentiation. Animal experiments showed that overexpressed SETDB1 could promote the increase of calcium level and differentiation of femoral tissues. In conclusion, upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/β-catenin pathways in osteoporosis.
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Affiliation(s)
- Lianying Hu
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China
- Department of Orthopedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, Anhui Province, People's Republic of China
| | - Zhen Cheng
- Clinical Laboratory, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, People's Republic of China
| | - Lunan Wu
- Department of Anesthesiology and Perioperative Medicine, The Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, The Second Hospital of Anhui Medical University, Hefei, 230601, People's Republic of China
| | - Liangliang Luo
- Department of Orthopedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, Anhui Province, People's Republic of China
| | - Ping Pan
- Department of Orthopedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, Anhui Province, People's Republic of China
| | - Shujin Li
- Clinical Laboratory, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, People's Republic of China
| | - Qiyu Jia
- Department of Orthopedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, Anhui Province, People's Republic of China.
| | - Ning Yang
- Department of Orthopedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, Anhui Province, People's Republic of China.
| | - Bin Xu
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China.
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Zhang K, Qiu W, Li H, Li J, Wang P, Chen Z, Lin X, Qian A. MACF1 overexpression in BMSCs alleviates senile osteoporosis in mice through TCF4/miR-335-5p signaling pathway. J Orthop Translat 2023; 39:177-190. [PMID: 36969134 PMCID: PMC10036500 DOI: 10.1016/j.jot.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/12/2023] [Accepted: 02/15/2023] [Indexed: 03/29/2023] Open
Abstract
Background The decreased osteogenic differentiation ability of mesenchymal stem cells (MSCs) is one of the important reasons for SOP. Inhibition of Wnt signaling in MSCs is closely related to SOP. Microtubule actin crosslinking factor 1 (MACF1) is an important regulator in Wnt/β-catenin signal transduction. However, whether the specific expression of MACF1 in MSC regulates SOP and its mechanism remains unclear. Methods We established MSC-specific Prrx1 (Prx1) promoter-driven MACF1 conditional knock-in (MACF-KI) mice, naturally aged male mice, and ovariectomized female mice models. Micro-CT, H&E staining, double calcein labeling, and the three-point bending test were used to explore the effects of MACF1 on bone formation and bone microstructure in the SOP mice model. Bioinformatics analysis, ChIP-PCR, qPCR, and ALP staining were used to explore the effects and mechanisms of MACF1 on MSCs' osteogenic differentiation. Results Microarray analysis revealed that the expression of MACF1 and positive regulators of the Wnt pathway (such as TCF4, β-catenin, Dvl) was decreased in human MSCs (hMSCs) isolated from aged osteoporotic than non-osteoporotic patients. The ALP activity and osteogenesis marker genes (Alp, Runx2, and Bglap) expression in mouse MSCs was downregulated during aging. Furthermore, Micro-CT analysis of the femur from 2-month-old MSC-specific Prrx1 (Prx1) promoter-driven MACF1 conditional knock-in (MACF-cKI) mice showed no significant trabecular bone changes compared to wild-type littermate controls, whereas 18- and 21-month-old MACF1 c-KI animals displayed increased bone mineral densities (BMD), improved bone microstructure, and increased maximum compression stress. In addition, the ovariectomy (OVX)-induced osteoporosis model of MACF1 c-KI mice had significantly higher trabecular volume and number, and increased bone formation rate than that in control mice. Mechanistically, ChIP-PCR showed that TCF4 could bind to the promoter region of the host gene miR-335-5p. Moreover, MACF1 could regulate the expression of miR-335-5p by TCF4 during the osteogenic differentiation of MSCs. Conclusion These data indicate that MACF1 positively regulates MSCs osteogenesis and bone formation through the TCF4/miR-335-5p signaling pathway in SOP, suggesting that targeting MACF1 may be a novel therapeutic approach against SOP. The translational potential of this article MACF1, an important switch in the Wnt signaling pathway, can alleviate SOP through the TCF4/miR-335-5p signaling pathway in mice model. It might act as a therapeutic target for the treatment of SOP to improve bone function.
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Affiliation(s)
- Kewen Zhang
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering; Key Lab for Space Biosciences and Biotechnology, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Wuxia Qiu
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering; Key Lab for Space Biosciences and Biotechnology, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, China
| | - Hui Li
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jun Li
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Pai Wang
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering; Key Lab for Space Biosciences and Biotechnology, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Zhihao Chen
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering; Key Lab for Space Biosciences and Biotechnology, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Xiao Lin
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering; Key Lab for Space Biosciences and Biotechnology, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen City, 518063, China
- Corresponding authorSchool of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Airong Qian
- Lab for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering; Key Lab for Space Biosciences and Biotechnology, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
- Corresponding authorSchool of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
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18
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Zhang M, Li Q, Wang KL, Dong Y, Mu YT, Cao YM, Liu J, Li ZH, Cui HL, Liu HY, Hu AQ, Zheng YJ. Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese. J Transl Med 2023; 21:47. [PMID: 36698149 PMCID: PMC9875546 DOI: 10.1186/s12967-023-03902-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Genetic knowledge of gestational diabetes mellitus (GDM) in Chinese women is quite limited. This study aimed to identify the risk factors and mechanism of GDM at the genetic level in a Chinese population. METHODS We conducted a genome-wide association study (GWAS) based on single nucleotide polymorphism (SNP) array genotyping (ASA-CHIA Bead chip, Illumina) and a case-cohort study design. Variants including SNPs, copy number variants (CNVs), and insertions-deletions (InDels) were called from genotyping data. A total of 2232 pregnant women were enrolled in their first/second trimester between February 2018 and December 2020 from Anqing Municipal Hospital in Anhui Province, China. The GWAS included 193 GDM patients and 819 subjects without a diabetes diagnosis, and risk ratios (RRs) and their 95% confidence intervals (CIs) were estimated by a regression-based method conditional on the population structure. The calling and quality control of genotyping data were performed following published guidelines. CNVs were merged into CNV regions (CNVR) to simplify analyses. To interpret the GWAS results, gene mapping and overexpression analyses (ORAs) were further performed to prioritize the candidate genes and related biological mechanisms. RESULTS We identified 14 CNVRs (false discovery rate corrected P values < 0.05) and two suggestively significant SNPs (P value < 0.00001) associated with GDM, and a total of 19 candidate genes were mapped. Ten genes were significantly enriched in gene sets related to lipase (triglyceride lipase and lipoprotein lipase) activity (LIPF, LIPK, LIPN, and LIPJ genes), oxidoreductase activity (TPH1 and TPH2 genes), and cellular components beta-catenin destruction complex (APC and GSK3B genes), Wnt signalosome (APC and GSK3B genes), and lateral element in the Gene Ontology resource (BRCA1 and SYCP2 genes) by two ORA methods (adjusted P values < 0.05). CONCLUSIONS Genes related to lipolysis, redox reaction, and proliferation of islet β-cells are associated with GDM in Chinese women. Energy metabolism, particularly lipolysis, may play an important role in GDM aetiology and pathology, which needs further molecular studies to verify.
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Affiliation(s)
- Miao Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Qing Li
- Department of Obstetrics and Gynecology, Anqing Municipal Hospital, Anqing, 246003, China
| | - Kai-Lin Wang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Yao Dong
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Yu-Tong Mu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Yan-Min Cao
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Jin Liu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Zi-Heng Li
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Hui-Lu Cui
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Hai-Yan Liu
- Department of Clinical Laboratory, Anqing Municipal Hospital, Anqing, 246003, China.
| | - An-Qun Hu
- Department of Clinical Laboratory, Anqing Municipal Hospital, Anqing, 246003, China.
| | - Ying-Jie Zheng
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China.
- Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China.
- Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, 200032, China.
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19
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Pulsed Electrical Stimulation Affects Osteoblast Adhesion and Calcium Ion Signaling. Cells 2022; 11:cells11172650. [PMID: 36078058 PMCID: PMC9454840 DOI: 10.3390/cells11172650] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022] Open
Abstract
An extensive research field in regenerative medicine is electrical stimulation (ES) and its impact on tissue and cells. The mechanism of action of ES, particularly the role of electrical parameters like intensity, frequency, and duration of the electric field, is not yet fully understood. Human MG-63 osteoblasts were electrically stimulated for 10 min with a commercially available multi-channel system (IonOptix). We generated alternating current (AC) electrical fields with a voltage of 1 or 5 V and frequencies of 7.9 or 20 Hz, respectively. To exclude liquid-mediated effects, we characterized the AC-stimulated culture medium. AC stimulation did not change the medium’s pH, temperature, and oxygen content. The H2O2 level was comparable with the unstimulated samples except at 5 V_7.9 Hz, where a significant increase in H2O2 was found within the first 30 min. Pulsed electrical stimulation was beneficial for the process of attachment and initial adhesion of suspended osteoblasts. At the same time, the intracellular Ca2+ level was enhanced and highest for 20 Hz stimulated cells with 1 and 5 V, respectively. In addition, increased Ca2+ mobilization after an additional trigger (ATP) was detected at these parameters. New knowledge was provided on why electrical stimulation contributes to cell activation in bone tissue regeneration.
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20
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Zhu M, Fan Z. The role of the Wnt signalling pathway in the energy metabolism of bone remodelling. Cell Prolif 2022; 55:e13309. [PMID: 35811348 DOI: 10.1111/cpr.13309] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/07/2022] [Accepted: 06/24/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVES Bone remodelling is necessary to repair old and impaired bone caused by aging and its effects. Injury in the process of bone remodelling generally leads to the development of various bone diseases. Energy metabolism plays crucial roles in bone cell formation and function, the disorder of which will disrupt the balance between bone formation and bone resorption. MATERIALS AND METHODS Here, we review the intrinsic interactions between bone remodelling and energy metabolism and the role of the Wnt signalling pathway. RESULTS We found a close interplay between metabolic pathways and bone homeostasis, demonstrating that bone plays an important role in the regulation of energy balance. We also discovered that Wnt signalling is associated with multiple biological processes regulating energy metabolism in bone cells. CONCLUSIONS Thus, targeted regulation of Wnt signalling and the recovery of the energy metabolism function of bone cells are key means for the treatment of metabolic bone diseases.
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Affiliation(s)
- Mengyuan Zhu
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
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21
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Sanabria-de la Torre R, García-Fontana C, González-Salvatierra S, Andújar-Vera F, Martínez-Heredia L, García-Fontana B, Muñoz-Torres M. The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus. Int J Mol Sci 2022; 23:6995. [PMID: 35805996 PMCID: PMC9266892 DOI: 10.3390/ijms23136995] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 02/01/2023] Open
Abstract
Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents "mandatory damage" in the development of microvascular complications and only "introductory damage" in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies.
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Affiliation(s)
- Raquel Sanabria-de la Torre
- Department of Medicine, University of Granada, 18016 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (M.M.-T.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - Cristina García-Fontana
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Sheila González-Salvatierra
- Department of Medicine, University of Granada, 18016 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (M.M.-T.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - Francisco Andújar-Vera
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Department of Computer Science and Artificial Intelligence, University of Granada, 18071 Granada, Spain
- Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI Institute), 18014 Granada, Spain
| | - Luis Martínez-Heredia
- Department of Medicine, University of Granada, 18016 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (M.M.-T.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
| | - Beatriz García-Fontana
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Manuel Muñoz-Torres
- Department of Medicine, University of Granada, 18016 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (M.M.-T.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain;
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
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22
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Kim R, Kim SW, Kim H, Ku SY. The impact of sex steroids on osteonecrosis of the jaw. Osteoporos Sarcopenia 2022; 8:58-67. [PMID: 35832420 PMCID: PMC9263170 DOI: 10.1016/j.afos.2022.05.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/24/2022] [Accepted: 05/18/2022] [Indexed: 12/30/2022] Open
Abstract
Sex steroid hormones play a major role in bone homeostasis. Therefore, the use of sex hormones or drugs may increase the risk of osteonecrosis of the jaw (ONJ), a complication caused by damaged bone homeostasis. However, few are known the impact of medications changing sex hormone levels on ONJ. The pathophysiology of ONJ is not clearly understood and many hypotheses exist: cessation of bone remodeling caused by its anti-resorptive effect on osteoclasts; compromised microcirculation due to medication affecting angiogenesis, including bisphosphonate; and impairment of defense mechanism toward local infection. The use of high-dose intravenous bisphosphonate in cancer patients is associated with a high prevalence of ONJ. Exogenous estrogen or androgen replacement was reported to be associated with ONJ. Polycystic ovarian syndrome (PCOS) patients demonstrate an androgen excess status, and androgen overproduction serves as a protective factor in the bone mineral density of young women. To date, there are no reports of ONJ occurrence due to androgen overproduction. In contrast, few reports on the occurrence of ONJ due to estrogen deficiency induced by drugs, such as selective estrogen receptor modulator (SERM), aromatase inhibitors, and gonadotropin-releasing hormone (GnRH) agonists, are available. Thus, the role of sex steroids in the development of ONJ is not known. Further studies are required to demonstrate the exact role of sex steroids in bone homeostasis and ONJ progression. In this review, we will discuss the relationship between medication associated with sex steroids and ONJ.
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Affiliation(s)
- Ranhee Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
- Department of Obstetrics and Gynecology, Dongguk University Ilsan Medical Center, Goyang, South Korea
| | - Sung Woo Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
| | - Hoon Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul, 03080, South Korea
| | - Seung-Yup Ku
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, South Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul, 03080, South Korea
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23
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Yu S, Li D, Zhang N, Ni S, Sun M, Wang L, Xiao H, Liu D, Liu J, Yu Y, Zhang Z, Yeung STY, Zhang S, Lu A, Zhang Z, Zhang B, Zhang G. Drug discovery of sclerostin inhibitors. Acta Pharm Sin B 2022; 12:2150-2170. [PMID: 35646527 PMCID: PMC9136615 DOI: 10.1016/j.apsb.2022.01.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/03/2021] [Accepted: 12/16/2021] [Indexed: 12/18/2022] Open
Abstract
Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.
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24
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Choi JUA, Kijas AW, Lauko J, Rowan AE. The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States. Front Cell Dev Biol 2022; 9:770143. [PMID: 35265628 PMCID: PMC8900535 DOI: 10.3389/fcell.2021.770143] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022] Open
Abstract
Bone homeostasis is a dynamic equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts. This process is primarily controlled by the most abundant and mechanosensitive bone cells, osteocytes, that reside individually, within chambers of porous hydroxyapatite bone matrix. Recent studies have unveiled additional functional roles for osteocytes in directly contributing to local matrix regulation as well as systemic roles through endocrine functions by communicating with distant organs such as the kidney. Osteocyte function is governed largely by both biochemical signaling and the mechanical stimuli exerted on bone. Mechanical stimulation is required to maintain bone health whilst aging and reduced level of loading are known to result in bone loss. To date, both in vivo and in vitro approaches have been established to answer important questions such as the effect of mechanical stimuli, the mechanosensors involved, and the mechanosensitive signaling pathways in osteocytes. However, our understanding of osteocyte mechanotransduction has been limited due to the technical challenges of working with these cells since they are individually embedded within the hard hydroxyapatite bone matrix. This review highlights the current knowledge of the osteocyte functional role in maintaining bone health and the key regulatory pathways of these mechanosensitive cells. Finally, we elaborate on the current therapeutic opportunities offered by existing treatments and the potential for targeting osteocyte-directed signaling.
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Affiliation(s)
- Jung Un Ally Choi
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Amanda W Kijas
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Jan Lauko
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Alan E Rowan
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
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25
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Ren LL, Zhou JY, Liang SJ, Wang XQ. Impaired intestinal stem cell activity in ETEC infection: enterotoxins, cyclic nucleotides, and Wnt signaling. Arch Toxicol 2022; 96:1213-1225. [PMID: 35226135 DOI: 10.1007/s00204-021-03213-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/21/2021] [Indexed: 12/25/2022]
Abstract
Enterotoxigenic Escherichia coli (ETEC) in humans and animals colonizes the intestine and thereafter secrets heat-stable enterotoxin (ST) with or without heat-labile enterotoxin (LT), which triggers massive fluid and electrolyte secretion into the gut lumen. The crosstalk between the cyclic nucleotide-dependent protein kinase/cystic fibrosis transmembrane conductance regulator (cAMP or cGMP/CFTR) pathway involved in ETEC-induced diarrhea channels, and the canonical Wnt/β-catenin signaling pathway leads to changes in intestinal stem cell (ISC) fates, which are strongly associated with developmental disorders caused by diarrhea. We review how alterations in enterotoxin-activated ion channel pathways and the canonical Wnt/β-catenin signaling pathway can explain inhibited intestinal epithelial activity, characterize alterations in the crosstalk of cyclic nucleotides, and predict harmful effects on ISCs in targeted therapy. Besides, we discuss current deficits in the understanding of enterotoxin-intestinal epithelial cell activity relationships that should be considered when interpreting sequelae of diarrhea.
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Affiliation(s)
- Lu-Lu Ren
- College of Animal Science, South China Agricultural University/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control/National Engineering Research Center for Breeding Swine Industry, Guangzhou, 510642, China
| | - Jia-Yi Zhou
- College of Animal Science, South China Agricultural University/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control/National Engineering Research Center for Breeding Swine Industry, Guangzhou, 510642, China
| | - Shao-Jie Liang
- College of Animal Science, South China Agricultural University/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control/National Engineering Research Center for Breeding Swine Industry, Guangzhou, 510642, China
| | - Xiu-Qi Wang
- College of Animal Science, South China Agricultural University/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control/National Engineering Research Center for Breeding Swine Industry, Guangzhou, 510642, China.
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26
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Liu S, Jin Z, Xia R, Zheng Z, Zha Y, Wang Q, Wan X, Yang H, Cai J. Protection of Human Lens Epithelial Cells from Oxidative Stress Damage and Cell Apoptosis by KGF-2 through the Akt/Nrf2/HO-1 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6933812. [PMID: 35222803 PMCID: PMC8872674 DOI: 10.1155/2022/6933812] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/20/2021] [Accepted: 01/25/2022] [Indexed: 12/12/2022]
Abstract
Oxidative stress exerts a significant influence on the pathogenesis of various cataracts by inducing degradation and aggregation of lens proteins and apoptosis of lens epithelial cells. Keratinocyte growth factor-2 (KGF-2) exerts a favorable cytoprotective effect against oxidative stress in vivo and in vitro. In this work, we investigated the molecular mechanisms of KGF-2 against hydrogen peroxide- (H2O2-) induced oxidative stress and apoptosis in human lens epithelial cells (HLECs) and rat lenses. KGF-2 pretreatment could reduce H2O2-induced cytotoxicity as well as reactive oxygen species (ROS) accumulation. KGF-2 also increases B-cell lymphoma-2 (Bcl-2), quinine oxidoreductase-1 (NQO-1), superoxide dismutase (SOD2), and catalase (CAT) levels while decreasing the expression level of Bcl2-associated X (Bax) and cleaved caspase-3 in H2O2-stimulated HLECs. LY294002, the phosphatidylinositol-3-kinase (PI3K)/Akt inhibitor, abolished KGF-2's effect to some extent, demonstrating that KGF-2 protected HLECs via the PI3K/Akt pathway. On the other hand, KGF-2 activated the Nrf2/HO-1 pathway by regulating the PI3K/Akt pathway. Silencing nuclear factor erythroid 2-related factor 2 (Nrf2) by targeted-siRNA and inhibiting heme oxygenase-1 (HO-1) through zinc protoporphyrin IX (ZnPP) significantly decreased cytoprotection of KGF-2. Furthermore, as revealed by lens organ culture assays, KGF-2 treatment decreased H2O2-induced lens opacity in a concentration-dependent manner. As demonstrated by these data, KGF-2 resisted H2O2-mediated apoptosis and oxidative stress in HLECs through Nrf2/HO-1 and PI3K/Akt pathways, suggesting a potential protective effect against the formation of cataracts.
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Affiliation(s)
- Shuyu Liu
- Department of Ophthalmology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Zi Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China
| | - Ruyue Xia
- Department of Ophthalmology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Zhuoni Zheng
- Department of Ophthalmology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yi Zha
- Department of Ophthalmology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Qiang Wang
- Department of Ophthalmology, Ruian People's Hospital, Wenzhou 325000, China
| | - Xinbei Wan
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada H3A 1G1
| | - Hui Yang
- Department of Ophthalmology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Jianqiu Cai
- Department of Ophthalmology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
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27
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Sheppard AJ, Barfield AM, Barton S, Dong Y. Understanding Reactive Oxygen Species in Bone Regeneration: A Glance at Potential Therapeutics and Bioengineering Applications. Front Bioeng Biotechnol 2022; 10:836764. [PMID: 35198545 PMCID: PMC8859442 DOI: 10.3389/fbioe.2022.836764] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/19/2022] [Indexed: 01/24/2023] Open
Abstract
Although the complex mechanism by which skeletal tissue heals has been well described, the role of reactive oxygen species (ROS) in skeletal tissue regeneration is less understood. It has been widely recognized that a high level of ROS is cytotoxic and inhibits normal cellular processes. However, with more recent discoveries, it is evident that ROS also play an important, positive role in skeletal tissue repair, specifically fracture healing. Thus, dampening ROS levels can potentially inhibit normal healing. On the same note, pathologically high levels of ROS cause a sharp decline in osteogenesis and promote nonunion in fracture repair. This delicate balance complicates the efforts of therapeutic and engineering approaches that aim to modulate ROS for improved tissue healing. The physiologic role of ROS is dependent on a multitude of factors, and it is important for future efforts to consider these complexities. This review first discusses how ROS influences vital signaling pathways involved in the fracture healing response, including how they affect angiogenesis and osteogenic differentiation. The latter half glances at the current approaches to control ROS for improved skeletal tissue healing, including medicinal approaches, cellular engineering, and enhanced tissue scaffolds. This review aims to provide a nuanced view of the effects of ROS on bone fracture healing which will inspire novel techniques to optimize the redox environment for skeletal tissue regeneration.
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Affiliation(s)
- Aaron J. Sheppard
- Department of Orthopaedic Surgery, Louisiana State University Health Shreveport, Shreveport, LA, United States
- School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Ann Marie Barfield
- Department of Orthopaedic Surgery, Louisiana State University Health Shreveport, Shreveport, LA, United States
- School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Shane Barton
- Department of Orthopaedic Surgery, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Yufeng Dong
- Department of Orthopaedic Surgery, Louisiana State University Health Shreveport, Shreveport, LA, United States
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28
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Anagnostis P, Florentin M, Livadas S, Lambrinoudaki I, Goulis DG. Bone Health in Patients with Dyslipidemias: An Underestimated Aspect. Int J Mol Sci 2022; 23:ijms23031639. [PMID: 35163560 PMCID: PMC8835770 DOI: 10.3390/ijms23031639] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 01/28/2022] [Accepted: 01/28/2022] [Indexed: 02/04/2023] Open
Abstract
Beyond being aging-related diseases, atherosclerosis and osteoporosis share common pathogenetic pathways implicated in bone and vascular mineralization. However, the contributory role of dyslipidemia in this interplay is less documented. The purpose of this narrative review is to provide epidemiological evidence regarding the prevalence of bone disease (osteoporosis, fracture risk) in patients with dyslipidemias and to discuss potential common pathophysiological mechanisms linking osteoporosis and atherosclerosis. The effect of hypolipidemic therapy on bone metabolism is also discussed. Despite the high data heterogeneity and the variable quality of studies, dyslipidemia, mainly elevated total and low-density lipoprotein cholesterol concentrations, is associated with low bone mass and increased fracture risk. This effect may be mediated directly by the increased oxidative stress and systemic inflammation associated with dyslipidemia, leading to increased osteoclastic activity and reduced bone formation. Moreover, factors such as estrogen, vitamin D and K deficiency, and increased concentrations of parathyroid hormone, homocysteine and lipid oxidation products, can also contribute. Regarding the effect of hypolipidemic medications on bone metabolism, statins may slightly increase BMD and reduce fracture risk, although the evidence is not robust, as it is for omega-3 fatty acids. No evidence exists for the effects of ezetimibe, fibrates, and niacin. In any case, more prospective studies are needed further to elucidate the association between lipids and bone strength.
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Affiliation(s)
- Panagiotis Anagnostis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece;
- Correspondence: ; Tel.: +30-2310-257150; Fax: +30-2310-281179
| | - Matilda Florentin
- Department of Internal Medicine, University Hospital of Ioannina, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | | | - Irene Lambrinoudaki
- 2nd Department of Obstetrics and Gynecology, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Dimitrios G. Goulis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece;
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29
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Usategui-Martín R, Pérez-Castrillón JL, Mansego ML, Lara-Hernández F, Manzano I, Briongos L, Abadía-Otero J, Martín-Vallejo J, García-García AB, Martín-Escudero JC, Chaves FJ. Association between genetic variants in oxidative stress-related genes and osteoporotic bone fracture. The Hortega follow-up study. Gene 2022; 809:146036. [PMID: 34688818 DOI: 10.1016/j.gene.2021.146036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 11/20/2022]
Abstract
The most widely accepted etiopathogenesis hypothesis of the origin of osteoporosis and its complications is that they are a consequence of bone aging and other environmental factors, together with a genetic predisposition. Evidence suggests that oxidative stress is crucial in bone pathologies associated with aging. The aim of this study was to determine whether genetic variants in oxidative stress-related genes modified the risk of osteoporotic fracture. We analysed 221 patients and 354 controls from the HORTEGA sample after 12-14 years of follow up. We studied the genotypic and allelic distribution of 53 SNPs in 24 genes involved in oxidative stress. The results showed that being a carrier of the variant allele of the SNP rs4077561 within TXNRD1 was the principal genetic risk factor associated with osteoporotic fracture and that variant allele of the rs1805754 M6PR, rs4964779 TXNRD1, rs406113 GPX6, rs2281082 TXN2 and rs974334 GPX6 polymorphisms are important genetic risk factors for fracture. This study provides information on the genetic factors associated with oxidative stress which are involved in the risk of osteoporotic fracture and reinforces the hypothesis that genetic factors are crucial in the etiopathogenesis of osteoporosis and its complications.
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Affiliation(s)
- Ricardo Usategui-Martín
- IOBA, University of Valladolid, Valladolid. Spain; Cooperative Health Network for Research (RETICS), Oftared, National Institute of Health Carlos III, ISCIII, Madrid. Spain.
| | - José Luis Pérez-Castrillón
- Department of Internal Medicine, Rio Hortega Universitary Hospital, Valladolid, Spain; Department of Medicine. Faculty of Medicine. University of Valladolid, Valladolid, Spain.
| | - María L Mansego
- Genomic and Genetic Diagnosis Unit, INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Bioinformatics. Making Genetics S.L. Pamplona. Spain
| | | | - Iris Manzano
- Genomic and Genetic Diagnosis Unit, INCLIVA Biomedical Research Institute, Valencia, Spain
| | - Laisa Briongos
- Department of Internal Medicine, Rio Hortega Universitary Hospital, Valladolid, Spain; Department of Medicine. Faculty of Medicine. University of Valladolid, Valladolid, Spain
| | - Jesica Abadía-Otero
- Department of Internal Medicine, Rio Hortega Universitary Hospital, Valladolid, Spain
| | - Javier Martín-Vallejo
- Department of Statistics. University of Salamanca. Salamanca Biomedical Research Institute (IBSAL), Salamanca. Spain
| | - Ana B García-García
- Genomic and Genetic Diagnosis Unit, INCLIVA Biomedical Research Institute, Valencia, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid. Spain
| | - Juan Carlos Martín-Escudero
- Department of Internal Medicine, Rio Hortega Universitary Hospital, Valladolid, Spain; Department of Medicine. Faculty of Medicine. University of Valladolid, Valladolid, Spain
| | - Felipe J Chaves
- Genomic and Genetic Diagnosis Unit, INCLIVA Biomedical Research Institute, Valencia, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid. Spain
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30
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Bjelić D, Finšgar M. Bioactive coatings with anti-osteoclast therapeutic agents for bone implants: Enhanced compliance and prolonged implant life. Pharmacol Res 2022; 176:106060. [PMID: 34998972 DOI: 10.1016/j.phrs.2022.106060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/24/2021] [Accepted: 01/03/2022] [Indexed: 12/18/2022]
Abstract
The use of therapeutic agents that inhibit bone resorption is crucial to prolong implant life, delay revision surgery, and reduce the burden on the healthcare system. These therapeutic agents include bisphosphonates, various nucleic acids, statins, proteins, and protein complexes. Their use in systemic treatment has several drawbacks, such as side effects and insufficient efficacy in terms of concentration, which can be eliminated by local treatment. This review focuses on the incorporation of osteoclast inhibitors (antiresorptive agents) into bioactive coatings for bone implants. The ability of bioactive coatings as systems for local delivery of antiresorptive agents to achieve optimal loading of the bioactive coating and its release is described in detail. Various parameters such as the suitable concentrations, release times, and the effects of the antiresorptive agents on nearby cells or bone tissue are discussed. However, further research is needed to support the optimization of the implant, as this will enable subsequent personalized design of the coating in terms of the design and selection of the coating material, the choice of an antiresorptive agent and its amount in the coating. In addition, therapeutic agents that have not yet been incorporated into bioactive coatings but appear promising are also mentioned. From this work, it can be concluded that therapeutic agents contribute to the biocompatibility of the bioactive coating by enhancing its beneficial properties.
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Affiliation(s)
- Dragana Bjelić
- Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000 Maribor, Slovenia.
| | - Matjaž Finšgar
- Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000 Maribor, Slovenia.
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31
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Starup-Linde J, Lykkeboe S, Handberg A, Vestergaard P, Høyem P, Fleischer J, Hansen TK, Poulsen PL, Laugesen E. Glucose variability and low bone turnover in people with type 2 diabetes. Bone 2021; 153:116159. [PMID: 34461287 DOI: 10.1016/j.bone.2021.116159] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is related to an increased fracture risk and low bone turnover. However, the mechanisms are not elucidated. In the present study we investigate the association between glycemic variability and bone turnover markers. METHODS 100 participants with T2D and 100 age and gender matched controls were included in this cross-sectional study. All participants with T2D were equipped with a continuous glucose monitoring (CGM) sensor for 3 days (CGMS iPro Continuous Glucose Recorder; Medtronic MiniMed). The dawn glucose levels were defined as a morning period starting 1 h before breakfast ending 1 h post ingestion. On all participants serum (s)-C-terminal cross-linked telopeptide of type-I collagen (CTX), s-procollagen type 1 amino terminal propeptide (P1NP), and s-sclerostin were measured. RESULTS Participants with T2D displayed significantly lower levels of the bone resorption marker s-CTX and the bone formation marker s-P1NP compared to controls. S-CTX was significantly negatively associated with the mean amplitude of glycemic excursions (MAGE) and the dawn glucose levels whereas s-P1NP only was significantly negatively associated with the dawn glucose levels while it was borderline significantly associated with MAGE (p = 0.05). S-CTX and s-P1NP were significantly lower among the 50% with the highest dawn glucose levels compared to the 50% lowest dawn glucose levels also after adjustment for age, gender, glycated hemoglobin A1c (HbA1c), and body mass index (BMI). CONCLUSION We observed that the amplitude of glycemic excursions and rise in dawn glucose was negatively associated with bone turnover markers. Future research is needed to determine whether reduction of the amplitude of glycemic excursions increase bone turnover markers.
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Affiliation(s)
- Jakob Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark; Steno Diabetes Center North Jutland, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark.
| | - Simon Lykkeboe
- Department of Clinical Biochemistry, Aalborg University Hospital, Denmark
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, Denmark; Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Jutland, Aalborg University Hospital, Denmark; Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Denmark; Department of Endocrinology, Aalborg University Hospital, Denmark
| | - Pernille Høyem
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark
| | - Jesper Fleischer
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark; Steno Diabetes Center Zealand, Holbaek, Denmark
| | | | - Per Løgstrup Poulsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark
| | - Esben Laugesen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark
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32
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Wang Y, Sun L, Wang L, Yu H, Yu X, Zou Y. PUM1 modulates trophoblast cell proliferation and migration through LRP6. Biochem Cell Biol 2021; 99:735-740. [PMID: 34734756 DOI: 10.1139/bcb-2021-0044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Preeclampsia is a severe pregnancy complication characterized by hypertension and may cause maternal morbidity and mortality. A better understanding of the essential genes involved in preeclampsia pathophysiology is urgently needed. This study investigated the function and molecular mechanisms of pumilio RNA binding family member 1 (PUM1) in extravillous trophoblast cells (EVTs). The interaction between protein and mRNA was verified by RNA pull-down assays, RNA immunoprecipitation assays, and luciferase reporter assays. The mRNA and protein levels of the genes involved were determined by RT-qPCR and western blot assays, respectively. Our results demonstrated that PUM1 could bind to the 3'-untranslated region of low-density lipoprotein receptor-related protein 6 (LRP6) mRNA, resulting in reduced expression of LRP6 mRNA and protein. Repression of PUM1 resulted in enhanced colony formation, cell proliferation, migration, and invasion of EVTs. The PUM1-depletion-mediated promotion effects on EVTs could be abrogated by LRP6 knockdown. PUM1 regulates the growth and mobility of EVTs by modulating LRP6 expression. Developing strategies to balance PUM1 and LRP6 levels may be beneficial for the management of preeclampsia patients.
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Affiliation(s)
- Yuping Wang
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China.,Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Li Sun
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China.,Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Lanlan Wang
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China.,Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Hui Yu
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China.,Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Xiaoyan Yu
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China.,Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Yanfen Zou
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China.,Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai, Shandong 264000, China
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Abstract
Significance: During aging, excessive production of reactive species in the liver leads to redox imbalance with consequent oxidative damage and impaired organ homeostasis. Nevertheless, slight amounts of reactive species may modulate several transcription factors, acting as second messengers and regulating specific signaling pathways. These redox-dependent alterations may impact the age-associated decline in liver regeneration. Recent Advances: In the last few decades, relevant findings related to redox alterations in the aging liver were investigated. Consistently, recent research broadened understanding of redox modifications and signaling related to liver regeneration. Other than reporting the effect of oxidative stress, epigenetic and post-translational modifications, as well as modulation of specific redox-sensitive cellular signaling, were described. Among them, the present review focuses on Wnt/β-catenin, the nuclear factor (erythroid-derived 2)-like 2 (NRF2), members of the Forkhead box O (FoxO) family, and the p53 tumor suppressor. Critical Issues: Even though alteration in redox homeostasis occurs both in aging and in impaired liver regeneration, the associative mechanisms are not clearly defined. Of note, antioxidants are not effective in slowing hepatic senescence, and do not clearly improve liver repopulation after hepatectomy or transplant in humans. Future Directions: Further investigations are needed to define mutual redox-dependent molecular pathways involved both in aging and in the decline of liver regeneration. Preclinical studies aimed at the characterization of these pathways would define possible therapeutic targets for human trials. Antioxid. Redox Signal. 35, 832-847.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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34
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Zheng H, Zhu H, Liu X, Huang X, Huang A, Huang Y. Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms. Front Cell Dev Biol 2021; 9:750382. [PMID: 34646830 PMCID: PMC8503602 DOI: 10.3389/fcell.2021.750382] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/06/2021] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular disease is the leading complication of diabetes mellitus (DM), and diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients. Multiple pathophysiologic mechanisms, including myocardial insulin resistance, oxidative stress and inflammation, are involved in the development of DCM. Recent studies have shown that mitochondrial dysfunction makes a substantial contribution to the development of DCM. Mitophagy is a type of autophagy that takes place in dysfunctional mitochondria, and it plays a key role in mitochondrial quality control. Although the precise molecular mechanisms of mitophagy in DCM have yet to be fully clarified, recent findings imply that mitophagy improves cardiac function in the diabetic heart. However, excessive mitophagy may exacerbate myocardial damage in patients with DCM. In this review, we aim to provide a comprehensive overview of mitochondrial quality control and the dual roles of mitophagy in DCM. We also propose that a balance between mitochondrial biogenesis and mitophagy is essential for the maintenance of cellular metabolism in the diabetic heart.
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Affiliation(s)
- Haoxiao Zheng
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Hailan Zhu
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Xinyue Liu
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Xiaohui Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Anqing Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou, China
- The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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35
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Kubo Y, Drescher W, Fragoulis A, Tohidnezhad M, Jahr H, Gatz M, Driessen A, Eschweiler J, Tingart M, Wruck CJ, Pufe T. Adverse Effects of Oxidative Stress on Bone and Vasculature in Corticosteroid-Associated Osteonecrosis: Potential Role of Nuclear Factor Erythroid 2-Related Factor 2 in Cytoprotection. Antioxid Redox Signal 2021; 35:357-376. [PMID: 33678001 DOI: 10.1089/ars.2020.8163] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Osteonecrosis (ON) is characterized by bone tissue death due to disturbance of the nutrient artery. The detailed process leading to the necrotic changes has not been fully elucidated. Clinically, high-dose corticosteroid therapy is one of the main culprits behind osteonecrosis of the femoral head (ONFH). Recent Advances: Numerous studies have proposed that such ischemia concerns various intravascular mechanisms. Of all reported risk factors, the involvement of oxidative stress in the irreversible damage suffered by bone-related and vascular endothelial cells during ischemia simply cannot be overlooked. Several articles also have sought to elucidate oxidative stress in relation to ON using animal models or in vitro cell cultures. Critical Issues: However, as far as we know, antioxidant monotherapy has still not succeeded in preventing ONFH in humans. To provide this desideratum, we herein summarize the current knowledge about the influence of oxidative stress on ON, together with data about the preventive effects of administering antioxidants in corticosteroid-induced ON animal models. Moreover, oxidative stress is counteracted by nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent cytoprotective network through regulating antioxidant expressions. Therefore, we also describe Nrf2 regulation and highlight its role in the pathology of ON. Future Directions: This is a review of all available literature to date aimed at developing a deeper understanding of the pathological mechanism behind ON from the perspective of oxidative stress. It may be hoped that this synthesis will spark the development of a prophylactic strategy to benefit corticosteroid-associated ONFH patients. Antioxid. Redox Signal. 35, 357-376.
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Affiliation(s)
- Yusuke Kubo
- Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
| | - Wolf Drescher
- Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany.,Department of Orthopaedics and Traumatology, Rummelsberg Hospital, Schwarzenbruck, Germany
| | | | | | - Holger Jahr
- Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
| | - Matthias Gatz
- Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany
| | - Arne Driessen
- Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany
| | - Jörg Eschweiler
- Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany
| | - Markus Tingart
- Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany
| | - Christoph Jan Wruck
- Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
| | - Thomas Pufe
- Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
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36
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Abstract
AbstractThe success of implant performance and arthroplasty is based on several factors, including oxidative stress-induced osteolysis. Oxidative stress is a key factor of the inflammatory response. Implant biomaterials can release wear particles which may elicit adverse reactions in patients, such as local inflammatory response leading to tissue damage, which eventually results in loosening of the implant. Wear debris undergo phagocytosis by macrophages, inducing a low-grade chronic inflammation and reactive oxygen species (ROS) production. In addition, ROS can also be directly produced by prosthetic biomaterial oxidation. Overall, ROS amplify the inflammatory response and stimulate both RANKL-induced osteoclastogenesis and osteoblast apoptosis, resulting in bone resorption, leading to periprosthetic osteolysis. Therefore, a growing understanding of the mechanism of oxidative stress-induced periprosthetic osteolysis and anti-oxidant strategies of implant design as well as the addition of anti-oxidant agents will help to improve implants’ performances and therapeutic approaches.
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37
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Romero-Márquez JM, Varela-López A, Navarro-Hortal MD, Badillo-Carrasco A, Forbes-Hernández TY, Giampieri F, Domínguez I, Madrigal L, Battino M, Quiles JL. Molecular Interactions between Dietary Lipids and Bone Tissue during Aging. Int J Mol Sci 2021; 22:ijms22126473. [PMID: 34204176 PMCID: PMC8233828 DOI: 10.3390/ijms22126473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/09/2021] [Accepted: 06/11/2021] [Indexed: 01/06/2023] Open
Abstract
Age-related bone disorders such as osteoporosis or osteoarthritis are a major public health problem due to the functional disability for millions of people worldwide. Furthermore, fractures are associated with a higher degree of morbidity and mortality in the long term, which generates greater financial and health costs. As the world population becomes older, the incidence of this type of disease increases and this effect seems notably greater in those countries that present a more westernized lifestyle. Thus, increased efforts are directed toward reducing risks that need to focus not only on the prevention of bone diseases, but also on the treatment of persons already afflicted. Evidence is accumulating that dietary lipids play an important role in bone health which results relevant to develop effective interventions for prevent bone diseases or alterations, especially in the elderly segment of the population. This review focuses on evidence about the effects of dietary lipids on bone health and describes possible mechanisms to explain how lipids act on bone metabolism during aging. Little work, however, has been accomplished in humans, so this is a challenge for future research.
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Affiliation(s)
- Jose M. Romero-Márquez
- Department of Physiology, Institute of Nutrition and Food Technology ‘‘José Mataix”, Biomedical Research Centre, University of Granada, Armilla, Avda. del Conocimiento s.n., 18100 Armilla, Spain; (J.M.R.-M.); (A.V.-L.); (M.D.N.-H.); (A.B.-C.)
| | - Alfonso Varela-López
- Department of Physiology, Institute of Nutrition and Food Technology ‘‘José Mataix”, Biomedical Research Centre, University of Granada, Armilla, Avda. del Conocimiento s.n., 18100 Armilla, Spain; (J.M.R.-M.); (A.V.-L.); (M.D.N.-H.); (A.B.-C.)
| | - María D. Navarro-Hortal
- Department of Physiology, Institute of Nutrition and Food Technology ‘‘José Mataix”, Biomedical Research Centre, University of Granada, Armilla, Avda. del Conocimiento s.n., 18100 Armilla, Spain; (J.M.R.-M.); (A.V.-L.); (M.D.N.-H.); (A.B.-C.)
| | - Alberto Badillo-Carrasco
- Department of Physiology, Institute of Nutrition and Food Technology ‘‘José Mataix”, Biomedical Research Centre, University of Granada, Armilla, Avda. del Conocimiento s.n., 18100 Armilla, Spain; (J.M.R.-M.); (A.V.-L.); (M.D.N.-H.); (A.B.-C.)
| | - Tamara Y. Forbes-Hernández
- Nutrition and Food Science Group, Department of Analytical and Food Chemistry, CITACA, CACTI, University of Vigo, 36310 Vigo, Spain;
| | - Francesca Giampieri
- Department of Clinical Sicences, Università Politecnica delle Marche, 60131 Ancona, Italy; (F.G.); (M.B.)
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Irma Domínguez
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, 39011 Santander, Spain;
- Universidad Internacional Iberoamericana, Calle 15 Num. 36, Entre 10 y 12 IMI III, Campeche 24560, Mexico;
| | - Lorena Madrigal
- Universidad Internacional Iberoamericana, Calle 15 Num. 36, Entre 10 y 12 IMI III, Campeche 24560, Mexico;
| | - Maurizio Battino
- Department of Clinical Sicences, Università Politecnica delle Marche, 60131 Ancona, Italy; (F.G.); (M.B.)
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
| | - José L. Quiles
- Department of Physiology, Institute of Nutrition and Food Technology ‘‘José Mataix”, Biomedical Research Centre, University of Granada, Armilla, Avda. del Conocimiento s.n., 18100 Armilla, Spain; (J.M.R.-M.); (A.V.-L.); (M.D.N.-H.); (A.B.-C.)
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, 39011 Santander, Spain;
- Correspondence:
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38
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Palui R, Pramanik S, Mondal S, Ray S. Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus. World J Diabetes 2021; 12:706-729. [PMID: 34168723 PMCID: PMC8192255 DOI: 10.4239/wjd.v12.i6.706] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/08/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
The risk of fracture is increased in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). However, in contrast to the former, patients with T2DM usually possess higher bone mineral density. Thus, there is a considerable difference in the pathophysiological basis of poor bone health between the two types of diabetes. Impaired bone strength due to poor bone microarchitecture and low bone turnover along with increased risk of fall are among the major factors behind elevated fracture risk. Moreover, some antidiabetic medications further enhance the fragility of the bone. On the other hand, antiosteoporosis medications can affect the glucose homeostasis in these patients. It is also difficult to predict the fracture risk in these patients because conventional tools such as bone mineral density and Fracture Risk Assessment Tool score assessment can underestimate the risk. Evidence-based recommendations for risk evaluation and management of poor bone health in diabetes are sparse in the literature. With the advancement in imaging technology, newer modalities are available to evaluate the bone quality and risk assessment in patients with diabetes. The purpose of this review is to explore the pathophysiology behind poor bone health in diabetic patients. Approach to the fracture risk evaluation in both T1DM and T2DM as well as the pragmatic use and efficacy of the available treatment options have been discussed in depth.
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Affiliation(s)
- Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Healthcare Centre, Siliguri 734010, West Bengal, India
| | - Sunetra Mondal
- Department of Endocrinology, Institute of Post Graduate Medical Education and Research (IPGMER), Kolkata 700020, West Bengal, India
| | - Sayantan Ray
- Department of Endocrinology, Medica Superspeciality Hospital and Medica Clinic, Kolkata 700099, West Bengal, India
- Department of Endocrinology, Jagannath Gupta Institute of Medical Sciences and Hospital, Kolkata 700137, West Bengal, India
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Terenzi DC, Verma S, Hess DA. Exploring the Clinical Implications of Wnt Signaling in Enucleated Erythrocytes. Arterioscler Thromb Vasc Biol 2021; 41:1654-1656. [PMID: 33792347 DOI: 10.1161/atvbaha.121.316169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Daniella C Terenzi
- Institute of Medical Science (D.C.T.), University of Toronto, Canada.,Division of Cardiac Surgery (D.C.T., S.V.), St Michael's Hospital, Toronto, Canada
| | - Subodh Verma
- Department of Surgery (S.V.), University of Toronto, Canada.,Division of Cardiac Surgery (D.C.T., S.V.), St Michael's Hospital, Toronto, Canada
| | - David A Hess
- Department of Pharmacology (D.A.H.), University of Toronto, Canada.,Division of Vascular Surgery (D.A.H.), St Michael's Hospital, Toronto, Canada.,Department of Physiology and Pharmacology, Western University, London, Canada (D.A.H.)
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40
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Shi W, Xu C, Gong Y, Wang J, Ren Q, Yan Z, Mei L, Tang C, Ji X, Hu X, Qv M, Hussain M, Zeng LH, Wu X. RhoA/Rock activation represents a new mechanism for inactivating Wnt/β-catenin signaling in the aging-associated bone loss. CELL REGENERATION (LONDON, ENGLAND) 2021; 10:8. [PMID: 33655459 PMCID: PMC7925793 DOI: 10.1186/s13619-020-00071-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022]
Abstract
The Wnt/β-catenin signaling pathway appears to be particularly important for bone homeostasis, whereas nuclear accumulation of β-catenin requires the activation of Rac1, a member of the Rho small GTPase family. The aim of the present study was to investigate the role of RhoA/Rho kinase (Rock)-mediated Wnt/β-catenin signaling in the regulation of aging-associated bone loss. We find that Lrp5/6-dependent and Lrp5/6-independent RhoA/Rock activation by Wnt3a activates Jak1/2 to directly phosphorylate Gsk3β at Tyr216, resulting in Gsk3β activation and subsequent β-catenin destabilization. In line with these molecular events, RhoA loss- or gain-of-function in mouse embryonic limb bud ectoderms interacts genetically with Dkk1 gain-of-function to rescue the severe limb truncation phenotypes or to phenocopy the deletion of β-catenin, respectively. Likewise, RhoA loss-of-function in pre-osteoblasts robustly increases bone formation while gain-of-function decreases it. Importantly, high RhoA/Rock activity closely correlates with Jak and Gsk3β activities but inversely correlates with β-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice, whereas systemic inhibition of Rock therefore activates the β-catenin signaling to antagonize aging-associated bone loss. Taken together, these results identify RhoA/Rock-dependent Gsk3β activation and subsequent β-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis.
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Affiliation(s)
- Wei Shi
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
- Department of Biology and Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Chengyun Xu
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
- Department of Orthopeadic Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Ying Gong
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Jirong Wang
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Qianlei Ren
- Department of Pharmacology, Zhejiang University City College, 51 Huzhou Street, Hangzhou, 310015, China
| | - Ziyi Yan
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Liu Mei
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Chao Tang
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Xing Ji
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
- Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Xinhua Hu
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Meiyu Qv
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Musaddique Hussain
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China
| | - Ling-Hui Zeng
- Department of Pharmacology, Zhejiang University City College, 51 Huzhou Street, Hangzhou, 310015, China.
| | - Ximei Wu
- Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.
- Department of Orthopeadic Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
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El Amrousy D, El-Afify D, Shabana A. Relationship between bone turnover markers and oxidative stress in children with type 1 diabetes mellitus. Pediatr Res 2021; 89:878-881. [PMID: 33038875 DOI: 10.1038/s41390-020-01197-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/15/2020] [Accepted: 09/23/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Oxidative stress in children with type 1 DM (T1DM) may negatively affect the bone. METHODS This study included 40 children with T1DM as the patient group and 40 healthy children of matched age and sex as the control group. Plasma alkaline phosphatase, procollagen type-1 amino-terminal propeptide (P1NP), and urinary deoxypyridinoline (DPD) were measured to assess bone turnover. Glutathione, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to assess oxidative stress. RESULTS Patients with T1DM had a significantly lower P1NP level but a significantly higher urinary DPD level compared to the control group. Moreover, there were significantly lower glutathione and SOD levels with significantly higher MDA levels in patients with T1DM. We found a significant positive correlation between P1NP level and both glutathione and SOD levels but a significant negative correlation between P1NP and MDA in patients with T1DM. There was a significant negative correlation between DPD levels and both glutathione and SOD levels and a significant positive correlation between DPD and MDA. Moreover, glutathione was a significant predictor for both P1NP and DPD levels, while MDA was a significant predictor for P1NP levels. CONCLUSIONS There is an association between oxidative stress and bone turnover markers in children with T1DM. IMPACT Oxidative stress can negatively affect bone but the exact relationship between oxidative stress and bone turnover in T1DM has not been previously studied in pediatrics. For the best of our knowledge, our study was the first to assess the relationship between oxidative stress and bone turnover in children with T1DM. We revealed that increased oxidative stress in children and adolescents with T1DM may be involved in the impairment of bone turnover process, so treatment strategies toward better glycemic control and decreasing oxidative stress may be beneficial in preventing and treating diabetic bone disease in these children.
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Affiliation(s)
- Doaa El Amrousy
- Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Dalia El-Afify
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Ahmed Shabana
- Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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Al-Dawood E, Zafar M. Association between metabolic syndrome and bone mineral density among menopausal Saudi women: Case-control study. Med J Islam Repub Iran 2021; 35:26. [PMID: 34169038 PMCID: PMC8214043 DOI: 10.47176/mjiri.35.26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Indexed: 11/21/2022] Open
Abstract
Background: Metabolic syndrome (MetS) and osteoporosis are two of the world's major healthcare issues. There are several studies which explored the association between MetS and bone mineral density (BMD), but all of them are cross-sectional. These studies cover all populations, including expatriated, which did not determine the actual problem among Saudi women. This is the first case-control study that determines the causal relationship between MetS and BMD. The objective of this study is to determine the relationship between metabolic syndrome and bone mass density among Saudi menopausal women in Eastern Province - Saudi Arabia.
Methods: It’s a case-control study and 380 menopausal Saudi women were selected through simple random sampling. They were divided into 190 cases with osteoporosis and 190 without osteoporosis. Bone Mineral Density (BMD) at the total hip was determined using dual-energy X-ray absorptiometry (DEXA). T score was calculated. The association between the risk factors of MetS and bone mineral density was determined by binary logistic regression analysis using SPSS (statistical package of social science) software.
Results: Among women, the prevalence of MetS was substantially higher in those with osteoporosis. The Mets is positively correlated with bone mineral density. (r=0.08, p=0.051). The occurrence of MetS was associated with increased osteoporosis among Saudi women (B=0.004; p=0.005) after adjustment of confounders. The existence of obesity was significantly associated with increased odds of Bone marrow density among women (OR 2.56; 95 % CI, 2.22-3.44; p=0.030) after adjustment of confounders.
Conclusion: The incidence of MetS was associated with osteoporosis in Saudi women.
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Affiliation(s)
- Essra Al-Dawood
- Primary Health Care Centre, Ministry of Health, Al-Jubail, KSA
| | - Mubashir Zafar
- Department of Family and Community Medicine, College of Medicine, University of Hail, Hail, KSA
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Nan K, Pei JP, Fan LH, Zhang YK, Zhang X, Liu K, Shi ZB, Dang XQ, Wang KZ. Resveratrol prevents steroid-induced osteonecrosis of the femoral head via miR-146a modulation. Ann N Y Acad Sci 2021; 1503:23-37. [PMID: 33454992 DOI: 10.1111/nyas.14555] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 11/13/2020] [Accepted: 12/08/2020] [Indexed: 12/11/2022]
Abstract
The purpose of this study was to investigate the possible use of resveratrol (Res) to reverse abnormal osteogenesis/osteoclastogenesis activity that occurs during femoral head osteonecrosis and to explore the detailed mechanisms. Application of Res to bone marrow-derived mesenchymal stem cells in vitro promoted survival, inhibited apoptosis, and downregulated expression of reactive oxygen species expression. Moreover, Res application was associated with elevated microRNA-146a (miR-146a) expression, osteogenic differentiation, and suppressed osteoclastic differentiation, which were markedly reversed by miR-146a inhibitor. Histopathological observations and micro-computed tomography scanning results indicated that the Res-treated group had lower incidence of osteonecrosis and better bone microstructure than the untreated group. Res inhibited osteoclastogenesis through altering the levels of sirtuin1 (Sirt1), nuclear transcription factor-κB (NF-κB), and receptor activator of NF-κB ligand (RANKL). Simultaneously, Res treatment improved bone formation and increased β-catenin and runt-related transcription factor 2 (Runt2) expression levels, while reducing forkhead box class O (FOXO) family protein levels. The results of our study suggest that Res prevents steroid-induced osteonecrosis by upregulating miR-146a, and thereby stabilizes osteogenesis/osteoclastogenesis homeostasis via Wnt/FOXO and Sirt1/NF-κB pathways.
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Affiliation(s)
- Kai Nan
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, People's Republic of China
| | - Jun-Peng Pei
- Department of Orthopaedics, Wuhan General Hospital of Guangzhou Command, Wuhan, People's Republic of China
| | - Li-Hong Fan
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, People's Republic of China
| | - Yuan-Kai Zhang
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, People's Republic of China
| | - Xin Zhang
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, People's Republic of China
| | - Kang Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Zhi-Bin Shi
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, People's Republic of China
| | - Xiao-Qian Dang
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, People's Republic of China
| | - Kun-Zheng Wang
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, People's Republic of China
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Falcetta P, Orsolini F, Benelli E, Agretti P, Vitti P, Di Cosmo C, Tonacchera M. Clinical features, risk of mass enlargement, and development of endocrine hyperfunction in patients with adrenal incidentalomas: a long-term follow-up study. Endocrine 2021; 71:178-188. [PMID: 32915435 PMCID: PMC7835305 DOI: 10.1007/s12020-020-02476-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/23/2020] [Indexed: 12/27/2022]
Abstract
PURPOSE To evaluate the risk of mass enlargement and endocrine function modification in patients with adrenal incidentaloma (AI). METHODS In this retrospective study, we examined clinical and hormonal characteristics of 310 patients with AI (200 females and 110 males; age: 58.3 ± 12.9 years), followed up for a median (interquartile range) of 31.4 months (13.0-78.6) and evaluated for possible modification in adrenal mass size and hormonal function. The hormonal evaluation included morning serum cortisol and plasma ACTH at 8 a.m., aldosterone, plasma renin activity/direct renin concentration, and 24-h urine metanephrines/normetanephrines. One microgram overnight dexamethasone suppression test (DST) was performed. Autonomous cortisol secretion (ACS) was diagnosed in the presence of cortisol after 1 mg DST > 5 μg/dl (138 nmol/l) or >1.8 and ≤5 μg/dl (50-138 nmol/l) and at least one of the following: (i) low ACTH; (ii) increased 24-h urinary-free cortisol; (iii) absence of cortisol rhythm; and (iv) post-LDDST cortisol level > 1.8 μg/dl (50 nmol/l). When there was no biochemical evidence of adrenal hormonal hyperactivity, AIs were classified as nonfunctioning (NFAIs). The mass was considered significantly enlarged when the size increase was more than 20% and at least 5 mm compared to baseline. RESULTS At diagnosis, NFAIs were found in 209 patients, while ACS and overt adrenal hyperfunction were diagnosed in 81 and 20 patients, respectively. During follow-up, 3.3% and 1.5% of patients with NFAI developed subtle and overt endocrine hyperfunction, respectively, while a significant mass enlargement was observed in 17.7% of all AIs. The risk of developing ACS was significantly higher in patients with adenoma >28 mm (hazard ratio [HR] 12.4; 95% confidence interval [CI], 2.33-66.52, P = 0.003), in those with bilateral adrenal tumors (HR: 5.36; 95% CI, 1.17-24.48, P = 0.030), and with low/suppressed ACTH values (HR: 11.2, 95% CI 2.06-60.77; P = 0.005). The risk of mass enlargement was lower for patients in the fourth quartile of body mass index than those in the first quartile (HR 0.33; 95% CI, 0.14-0.78; P = 0.012). CONCLUSIONS In patients with AI, the risk of developing hormonal hyperfunction and mass enlargement is overall low, although some tumor characteristics and anthropometric features might increase this risk. Taking account of all these aspects is important for planning a tailored follow-up in AI patients.
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Affiliation(s)
- Pierpaolo Falcetta
- Section of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.
| | - Francesca Orsolini
- Section of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Elena Benelli
- Section of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Patrizia Agretti
- Laboratory of Chemistry and Endocrinology, University Hospital of Pisa, Pisa, Italy
| | - Paolo Vitti
- Section of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Caterina Di Cosmo
- Section of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Massimo Tonacchera
- Section of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
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Aldawood E, Zafar M. Metabolic Syndrome In Saudi Women With Low Bone Mineral Density. RUSSIAN OPEN MEDICAL JOURNAL 2020. [DOI: 10.15275/rusomj.2020.0412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background ― Metabolic syndrome (MetS) is the world's major public health problem. Objectives ― Assessment of metabolic syndrome impact on bone mineral density (BMD) among Saudi menopausal women in Eastern Province – Saudi Arabia. Material and Methods ― It’s a case control study and 380 menopausal Saudi women were selected through stratified random sampling; they are divided into 190 cases with osteoporosis and 190 without osteoporosis. BMD at the total hip were determined using dual-energy X-ray absorptiometry (DEXA). The T score was calculated, the relationship between the risk factors of MetS and bone mineral density were analyzed by statistical methods. Results ― Prevalence of MetS was substantially higher among osteoprotic women. The MetS is significantly correlated with bone mineral density (r=0.08, P=0.05). The occurrence of MetS was associated with increased osteoporosis among Saudi women (B=0.004; 0.05) after adjustment of confounders. The presence of obesity (component of MetS) was significantly associated with increased odds of Bone marrow density among women (OR 2.56, 95% CI, 2.22–3.44, P=0.030) after adjustment of confounders. Conclusion ― MetS was significantly associated with an osteoporosis in Saudi women.
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Huang HT, Cheng TL, Lin SY, Ho CJ, Chyu JY, Yang RS, Chen CH, Shen CL. Osteoprotective Roles of Green Tea Catechins. Antioxidants (Basel) 2020; 9:E1136. [PMID: 33207822 PMCID: PMC7696448 DOI: 10.3390/antiox9111136] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 11/08/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
Osteoporosis is the second most common disease only secondary to cardiovascular disease, with the risk of fracture increasing with age. Osteoporosis is caused by an imbalance between osteoblastogenesis and osteoclastogenesis processes. Osteoclastogenesis may be enhanced, osteoblastogenesis may be reduced, or both may be evident. Inflammation and high reactive oxygen enhance osteoclastogenesis while reducing osteoblastogenesis by inducing osteoblast apoptosis and suppressing osteoblastic proliferation and differentiation. Catechins, the main polyphenols found in green tea with potent anti-oxidant and anti-inflammatory properties, can counteract the deleterious effects of the imbalance of osteoblastogenesis and osteoclastogenesis caused by osteoporosis. Green tea catechins can attenuate osteoclastogenesis by enhancing apoptosis of osteoclasts, hampering osteoclastogenesis, and prohibiting bone resorption in vitro. Catechin effects can be directly exerted on pre-osteoclasts/osteoclasts or indirectly exerted via the modulation of mesenchymal stem cells (MSCs)/stromal cell regulation of pre-osteoclasts through activation of the nuclear factor kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. Catechins also can enhance osteoblastogenesis by enhancing osteogenic differentiation of MSCs and increasing osteoblastic survival, proliferation, differentiation, and mineralization. The in vitro effects of catechins on osteogenesis have been confirmed in several animal models, as well as in epidemiological observational studies on human subjects. Even though randomized control trials have not shown that catechins provide anti-fracture efficacy, safety data in the trials are promising. A large-scale, placebo-controlled, long-term randomized trial with a tea regimen intervention of optimal duration is required to determine anti-fracture efficacy.
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Affiliation(s)
- Hsuan-Ti Huang
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (H.-T.H.); (T.-L.C.); (S.-Y.L.); (C.-J.H.)
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Departments of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Tsung-Lin Cheng
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (H.-T.H.); (T.-L.C.); (S.-Y.L.); (C.-J.H.)
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Sung-Yen Lin
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (H.-T.H.); (T.-L.C.); (S.-Y.L.); (C.-J.H.)
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Departments of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan
| | - Cheng-Jung Ho
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (H.-T.H.); (T.-L.C.); (S.-Y.L.); (C.-J.H.)
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Departments of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Joanna Y. Chyu
- School of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA;
| | - Rong-Sen Yang
- Department of Orthopedics, National Taiwan University Hospital, Taipei 100229, Taiwan;
| | - Chung-Hwan Chen
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (H.-T.H.); (T.-L.C.); (S.-Y.L.); (C.-J.H.)
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Departments of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Chwan-Li Shen
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
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Kanazawa I, Inaba M, Inoue D, Uenishi K, Saito M, Shiraki M, Suzuki A, Takeuchi Y, Hagino H, Fujiwara S, Sugimoto T. Executive summary of clinical practice guide on fracture risk in lifestyle diseases. J Bone Miner Metab 2020; 38:746-758. [PMID: 32892240 DOI: 10.1007/s00774-020-01149-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/23/2020] [Indexed: 12/16/2022]
Abstract
Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.
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Affiliation(s)
- Ippei Kanazawa
- Kanazawa Diabetes and Osteoporosis Clinic, 990-2-1 Enya-cho, Izumo, Shimane, 693-0021, Japan.
| | - Masaaki Inaba
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Inoue
- Third Department of Medicine, Teikyo University Chiba Medical Center, Chiba, Japan
| | - Kazuhiro Uenishi
- Division of Nutritional Physiology, Kagawa Nutrition University, Saitama, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, Nagano, Japan
| | - Atsushi Suzuki
- Department of Endocrinology and Metabolism, Fujita Health University, Aichi, Japan
| | - Yasuhiro Takeuchi
- Endocrine Center, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Hiroshi Hagino
- School of Health Science Faculty of Medicine, Tottori University, Tottori, Japan
| | - Saeko Fujiwara
- Department of Pharmacy, Yasuda Women's University, Hiroshima, Japan
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Schreurs AS, Torres S, Truong T, Moyer EL, Kumar A, Tahimic CGT, Alwood JS, Globus RK. Skeletal tissue regulation by catalase overexpression in mitochondria. Am J Physiol Cell Physiol 2020; 319:C734-C745. [PMID: 32783660 DOI: 10.1152/ajpcell.00068.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Accumulation of oxidative damage from excess reactive oxygen species (ROS) may contribute to skeletal aging and mediate adverse responses to physiological challenges. Wild-type (WT) mice and transgenic mice (male, 16 wk of age) with human catalase targeted to the mitochondria (mCAT) were analyzed for skeletal responses to the remodeling stimuli of combined hind-limb unloading and exposure to ionizing radiation (137Cs, 2 Gy). Treatment for 2 wk caused lipid peroxidation in the bones WT but not mCAT mice, showing that transgene expression mitigated oxidative stress. Ex vivo osteoblast colony growth rate was 95% greater in mCAT than WT mice and correlated with catalase activity levels (P < 0.005, r = 0.67), although terminal osteoblast and osteoclast differentiation were unaffected. mCAT mice had lower cancellous bone volume and cortical size than WT mice. Ambulatory control mCAT animals also displayed reduced cancellous and cortical structural properties compared with control WT mice. In mCAT but not WT mice, treatment caused an unexpectedly rapid radial expansion (+8% cortical area, +22% moment of inertia), reminiscent of compensatory bone growth during advancing age. In contrast, treatment caused similar structural deficits in cancellous tissue of mCAT and WT mice. In sum, mitochondrial ROS signaling via H2O2 was important for the acquisition of adult bone structure and catalase overexpression failed to protect cancellous tissue from treatment. In contrast, catabolic stimuli caused radial expansion in mCAT not WT mice, suggesting that mitochondrial ROS in skeletal cells act to suppress tissue turnover in response to remodeling challenges.
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Affiliation(s)
- Ann-Sofie Schreurs
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.,Universities Space Research Association, Moffett Field, California
| | - Samantha Torres
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.,Blue Marble Space Institute of Science, Seattle, Washington
| | - Tiffany Truong
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.,Blue Marble Space Institute of Science, Seattle, Washington
| | - Eric L Moyer
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.,Blue Marble Space Institute of Science, Seattle, Washington
| | - Akhhilesh Kumar
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.,Universities Space Research Association, Moffett Field, California
| | - Candice G T Tahimic
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California.,KBR, Moffett Field, California
| | - Joshua S Alwood
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California
| | - Ruth K Globus
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, California
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Viggers R, Al-Mashhadi Z, Fuglsang-Nielsen R, Gregersen S, Starup-Linde J. The Impact of Exercise on Bone Health in Type 2 Diabetes Mellitus-a Systematic Review. Curr Osteoporos Rep 2020; 18:357-370. [PMID: 32529455 DOI: 10.1007/s11914-020-00597-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Type 2 diabetes mellitus (T2DM) is associated with an increased fracture risk. Weight loss in T2DM management may result in lowering of bone mass. In this systematic literature review, we aimed to investigate how exercise affects bone health in people with T2DM. Furthermore, we examined the types of exercise with the potential to prevent and treat bone fragility in people with T2DM. RECENT FINDINGS Exercise differs in type, mechanical load, and intensity, as does the osteogenic response to exercise. Aerobic exercise improves metabolic health in people with T2DM. However, the weight-bearing component of exercise is essential to bone health. Weight loss interventions in T2DM induce a loss of bone mass that may be attenuated if accompanied by resistance or weight-bearing exercise. Combination of weight-bearing aerobic and resistance exercise seems to be preventive against excessive bone loss in people with T2DM. However, evidence is sparse and clinical trials investigating the effects of exercise on bone health in people with T2DM are warranted.
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Affiliation(s)
- R Viggers
- Steno Diabetes Center North Jutland, Aalborg University Hospital, Mølleparkvej 4, 9000, Aalborg, Denmark.
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
| | - Z Al-Mashhadi
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus C, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark
| | - R Fuglsang-Nielsen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus C, Denmark
- Department of Internal Medicine, Regional Hospital Randers, Randers, Denmark
| | - S Gregersen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus C, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark
| | - J Starup-Linde
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus C, Denmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark
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Staehlke S, Haack F, Waldner AC, Koczan D, Moerke C, Mueller P, Uhrmacher AM, Nebe JB. ROS Dependent Wnt/β-Catenin Pathway and Its Regulation on Defined Micro-Pillars-A Combined In Vitro and In Silico Study. Cells 2020; 9:E1784. [PMID: 32726949 PMCID: PMC7464713 DOI: 10.3390/cells9081784] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 12/15/2022] Open
Abstract
The physico-chemical surface design of implants influences the surrounding cells. Osteoblasts on sharp-edged micro-topographies revealed an impaired cell phenotype, function and Ca2+ mobilization. The influence of edges and ridges on the Wnt/β-catenin pathway in combination with the cells' stress response has not been clear. Therefore, MG-63 osteoblasts were studied on defined titanium-coated micro-pillars (5 × 5 × 5 µm) in vitro and in silico. MG-63s on micro-pillars indicated an activated state of the Wnt/β-catenin pathway. The β-catenin protein accumulated in the cytosol and translocated into the nucleus. Gene profiling indicated an antagonism mechanism of the transcriptional activity of β-catenin due to an increased expression of inhibitors like ICAT (inhibitor of β-catenin and transcription factor-4). Cells on pillars produced a significant reactive oxygen species (ROS) amount after 1 and 24 h. In silico analyses provided a detailed view on how transcriptional activity of Wnt signaling is coordinated in response to the oxidative stress induced by the micro-topography. Based on a coordinated expression of regulatory elements of the Wnt/β-catenin pathway, MG-63s are able to cope with an increased accumulation of β-catenin on micro-pillars and suppress an unintended target gene expression. Further, β-catenin may be diverted into other signaling pathways to support defense mechanisms against ROS.
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Affiliation(s)
- Susanne Staehlke
- Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, 18057 Rostock, Germany; (A.-C.W.); (C.M.); (P.M.); (J.B.N.)
| | - Fiete Haack
- Modeling and Simulation Group, Institute for Visual and Analytic Computing, University of Rostock, Albert-Einstein-Str. 22, 18059 Rostock, Germany; (F.H.); (A.M.U.)
| | - Anna-Christin Waldner
- Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, 18057 Rostock, Germany; (A.-C.W.); (C.M.); (P.M.); (J.B.N.)
| | - Dirk Koczan
- Institute for Immunology, Core Facility for Microarray Analysis, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany;
| | - Caroline Moerke
- Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, 18057 Rostock, Germany; (A.-C.W.); (C.M.); (P.M.); (J.B.N.)
| | - Petra Mueller
- Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, 18057 Rostock, Germany; (A.-C.W.); (C.M.); (P.M.); (J.B.N.)
| | - Adelinde M. Uhrmacher
- Modeling and Simulation Group, Institute for Visual and Analytic Computing, University of Rostock, Albert-Einstein-Str. 22, 18059 Rostock, Germany; (F.H.); (A.M.U.)
- Department Science and Technology of Life, Light and Matter, University of Rostock, Albert-Einstein-Str. 25, 18059 Rostock, Germany
| | - J. Barbara Nebe
- Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, 18057 Rostock, Germany; (A.-C.W.); (C.M.); (P.M.); (J.B.N.)
- Department Science and Technology of Life, Light and Matter, University of Rostock, Albert-Einstein-Str. 25, 18059 Rostock, Germany
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