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Li S, Zou J, Ran J, Wang L, Nie G, Liu Y, Tian C, Yang X, Liu Y, Wan J, Peng W. Advances in the Study of Denosumab Treatment for Osteoporosis and Sarcopenia in the Chinese Middle-Aged and Elderly Population. Int J Gen Med 2024; 17:6089-6099. [PMID: 39678680 PMCID: PMC11646433 DOI: 10.2147/ijgm.s494759] [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: 09/17/2024] [Accepted: 11/22/2024] [Indexed: 12/17/2024] Open
Abstract
Osteosarcopenia (OS) is a geriatric syndrome characterized by the concurrent presence of osteoporosis and sarcopenia, predominantly affecting the elderly population. Osteoporosis (OP) is a systemic skeletal disorder characterized by decreased bone mass, compromised bone microarchitecture, and heightened bone fragility, substantially elevating fracture risk. Sarcopenia (SP) is defined by decreased muscle mass, strength, and/or functional capacity. Both conditions are age-related degenerative diseases with overlapping pathophysiological mechanisms, commonly co-occurring in elderly individuals and substantially increasing fracture risk. Denosumab, a targeted anti-osteoporotic agent, mediates therapeutic effects by inhibiting bone resorption through the RANK-RANKL-OPG (RRO) pathway, consequently enhancing bone mineral density. International studies indicate that Denosumab not only treats osteoporosis but also improves sarcopenia-related metrics, suggesting its potential as a sarcopenia treatment. However, research focusing on the Chinese population remains limited. Additionally, the pathophysiological mechanisms of sarcopenia and the pathways through which Denosumab ameliorates sarcopenia are not yet fully understood, warranting further experimental investigation. In summary, Denosumab's therapeutic efficacy in osteoporosis treatment and its potential impact on sarcopenia are of substantial research interest. However, research and literature on these topics in China remain notably scarce. This article aims to offer a systematic review and critical analysis of these topics.
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Affiliation(s)
- Shaotian Li
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jingfeng Zou
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jiajia Ran
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Liping Wang
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Guqiao Nie
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yiting Liu
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Chunhui Tian
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Xin Yang
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yun Liu
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jingjing Wan
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Wen Peng
- General Practice Department, Union Hospital TongJi Medical College HuaZhong University of Science and Technology, Wuhan, People’s Republic of China
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Ronghe R, Tavares AAS. The skeleton: an overlooked regulator of systemic glucose metabolism in cancer? Front Oncol 2024; 14:1481241. [PMID: 39588310 PMCID: PMC11586348 DOI: 10.3389/fonc.2024.1481241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/22/2024] [Indexed: 11/27/2024] Open
Abstract
Recent discoveries demonstrated the skeleton's role as an endocrine organ regulating whole-body glucose homeostasis. Glucose metabolism is critical for rapid cell proliferation and tumour growth through increasing glucose uptake and fermentation of glucose to lactate despite being in an aerobic environment. This hypothesis paper discusses emerging evidence on how bones can regulate whole-body glucose homeostasis with potential to impact on tumour growth and proliferation. Moreover, it proposes a clinical link between bone glucose metabolism and prognosis of cancer based on recent clinical trial data. Targeting metabolic pathways related with classic glucose metabolism and also bone metabolism, novel methods of cancer therapy and treatment could be developed. This paper objective is to highlight the need for future research on this altered metabolism with potential to change future management of cancer patients.
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Affiliation(s)
- Rucha Ronghe
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, United Kingdom
| | - Adriana A. S. Tavares
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, United Kingdom
- Edinburgh Imaging, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, United Kingdom
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Al-Daghri NM, Wani K, Khattak MNK, Alnaami AM, Al-Saleh Y, Sabico S. The single point insulin sensitivity estimator (SPISE) is associated with bone health in Arab adults. Aging Clin Exp Res 2024; 36:136. [PMID: 38904881 PMCID: PMC11192813 DOI: 10.1007/s40520-024-02789-5] [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: 03/10/2024] [Accepted: 06/05/2024] [Indexed: 06/22/2024]
Abstract
BACKGROUND The Single Point Insulin Sensitivity Estimator (SPISE) index is a surrogate marker for insulin sensitivity. Given the emerging role of bone as an active endocrine organ, its associations with non-invasive measures of extra-skeletal functions such as insulin sensitivity warrant investigation. AIMS This study aimed to explore the relationship between the SPISE index and Bone Mineral Density (BMD) in an adult population. METHODS Data from a total of 1270 Arab adults (84% females, mean age 56.7 ± 8.1 years) from the Osteoporosis Registry Database of the Chair for Biomarkers of Chronic Diseases in King Saud University, Riyadh, Saudi Arabia was used in this study. T-scores and SPISE were calculated. Regression models were used to determine associations between SPISE and bone health indices. RESULTS The low BMD group (N = 853; T-score <-1.0) had significantly higher SPISE values than those with normal BMD (N = 417; T-score - 1.0 and above) (4.6 ± 1.3 vs. 4.3 ± 1.2, p < 0.001). Multivariate linear regression, adjusted for covariates, confirmed a significant inverse association between SPISE and BMD for all participants (β=-0.22, p < 0.001), as well as both groups [normal BMD (β = -0.10, p = 0.02) and low BMD groups (β = -0.15, p < 0.001)]. SPISE, family history of T2DM, and history of fractures collectively account for 17% of the variances perceived in T-score for all participants (p < 0.001). CONCLUSIONS A significant inverse association between the SPISE index and BMD was observed in adults, suggesting a link between BMD and extra-skeletal health. Underlying mechanisms need to be investigated prospectively using BMD as secondary outcomes in lifestyle modification programs.
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Affiliation(s)
- Nasser M Al-Daghri
- Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.
| | - Kaiser Wani
- Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Malak N K Khattak
- Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Abdullah M Alnaami
- Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Yousef Al-Saleh
- Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
- Department of Medicine, Health Oasis Hospital, Riyadh, Saudi Arabia
| | - Shaun Sabico
- Biochemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
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Cherian P, Al-Khairi I, Abu-Farha M, Alramah T, Albatineh AN, Alhomaidah D, Safadi F, Ali H, Abdul-Ghani M, Tuomilehto J, Koistinen HA, Al-Mulla F, Abubaker J. Ethnic Variations in the Levels of Bone Biomarkers (Osteoprostegerin, Receptor Activator of Nuclear Factor Kappa-Β Ligand and Glycoprotein Non-Metastatic Melanoma Protein B) in People with Type 2 Diabetes. Biomedicines 2024; 12:1019. [PMID: 38790981 PMCID: PMC11117910 DOI: 10.3390/biomedicines12051019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/25/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
The global incidence of Type 2 diabetes (T2D) is on the rise, fueled by factors such as obesity, sedentary lifestyles, socio-economic factors, and ethnic backgrounds. T2D is a multifaceted condition often associated with various health complications, including adverse effects on bone health. This study aims to assess key biomarkers linked to bone health and remodeling-Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), and Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB)-among individuals with diabetes while exploring the impact of ethnicity on these biomarkers. A cross-sectional analysis was conducted on a cohort of 2083 individuals from diverse ethnic backgrounds residing in Kuwait. The results indicate significantly elevated levels of these markers in individuals with T2D compared to non-diabetic counterparts, with OPG at 826.47 (405.8) pg/mL, RANKL at 9.25 (17.3) pg/mL, and GPNMB at 21.44 (7) ng/mL versus 653.75 (231.7) pg/mL, 0.21 (9.94) pg/mL, and 18.65 (5) ng/mL in non-diabetic individuals, respectively. Notably, this elevation was consistent across Arab and Asian populations, except for lower levels of RANKL observed in Arabs with T2D. Furthermore, a positive and significant correlation between OPG and GPNMB was observed regardless of ethnicity or diabetes status, with the strongest correlation (r = 0.473, p < 0.001) found among Arab individuals with T2D. Similarly, a positive and significant correlation between GPNMB and RANKL was noted among Asian individuals with T2D (r = 0.401, p = 0.001). Interestingly, a significant inverse correlation was detected between OPG and RANKL in non-diabetic Arab individuals. These findings highlight dysregulation in bone remodeling markers among individuals with T2D and emphasize the importance of considering ethnic variations in T2D-related complications. The performance of further studies is warranted to understand the underlying mechanisms and develop interventions based on ethnicity for personalized treatment approaches.
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Affiliation(s)
- Preethi Cherian
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.C.); (I.A.-K.); (M.A.-F.); (T.A.)
| | - Irina Al-Khairi
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.C.); (I.A.-K.); (M.A.-F.); (T.A.)
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.C.); (I.A.-K.); (M.A.-F.); (T.A.)
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Tahani Alramah
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.C.); (I.A.-K.); (M.A.-F.); (T.A.)
| | | | - Doha Alhomaidah
- Department of Population Health, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Fayez Safadi
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH 44272, USA;
- Rebecca D. Considine Research Institute, Akron Children Hospital, Akron, OH 44308, USA
| | - Hamad Ali
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Kuwait 15462, Kuwait;
| | - Muhammad Abdul-Ghani
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait;
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX 78030, USA
| | - Jaakko Tuomilehto
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, 00271 Helsinki, Finland; (J.T.); (H.A.K.)
- Saudi Diabetes Research Group, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Heikki A. Koistinen
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, 00271 Helsinki, Finland; (J.T.); (H.A.K.)
- Department of Medicine, University of Helsinki and Helsinki University Hospital, P.O. Box 340, 00029 Helsinki, Finland
- Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland
| | - Fahd Al-Mulla
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.C.); (I.A.-K.); (M.A.-F.); (T.A.)
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Zhao M, Ma L, Honda T, Kato A, Ohshiro T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Nakamura M, Kawashima H, Tsuji NM, Ishigami M, Fujishiro M. Astaxanthin Attenuates Nonalcoholic Steatohepatitis with Downregulation of Osteoprotegerin in Ovariectomized Mice Fed Choline-Deficient High-Fat Diet. Dig Dis Sci 2023; 68:155-163. [PMID: 35397697 DOI: 10.1007/s10620-022-07489-6] [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: 12/06/2021] [Accepted: 03/14/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. AIMS This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. METHODS Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. RESULTS The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. CONCLUSIONS Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.
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Affiliation(s)
- Meng Zhao
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Lingyun Ma
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Asuka Kato
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
- ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Taichi Ohshiro
- ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Noriko M Tsuji
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
- Division of Immune Homeostasis, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
- Department of Food Science, Jumonji University, Saitama, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
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Faienza MF, Pontrelli P, Brunetti G. Type 2 diabetes and bone fragility in children and adults. World J Diabetes 2022; 13:900-911. [PMID: 36437868 PMCID: PMC9693736 DOI: 10.4239/wjd.v13.i11.900] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/17/2022] [Accepted: 10/11/2022] [Indexed: 11/11/2022] Open
Abstract
Type 2 diabetes (T2D) is a global epidemic disease. The prevalence of T2D in adolescents and young adults is increasing alarmingly. The mechanisms leading to T2D in young people are similar to those in older patients. However, the severity of onset, reduced insulin sensitivity and defective insulin secretion can be different in subjects who develop the disease at a younger age. T2D is associated with different complications, including bone fragility with consequent susceptibility to fractures. The purpose of this systematic review was to describe T2D bone fragility together with all the possible involved pathways. Numerous studies have reported that patients with T2D show preserved, or even increased, bone mineral density compared with controls. This apparent paradox can be explained by the altered bone quality with increased cortical bone porosity and compr-omised mechanical properties. Furthermore, reduced bone turnover has been described in T2D with reduced markers of bone formation and resorption. These findings prompted different researchers to highlight the mechanisms leading to bone fragility, and numerous critical altered pathways have been identified and studied. In detail, we focused our attention on the role of microvascular disease, advanced glycation end products, the senescence pathway, the Wnt/β-catenin pathway, the osteoprotegerin/receptor-activator of nuclear factor kappa B ligand, osteonectin and fibroblast growth factor 23. The understanding of type 2 myeloid bone fragility is an important issue as it could suggest possible interventions for the prevention of poor bone quality in T2D and/or how to target these pathways when bone disease is clearly evident.
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Affiliation(s)
- Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Paola Pontrelli
- Division of Nephrology, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari 70124, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari 70125, Italy
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Huang D, Niu Y, Zhang W, Li X, Lin N, Yang Z, Qin L, Su Q, Ran H, Zhang H. OPG
is associated with thyroid nodule development in type 2 diabetes. J Clin Lab Anal 2022; 36:e24615. [PMID: 35870175 PMCID: PMC9459264 DOI: 10.1002/jcla.24615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/27/2022] [Accepted: 07/03/2022] [Indexed: 11/13/2022] Open
Abstract
Background Thyroid nodule prevalence is increasing lately, especially in diabetes, but the mechanism of which is not clear. In this study, we investigated if osteoprotegerin (OPG) is involved in the pathogenesis of thyroid nodules in diabetes. Methods A total of 7568 individuals with detailed information and ultrasound examination results were studied for the prevalence of thyroid nodules. Among them, 1883 were with type 2 diabetes and 5685 were non‐diabetic. Then, 1120 individuals were randomly selected for the measurement of OPG. Diabetic rats were made by feeding a high‐fat‐high‐fructose diet for 28 weeks. Rats fed with a normal diet were as controls. Fresh thyroid tissues were obtained and fixed, dehydrated, and embedded in paraffin for hematoxylin‐eosin staining and observing pathological changes. qPCR and western blot were used to detect OPG expression in rat thyroid tissues. Results We found that HbA1c is an independent risk factor for thyroid nodules (Exp [β] = 1.158, p < 0.001). The prevalence of thyroid nodules in type 2 diabetes was higher than that in non‐diabetes (53.9% vs. 46.7%, p < 0.001). Serum OPG levels were significantly elevated in the diabetes group than in the non‐diabetes group (3160.17 pg/ml vs. 2819.39 pg/ml, p < 0.01). The expression of OPG increased significantly in the thyroid tissues of diabetic rats. Conclusion Osteoprotegerin may be associated with thyroid nodule development in diabetes.
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Affiliation(s)
- Dazhi Huang
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
- Pudong New Area Gaoqiao community health center Shanghai China
| | - Yixin Niu
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Weiwei Zhang
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Xiaoyong Li
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Ning Lin
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Li Qin
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
- Department of Endocrinology, Xinhua Hospital Chongming Branch Shanghai Jiaotong University School of Medicine Shanghai China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Hui Ran
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Hongmei Zhang
- Department of Endocrinology, Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
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Inverse Regulation of Serum Osteoprotegerin and B-Type Natriuretic Peptide Concentrations by Free Fatty Acids Elevation in Young Healthy Humans. Nutrients 2022; 14:nu14040837. [PMID: 35215487 PMCID: PMC8879157 DOI: 10.3390/nu14040837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/06/2022] [Accepted: 02/15/2022] [Indexed: 02/05/2023] Open
Abstract
Osteoprotegerin (OPG) and B-type natriuretic peptide (BNP) are cardiovascular risk factors, interrelated with each other, with possible associations with insulin sensitivity and glucose homeostasis. The aim of this study was to assess association between OPG and BNP concentrations in a young healthy population, their relation to insulin sensitivity and obesity and their regulation by hyperinsulinemia and serum free fatty acids (FFA) elevation. The study group consisted of 59 male volunteers, 30 of whom were of a normal weight (BMI < 25 kg/m2), and 29 were overweight/obese (BMI > 25 kg/m2). Insulin sensitivity was assessed with the 2-h hyperinsulinemic-euglycemic clamp (HEC). In the subgroup of 20 subjects, the clamp was prolonged to 6 h. After one week, another 6-h clamp, with concurrent Intralipid/heparin infusion, was performed. Serum OPG was positively associated with insulin sensitivity (p = 0.002) and negatively with BMI (p = 0.019) and serum BNP (p = 0.025). In response to 6-h hyperinsulinemia, circulating BNP decreased (p < 0.001). In response to HEC with Intralipid/heparin infusion, OPG decreased (p < 0.001) and BNP increased (p < 0.001). Our data show that OPG and BNP are differentially regulated by FFA, which suggests their association with lipid-induced insulin resistance. The assessment of these cardiovascular risk factors should take into account both long-term and short-term effects associated with insulin resistance.
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Lou X, Yang Z, Wu K, Li W, Hu W, Nie R, Tu P, Duan P. Elevated Serum Osteoprotegerin is Associated with Reduced Risks of Albuminuria and CKD Progression in Patients with Type 2 Diabetes. Diabetes Metab Syndr Obes 2022; 15:3831-3841. [PMID: 36530588 PMCID: PMC9756793 DOI: 10.2147/dmso.s390483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/26/2022] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE To analyze the correlation between serum osteoprotegerin (OPG) level and chronic kidney disease (CKD) at different CKD stages in patients with type 2 diabetes. METHODS All subjects were hospitalized patients with type 2 diabetes. Medical history collection, physical examinations, and blood and urine samples testing were performed. Stages of CKD (G1-5) were defined by eGFR, groups of persistent albuminuria (normal, microalbuminuria and massive albuminuria) were divided by UACR, and categories of CKD progression risks (low, moderate and high or very high risk) were recommended by the Kidney Disease: Improving Global Outcomes (KDIGO). Serum OPG level was determined by enzyme-linked immunosorbent assay in the central laboratory. RESULTS Four hundred and eighty-four patients were included in the study. The average level of OPG of all subjects was 941.30 (547.53-1332.62) pg/mL. The levels of OPG decreased gradually with the aggravation of albuminuria (P = 0.007, P for trend=0.003) and CKD progression (P = 0.001, P for trend=0.001). No differences were found between OPG levels and stages of CKD (P = 0.31). After the adjustment, each 100 pg/mL increase in OPG levels could reduce the risk of massive albuminuria (OR 0.92, 95% CI 0.86-0.99, P = 0.02) and the high or very high risk of CKD progression (OR 0.94, 95% CI 0.89-0.99, P = 0.04) by multivariate logistic regression analysis. No correlations were found between OPG and stages of CKD. CONCLUSION In patients with type 2 diabetes, elevated serum osteoprotegerin is associated with albuminuria and the risk of CKD progression, and may delay the progression of CKD.
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Affiliation(s)
- Xiaoyang Lou
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
- Department of Postgraduate Studies, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, People’s Republic of China
| | - Zhi Yang
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
| | - Kexia Wu
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
| | - Weihong Li
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
| | - Wan Hu
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
| | - Ronghui Nie
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
- Third Clinical School of Medicine, Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Ping Tu
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
| | - Peng Duan
- Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China
- Correspondence: Peng Duan, Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, Jiangxi, 330000, People’s Republic of China, Tel +86 13479111177, Email
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10
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Pacheco-Soto BT, Elguezabal-Rodelo RG, Porchia LM, Torres-Rasgado E, Pérez-Fuentes R, Gonzalez-Mejia ME. Denosumab improves glucose parameters in patients with impaired glucose tolerance: a systematic review and meta-analysis. J Drug Assess 2021; 10:97-105. [PMID: 34676131 PMCID: PMC8525927 DOI: 10.1080/21556660.2021.1989194] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Objective Receptor activator of NF-κβ ligand (RANKL) is crucial for the development of hepatic insulin resistance and poor glucose uptake; therefore, inhibiting RANKL with Denosumab could improve fasting plasma glucose (FPG) and insulin (FPI). Methods A systematic review was conducted to evaluate the effects of Denosumab on glycemic parameters. PubMed, SCOPUS, EBSCO, and LILACS databases were searched for studies that investigated the effect of Denosumab on FPG, glycated hemoglobin (HbA1c), FPI, and Homeostatic Model Assessment for Insulin Resistance (HOMA1-IR). The pooled standard difference in means (SDM) and 95% confidence intervals (95%CI) were calculated. The results were stratified into (1) Normal Glucose Tolerance (NGT) and (2) Impaired Glucose Tolerance (IGT). Results Six publications (1203 participants) were included. There was a significant association between Denosumab and FPG (SDM = -0.388, 95%CI: -0.705 to -0.070, p = .017) and with HOMA1-IR (SDM = -0.223, 95%CI: -0.388 to -0.058, p = .008), but not for HbA1c and FPI. When stratified by glucose tolerance, the association between Denosumab and FPG, HbA1c, and HOMA1-IR was present for the IGT group. Lastly, Denosumab had a time-dependent effect on HbA1c (slope = -0.037, 95%CI: -0.059 to -0.015, p < .005). Conclusions Denosumab significantly improved glycemic parameters. This outcome was more prominent for subjects with compromised glucose tolerance, positing that Denosumab can be used as a treatment to improve glucose metabolism for persons with pre-diabetes and diabetes.
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Affiliation(s)
| | | | - Leonardo M Porchia
- Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
| | | | - Ricardo Pérez-Fuentes
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.,Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
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11
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Endocrine role of bone in the regulation of energy metabolism. Bone Res 2021; 9:25. [PMID: 34016950 PMCID: PMC8137703 DOI: 10.1038/s41413-021-00142-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 12/20/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
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12
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Ochoa-Précoma R, Pacheco-Soto BT, Porchia LM, Torres-Rasgado E, Pérez-Fuentes R, Gonzalez-Mejia ME. Association between Osteoprotegerin and Charcot Neuroarthropathy: a systematic review. Acta Diabetol 2021; 58:475-484. [PMID: 33394132 DOI: 10.1007/s00592-020-01638-x] [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: 08/25/2020] [Accepted: 11/08/2020] [Indexed: 11/09/2022]
Abstract
AIMS Osteoprotegerin (OPG) has been associated with Charcot Neuroarthropathy (CN); however, three studied OPG polymorphisms (1181C > G, 245A > C and 950 T > C) have yielded conflicting results. Therefore, this meta-analysis was conducted to determine the difference in serum OPG concentrations between healthy controls and diabetics with and without CN and the effect OPG polymorphisms have on CN development. METHODS PubMed, LILAC, SCOPUS, and EBSCO databases and retrieved publications' bibliographies were searched for studies that examined for OPG and CN. Depending on the heterogeneity, fixed or random effects were used to calculate the pooled odds ratio (OR) or standard difference in means (SDM) with 95% confidence intervals (95%CI) for 5 genetic models (heterozygous, homozygous, dominant, recessive, and allelic) and serum concentrations, respectively. RESULTS Seven publications (12 studies) demonstrated that serum OPG concentrations were more elevated in subjects with CN (SDM = 0.719, 95%CI = 0.555-0.883, p < 0.001). When CN was compared to healthy controls or diabetics, the difference was more prominent for healthy controls (SDM = 1.043, 95%CI = 0.676-1.409, p < 0.001) than diabetics (SDM = 0.639, 95%CI = 0.456-0.821, p < 0.001) and the SDM difference was significant (p = 0.013). Using 6 publications (9 studies), neither the 1181C > G or the 950 T > C polymorphisms showed any significant associations for any genetic model. For the 245A > C polymorphism, only the homozygous genetic model showed a significant association between the polymorphism and CN (OR = 2.850, 95%CI: 1.051-7.729, p = 0.040). CONCLUSIONS Here, we determined a potential correlation between the CN and serum OPG concentrations and that only the CC genotype of the 245A > C polymorphism showed an increased risk of developing CN.
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Affiliation(s)
- Renata Ochoa-Précoma
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México
| | - Blanca T Pacheco-Soto
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México
| | - Leonardo M Porchia
- Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, IMSS. Delegación Puebla. Carretera Federal Atlixco Metepec Km, 4.5, Colonia Centro, 74360, Atlixco, Puebla, México
| | - Enrique Torres-Rasgado
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México
| | - Ricardo Pérez-Fuentes
- Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, IMSS. Delegación Puebla. Carretera Federal Atlixco Metepec Km, 4.5, Colonia Centro, 74360, Atlixco, Puebla, México
| | - M Elba Gonzalez-Mejia
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México.
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Niță G, Niță O, Gherasim A, Arhire L, Herghelegiu A, Mihalache L, Tuchilus C, Graur M. The role of RANKL and FGF23 in Assessing Bone Turnover in Type 2 Diabetic Patients. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2021; 17:51-59. [PMID: 34539910 PMCID: PMC8417483 DOI: 10.4183/aeb.2021.51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
CONTEXT Type 2 diabetes is a chronic metabolic disease which affects bone. There is evidence in the literature about some serum markers that reflect the bone turnover metabolism, such as RANKL (Receptor Activator of Nuclear factor Kappa-b Ligand) and Fibroblast Growth Factor (FGF) 23. OBJECTIVE We aimed to investigate the correlations between RANKL and FGF23 and other diabetes-related factors possibly influencing early bone turnover changes. SUBJECTS AND METHOD We conducted a cross-sectional analytical study on a group of 171 patients with type 2 diabetes, without Charcot's arthropathy or a history of amputations, in which a complete history and anthropometric, clinical, biochemical and dietary evaluation were performed. We evaluated the serum level of RANKL and FGF 23. RESULTS RANKL was significantly lower in patients with macroangiopathy (0.42±0.15 pmol/L vs. 0.47±0.2 pmol/L, p=0.001). The level of FGF23 was lower in patients with neuropathy (0.37±0.36 pmol/L vs. 0.41±0.17 pmol/L, p=0.001). We found that FGF23 increased with age, but decreased with the duration of diabetes. We also found an inverse relationship between FGF23 levels and HbA1c, triglycerides, diastolic blood pressure, total proteins, albuminemia. CONCLUSIONS RANKL was significantly lower in patients with macroangiopathy, and FGF 23 in patients with neuropathy. Therefore, more studies are needed to elucidate their role in early bone turnover changes.
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Affiliation(s)
- G. Niță
- “Grigore T Popa” University of Medicine and Pharmacy, Faculty of Medicine, Iasi
| | - O. Niță
- “Grigore T Popa” University of Medicine and Pharmacy, Faculty of Medicine, Iasi
| | - A. Gherasim
- “Grigore T Popa” University of Medicine and Pharmacy, Faculty of Medicine, Iasi
| | - L.I. Arhire
- “Grigore T Popa” University of Medicine and Pharmacy, Faculty of Medicine, Iasi
| | - A.M Herghelegiu
- “Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Bucharest, Romania
| | - L. Mihalache
- “Grigore T Popa” University of Medicine and Pharmacy, Faculty of Medicine, Iasi
| | - C. Tuchilus
- “Grigore T Popa” University of Medicine and Pharmacy, Faculty of Medicine, Iasi
| | - M. Graur
- “Grigore T Popa” University of Medicine and Pharmacy, Faculty of Medicine, Iasi
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14
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Cherian P, Al-Khairi I, Jamal M, Al-Sabah S, Ali H, Dsouza C, Alshawaf E, Al-Ali W, Al-Khaledi G, Al-Mulla F, Abu-Farha M, Abubaker J. Association Between Factors Involved in Bone Remodeling (Osteoactivin and OPG) With Plasma Levels of Irisin and Meteorin-Like Protein in People With T2D and Obesity. Front Endocrinol (Lausanne) 2021; 12:752892. [PMID: 34777249 PMCID: PMC8588843 DOI: 10.3389/fendo.2021.752892] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/08/2021] [Indexed: 01/05/2023] Open
Abstract
The musculoskeletal system consisting of bones and muscles have been recognized as endocrine organs secreting hormones that are involved in regulating metabolic and inflammatory pathways. Obesity and type 2 diabetes (T2D) are associated with several musculoskeletal system complications. We hypothesized that an interaction exists between adipomyokines namely, irisin and METRNL, and various molecules involved in bone remodeling in individuals with obesity and T2D. A total of 228 individuals were enrolled in this study, including 124 non-diabetic (ND) and 104 T2D. A Multiplex assay was used to assess the level of various osteogenic molecules namely osteoactivin, Syndecan, osteoprotegerin (OPG) and osteonectin/SPARC. Our data shows elevated levels of Osteoactivin, Syndecan, OPG and SPARC in T2D as compared to ND individuals (p ≤ 0.05). Using Spearman's correlation, a positive correlation was observed between irisin and Osteoactivin as well as OPG (p < 0.05). Similarly, a positive association was observed between METRNL and Osteoactivin (p < 0.05). The strong positive association shown in this study between irisin, METRNL and various molecules with osteogenic properties emphasize a possible interaction between these organs. This report suggests that having a dysregulation in the level of the aforementioned molecules could potentially affect the development of bone and muscle related complications that are associated with obesity and T2D.
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Affiliation(s)
- Preethi Cherian
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Irina Al-Khairi
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohammad Jamal
- Department of Surgery, Faculty of Medicine, Health Sciences Centre, Kuwait University, Sulaibekhat, Kuwait
| | - Suleiman Al-Sabah
- Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait
| | - Hamad Ali
- Department of Genetic and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Carol Dsouza
- Department of Surgery, Faculty of Medicine, Health Sciences Centre, Kuwait University, Sulaibekhat, Kuwait
| | - Eman Alshawaf
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Waleed Al-Ali
- Department of Surgery, Faculty of Medicine, Health Sciences Centre, Kuwait University, Sulaibekhat, Kuwait
| | - Ghanim Al-Khaledi
- Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait
| | - Fahd Al-Mulla
- Department of Genetic and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
- *Correspondence: Mohamed Abu-Farha, ; Jehad Abubaker,
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
- *Correspondence: Mohamed Abu-Farha, ; Jehad Abubaker,
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15
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Cipriani C, Colangelo L, Santori R, Renella M, Mastrantonio M, Minisola S, Pepe J. The Interplay Between Bone and Glucose Metabolism. Front Endocrinol (Lausanne) 2020; 11:122. [PMID: 32265831 PMCID: PMC7105593 DOI: 10.3389/fendo.2020.00122] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 02/24/2020] [Indexed: 12/13/2022] Open
Abstract
The multiple endocrine functions of bone other than those related to mineral metabolism, such as regulation of insulin sensitivity, glucose homeostasis, and energy metabolism, have recently been discovered. In vitro and murine studies investigated the impact of several molecules derived from osteoblasts and osteocytes on glucose metabolism. In addition, the effect of glucose on bone cells suggested a mutual cross-talk between bone and glucose homeostasis. In humans, these mechanisms are the pivotal determinant of the skeletal fragility associated with both type 1 and type 2 diabetes. Metabolic abnormalities associated with diabetes, such as increase in adipose tissue, reduction of lean mass, effects of hyperglycemia per se, production of the advanced glycation end products, diabetes-associated chronic kidney disease, and perturbation of the calcium-PTH-vitamin D metabolism, are the main mechanisms involved. Finally, there have been multiple reports of antidiabetic drugs affecting the skeleton, with differences among basic and clinical research data, as well as of anti-osteoporosis medication influencing glucose metabolism. This review focuses on the aspects linking glucose and bone metabolism by offering insight into the most recent evidence in humans.
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16
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Jorde R, Stunes AK, Kubiak J, Grimnes G, Thorsby PM, Syversen U. Smoking and other determinants of bone turnover. PLoS One 2019; 14:e0225539. [PMID: 31765401 PMCID: PMC6876776 DOI: 10.1371/journal.pone.0225539] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 11/04/2019] [Indexed: 12/19/2022] Open
Abstract
The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type 1 collagen (CTX-1) and procollagen type 1 amino-terminal propeptide (P1NP). Smoking has been shown to influence bone turnover and to reduce bone mass density (BMD), the exact mechanism for this is, however, not settled. In this post-hoc study including 406 subjects (mean age 51.9 years), we aimed to study the impact of smoking on bone turnover. Moreover, we wanted to assess the inter-correlation between substances regulating bone metabolism and BTMs, as well as tracking over time. BMD measurements and serum analyses of CTX-1, P1NP, osteoprotegerin (OPG), receptor activator of nuclear factor ĸB ligand (RANKL), Dickkopf-1 (DKK1), sclerostin, tumor necrosis factor-α (TNF-α), and leptin were performed. Repeated serum measurements were made in 195 subjects after four months. Adjustments were made for sex, age, body mass index (BMI), smoking status, insulin resistance, serum calcium, parathyroid hormone, 25-hydroxyvitamin D and creatinine. Smokers had higher levels of DKK1 and OPG, and lower levels of RANKL, as reflected in lower BTMs and BMD compared to non-smokers. There were strong and predominantly positive inter-correlations between BTMs and the other substances, and there was a high degree of tracking with Spearman’s rho from 0.72 to 0.92 (P < 0.001) between measurements four months apart. In conclusion, smokers exhibited higher levels of DKK1 and OPG and a lower bone turnover than did non-smokers. The strong inter-correlations between the serum parameters illustrate the coupling between bone resorption and formation and crosstalk between cells.
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Affiliation(s)
- Rolf Jorde
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway
- Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
- * E-mail:
| | - Astrid Kamilla Stunes
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Julia Kubiak
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Guri Grimnes
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway
- Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Per Medbøe Thorsby
- Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital, Aker Hospital, Oslo, Norway
| | - Unni Syversen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Endocrinology, Clinic of Medicine, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway
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17
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Costantini S, Conte C. Bone health in diabetes and prediabetes. World J Diabetes 2019; 10:421-445. [PMID: 31523379 PMCID: PMC6715571 DOI: 10.4239/wjd.v10.i8.421] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 06/03/2019] [Accepted: 07/20/2019] [Indexed: 02/05/2023] Open
Abstract
Bone fragility has been recognized as a complication of diabetes, both type 1 diabetes (T1D) and type 2 diabetes (T2D), whereas the relationship between prediabetes and fracture risk is less clear. Fractures can deeply impact a diabetic patient's quality of life. However, the mechanisms underlying bone fragility in diabetes are complex and have not been fully elucidated. Patients with T1D generally exhibit low bone mineral density (BMD), although the relatively small reduction in BMD does not entirely explain the increase in fracture risk. On the contrary, patients with T2D or prediabetes have normal or even higher BMD as compared with healthy subjects. These observations suggest that factors other than bone mass may influence fracture risk. Some of these factors have been identified, including disease duration, poor glycemic control, presence of diabetes complications, and certain antidiabetic drugs. Nevertheless, currently available tools for the prediction of risk inadequately capture diabetic patients at increased risk of fracture. Aim of this review is to provide a comprehensive overview of bone health and the mechanisms responsible for increased susceptibility to fracture across the spectrum of glycemic status, spanning from insulin resistance to overt forms of diabetes. The management of bone fragility in diabetic patient is also discussed.
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Affiliation(s)
- Silvia Costantini
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- Epatocentro Ticino, Lugano 6900, Switzerland
| | - Caterina Conte
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- IRCCS Ospedale San Raffaele, Internal Medicine and Transplantation, Milan 20123, Italy
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18
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Bonnet N, Bourgoin L, Biver E, Douni E, Ferrari S. RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass. J Clin Invest 2019; 129:3214-3223. [PMID: 31120440 PMCID: PMC6668701 DOI: 10.1172/jci125915] [Citation(s) in RCA: 195] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 05/14/2019] [Indexed: 12/13/2022] Open
Abstract
Receptor activator of Nfkb ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. In turn a neutralizing Ab against RANKL, denosumab improves bone strength in osteoporosis. OPG also improves muscle strength in mouse models of Duchenne's muscular dystrophy (mdx) and denervation-induce atrophy, but its role and mechanisms of action on muscle weakness in other conditions remains to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKL-Tg+), or lack Pparb and concomitantly develop sarcopenia (Pparb-/-). In women, denosumab over 3 years improved appendicular lean mass and handgrip strength compared to no treatment, whereas bisphosphonate did not. HuRANKL-Tg+ mice displayed lower limb force and maximal speed, while their leg muscle mass was diminished, with a lower number of type I and II fibers. Both OPG and denosumab increased limb force proportionally to the increase in muscle mass. They markedly improved muscle insulin sensitivity and glucose uptake, and decrease anti-myogenic and inflammatory gene expression in muscle, such as myostatin and protein tyrosine phosphatase receptor-γ. Similarly, in Pparb-/-, OPG increased muscle volume and force, while also normalizing their insulin signaling and higher expression of inflammatory genes in skeletal muscle. In conclusions, RANKL deteriorates, while its inhibitor improves, muscle strength and insulin sensitivity in osteoporotic mice and humans. Hence denosumab could represent a novel therapeutic approach for sarcopenia.
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Affiliation(s)
- Nicolas Bonnet
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva, Switzerland
| | - Lucie Bourgoin
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva, Switzerland
| | - Emmanuel Biver
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva, Switzerland
| | - Eleni Douni
- Biomedical Sciences Research Center “Alexander Fleming,” Athens, Greece
- Department of Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Serge Ferrari
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva, Switzerland
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19
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Barchetta I, Ceccarelli V, Cimini FA, Bertoccini L, Fraioli A, Alessandri C, Lenzi A, Baroni MG, Cavallo MG. Impaired bone matrix glycoprotein pattern is associated with increased cardio-metabolic risk profile in patients with type 2 diabetes mellitus. J Endocrinol Invest 2019; 42:513-520. [PMID: 30132286 DOI: 10.1007/s40618-018-0941-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE Osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC) are matrix glycoproteins which mediate bone mineralization; moreover, their effects on glucose/insulin homeostasis have recently been demonstrated. Higher circulating OPN and OPG levels have been associated with the presence of insulin resistance, atherosclerosis and coronary heart disease. No data are available on contextual changes of these markers in type 2 diabetes mellitus (T2DM). Therefore, aims of this study were to evaluate serum OPN, OPG and OC levels in T2DM patients and their clinical correlates. METHODS We recruited 83 consecutive T2DM patients referring to our diabetes outpatient clinics at Sapienza, University of Rome, and 71 non-diabetic sex and age-comparable subjects as a control group. Study population underwent metabolic characterization and carotid ultrasound for intima-media thickness measurement. Plasma OPN, OPG and OC were measured by MILLIPLEX Multiplex Assays Luminex. RESULTS T2DM patients had significantly higher circulating OPN and OPG levels than controls (14.3 ± 13.6 vs 10.6 ± 13.7 ng/ml p < 0.001, 0.70 ± 0.60 vs 0.54 ± 4.1 ng/ml, p = 0.02) while OC levels were similar in the two cohorts (6.35 ± 5.8 vs 7.80 ± 7.0 ng/ml, p = n.s). OPN and OPG positively correlated with greater systolic blood pressure (SBP) values, HOMA-IR and HOMA-β, and with the presence of dyslipidemia and carotid atherosclerosis. The association between greater OPN and OPG levels and SBP was independent from possible confounders (both p = 0.01). CONCLUSIONS Circulating OPN and OPG levels are increased in T2DM patients and identify a particularly unfavourable metabolic profile, mostly expressed by higher SBP. Bone peptides may represent novel markers of vascular stress and accelerated atherosclerosis in diabetes, constituting a possible tool for cardiovascular risk stratification in diabetes.
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Affiliation(s)
- I Barchetta
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - V Ceccarelli
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - F A Cimini
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - L Bertoccini
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - A Fraioli
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - C Alessandri
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - A Lenzi
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - M G Baroni
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - M G Cavallo
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.
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Yu HM, Chen XL, Wei W, Yao XD, Sun JQ, Su XT, Lin SF. Effect of osteoprotegerin gene polymorphisms on the risk of cervical spondylotic myelopathy in a Chinese population. Clin Neurol Neurosurg 2018; 175:149-154. [PMID: 30447607 DOI: 10.1016/j.clineuro.2018.09.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 08/13/2018] [Accepted: 09/05/2018] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction. Our study aims to explore the correlation of osteoprotegerin (OPG) gene polymorphisms and the risk factors and severity of CSM. PATIENTS AND METHODS The peripheral blood samples from 494 CSM patients and 515 healthy individuals were collected for detecting the 950T/C, 1181G/C and 163A/G genotypes and genetic equilibrium of OPG in the CSM and control groups and analyzing the genotype distribution and allele frequency. The severity of CSM and the impaired segments were evaluated by the Japanese Orthopedic Association (JOA) scoring combined with cervical magnetic resonance imaging (MRI), in order to investigate the relations between the three genotypes of OPG promoter gene loci (950T/C, 163A/G and 1181G/C) and occurrence as well as severity of CSM. RESULTS The risk rate of TC genotype carrier suffered from CSM was 0.46, of TT genotype carrier was 0.27. The risk rate of T allele carrier suffered from CSM was 0.37. In 950T/C single nucleotide polymorphism (SNP), patients with TC, TT and T genotypes had lower risk to suffer from CSM. CONCLUSION Taken together, OPG 950T/C SNP protects against CSM, and it is correlated with the severity of CSM, providing a new idea for the prevention and treatment of CSM.
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Affiliation(s)
- Hai-Ming Yu
- Department of Orthopaedics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, PR China.
| | - Xiao-Lei Chen
- Department of Orthopedics, The Second People's Hospital of Henan Province, Zhengzhou, 451191, PR China
| | - Wu Wei
- The First Department of Orthopedics, Wuzhou Red Cross Hospital of Guangxi, Wuzhou, 543002, PR China
| | - Xue-Dong Yao
- Department of Orthopaedics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, PR China
| | - Jing-Qun Sun
- Department of Orthopaedics, The Third Hospital of Xiamen, Xiamen, 361100, PR China
| | - Xiao-Tao Su
- Affiliated NanHua Hospital, University of South China, Hengyang, 421002, PR China
| | - Shu-Feng Lin
- Department of Orthopaedics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, PR China
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21
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García-Gavilán JF, Bulló M, Camacho-Barcia L, Rosique-Esteban N, Hernández-Alonso P, Basora J, Martínez-González MA, Estruch R, Fitó M, Salas-Salvadó J. Higher dietary glycemic index and glycemic load values increase the risk of osteoporotic fracture in the PREvención con DIeta MEDiterránea (PREDIMED)-Reus trial. Am J Clin Nutr 2018; 107:1035-1042. [PMID: 29746627 DOI: 10.1093/ajcn/nqy043] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 02/16/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND High glucose and insulin concentrations seem to have a negative impact on bone health. However, the relation between the dietary glycemic index (DGI) and the dietary glycemic load (DGL), which has proved to be effective at modulating blood glucose concentrations after carbohydrate consumption, has yet to be explored in relation to bone health. OBJECTIVE The aim of the study was to examine the associations between the DGI or DGL and the risk of osteoporotic-related fractures in an elderly Mediterranean population. DESIGN The study was conducted in 870 subjects aged 55-80 y at high cardiovascular disease risk participating in the PREvención con DIeta MEDiterránea (PREDIMED)-Reus study. The DGI and DGL were estimated from validated food-frequency questionnaires with the use of the international glycemic index and glycemic load values, with glucose as reference. Data on osteoporotic fractures were acquired from a systematic review of medical records. We used Cox proportional hazard models to assess the risk of osteoporotic fracture according to tertiles of average DGI and DGL. RESULTS A total of 114 new cases of osteoporotic-related fractures were documented after a mean follow-up of 8.9 y. Participants in the highest tertile of DGI and DGL had a significantly higher risk of osteoporotic fractures than those in the lowest tertile after adjusting for potential confounders (HR: 1.80; 95% CI: 1.03, 3.15 and HR: 3.20; 95% CI: 1.25, 8.18, respectively). CONCLUSIONS A high DGI and DGL are associated with a higher risk of osteoporosis-related fractures in an elderly Mediterranean population at high cardiovascular disease risk. This trial was registered at isrctn.com as ISRCTN35739639.
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Affiliation(s)
- Jesús Francisco García-Gavilán
- Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, University Hospital of Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
| | - Mònica Bulló
- Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, University Hospital of Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
| | - Lucia Camacho-Barcia
- Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, University Hospital of Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
| | - Nuria Rosique-Esteban
- Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, University Hospital of Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
| | - Pablo Hernández-Alonso
- Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, University Hospital of Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Basora
- Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, University Hospital of Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain
| | - Miguel Angel Martínez-González
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
- Medical School, Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
| | - Ramón Estruch
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
- Department of Internal Medicine, August Pi i Sunyer Institute of Biomedical Research (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Montserrat Fitó
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular Risk and Nutrition (Regicor Study Group), Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Jordi Salas-Salvadó
- Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, University Hospital of Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain
- CIBER Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
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22
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Pacifico L, Andreoli GM, D’Avanzo M, De Mitri D, Pierimarchi P. Role of osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand axis in nonalcoholic fatty liver disease. World J Gastroenterol 2018; 24:2073-2082. [PMID: 29785076 PMCID: PMC5960813 DOI: 10.3748/wjg.v24.i19.2073] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/03/2018] [Accepted: 05/11/2018] [Indexed: 02/06/2023] Open
Abstract
Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease (NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome (MetS), like insulin resistance (IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, MetS, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin (OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesity-related comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of MetS as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.
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Affiliation(s)
- Lucia Pacifico
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Gian Marco Andreoli
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Miriam D’Avanzo
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Delia De Mitri
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Pasquale Pierimarchi
- Institute of Translational Pharmacology, National Research Council, Rome 00083, Italy
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