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Luo X, Huang B, Xu P, Wang H, Zhang B, Lin L, Liao J, Hu M, Liu X, Huang J, Fu Y, Kilby MD, Kellems RE, Fan X, Xia Y, Baker PN, Qi H, Tong C. The Placenta Regulates Intrauterine Fetal Growth via Exosomal PPARγ. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2404983. [PMID: 39951006 PMCID: PMC12005745 DOI: 10.1002/advs.202404983] [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: 05/08/2024] [Revised: 12/25/2024] [Indexed: 04/19/2025]
Abstract
Abnormal adipogenesis is a major contributor to fetal growth restriction (FGR) and its associated complications. However, the underlying etiology remains unclear. Here, it is reported that the placentas of women with pregnancies complicated with FGR exhibit peroxisome proliferator-activated receptor γ (PPARγ) inactivation. In mice, trophoblast-specific ablation of murine PPARγ reproduces the phenotype of human fetuses with FGR and defective adipogenesis. Coculture of trophoblasts with preadipocytes significantly improves preadipocyte commitment and differentiation and increases the transcription of a series of adipogenic genes via intercellular transfer of exosomal PPARγ proteins. Moreover, nanoparticle-mediated placenta-specific delivery of rosiglitazone (RGZ) significantly rescues adipogenesis defects in an FGR-induced mouse model. In summary, the placenta is a major reservoir of PPARγ. An insufficient supply of placental PPARγ to fetal preadipocytes via exosomes during late gestation is a major mechanism underlying FGR. Preclinically, placenta-targeted RGZ administration can be a promising interventional therapy for FGR and/or defective intrauterine fat development.
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Affiliation(s)
- Xiaofang Luo
- Reproductive Medicine CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing MunicipalityThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- Ministry of Education International Collaborative Laboratory of Reproduction and DevelopmentChongqing400016China
| | - Biao Huang
- Department of ObstetricsWomen and Children's Hospital of Chongqing Medical UniversityChongqing401147China
| | - Ping Xu
- Department of Biochemistry & Molecular BiologyUniversity of Texas McGovern Medical School at HoustonHoustonTX77030USA
| | - Hao Wang
- Department of ObstetricsWomen and Children's Hospital of Chongqing Medical UniversityChongqing401147China
| | - Baozhen Zhang
- Department of ObstetricsWomen and Children's Hospital of Chongqing Medical UniversityChongqing401147China
| | - Li Lin
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing MunicipalityThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- Ministry of Education International Collaborative Laboratory of Reproduction and DevelopmentChongqing400016China
- Department of ObstetricsWomen and Children's Hospital of Chongqing Medical UniversityChongqing401147China
| | - Jiujiang Liao
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing MunicipalityThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- Ministry of Education International Collaborative Laboratory of Reproduction and DevelopmentChongqing400016China
- Department of ObstetricsWomen and Children's Hospital of Chongqing Medical UniversityChongqing401147China
| | - Mingyu Hu
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing MunicipalityThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- Ministry of Education International Collaborative Laboratory of Reproduction and DevelopmentChongqing400016China
| | - Xiyao Liu
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing MunicipalityThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- Ministry of Education International Collaborative Laboratory of Reproduction and DevelopmentChongqing400016China
| | - Jiayu Huang
- Reproductive Medicine CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Yong Fu
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing MunicipalityThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- Ministry of Education International Collaborative Laboratory of Reproduction and DevelopmentChongqing400016China
| | - Mark D. Kilby
- Institute of Metabolism and System ResearchUniversity of Birmingham, and the Fetal Medicine CentreBirmingham Women's and Children's Foundation TrustEdgbastonB15 2TTUK
| | - Rodney E. Kellems
- Department of ObstetricsWomen and Children's Hospital of Chongqing Medical UniversityChongqing401147China
| | - Xiujun Fan
- Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong518055China
| | - Yang Xia
- Department of ObstetricsWomen and Children's Hospital of Chongqing Medical UniversityChongqing401147China
| | - Philip N. Baker
- College of Life SciencesUniversity of LeicesterLeicesterLE1 7RHUK
| | - Hongbo Qi
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing MunicipalityThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
- Ministry of Education International Collaborative Laboratory of Reproduction and DevelopmentChongqing400016China
| | - Chao Tong
- National Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChildren's Hospital of Chongqing Medical UniversityChongqing401122China
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Psachna S, Chondrogianni ME, Stathopoulos K, Polymeris A, Chatzigeorgiou A, Chronopoulos E, Tournis S, Kassi E. The effect of antidiabetic drugs on bone metabolism: a concise review. Endocrine 2025; 87:907-919. [PMID: 39402366 DOI: 10.1007/s12020-024-04070-1] [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: 04/29/2024] [Accepted: 10/06/2024] [Indexed: 01/06/2025]
Abstract
Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, which derives from either insufficient insulin production [type 1 diabetes mellitus (T1DM)] or both impaired insulin sensitivity along with inadequate insulin production [type 2 diabetes mellitus (T2DM)] and affects millions of people worldwide. In addition to the adverse effects of DM on classical target organs and tissues, skeletal health can also be adversely affected. There is considerable evidence linking DM with osteoporosis. The fracture risk in patients with DM differs upon the type of diabetes, and it appears to be related to the type of anti-diabetic treatment. Antidiabetic drugs may have various effects on bone health. Most of them have neutral or even favorable effects on bone metabolism with the exception of thiazolidinediones (TZDs). Some studies suggest that TZDs may have negative impact on bone health by decreasing bone formation and increasing the fracture risk. There are also limited studies linking the use of canagliflozin, a Sodium-glucose contransporter-2 inhibitor (SGLT2i), with increased fracture risk. On the other hand, therapies that are based on incretin effect, like Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonizts (GLP-1RAs) might have positive effects on bone health by promoting bone formation. Herein we review the impact of antidiabetic drugs on bone health, highlighting the potential benefits and risks associated with these medications in an attempt to contribute to the development of personalized treatment strategies for individuals with DM.
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Affiliation(s)
- Stavroula Psachna
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Department of Endocrinology, Metabolism and Diabetes Mellitus, Attica General Hospital "Sismanoglio-Amalia Fleming", Athens, Greece
| | - Maria Eleni Chondrogianni
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, Medical Scool, National and Kapodistrian University of Athens, Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Stathopoulos
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonis Polymeris
- Department of Endocrinology, Metabolism and Diabetes Mellitus, Attica General Hospital "Sismanoglio-Amalia Fleming", Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Efstathios Chronopoulos
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Symeon Tournis
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, Medical Scool, National and Kapodistrian University of Athens, Athens, Greece.
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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Desai SA, Patel VP, Bhosle KP, Nagare SD, Thombare KC. The tumor microenvironment: shaping cancer progression and treatment response. J Chemother 2025; 37:15-44. [PMID: 38179655 DOI: 10.1080/1120009x.2023.2300224] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/06/2024]
Abstract
The tumor microenvironment (TME) plays a crucial role in cancer progression and treatment response. It comprises a complex network of stromal cells, immune cells, extracellular matrix, and blood vessels, all of which interact with cancer cells and influence tumor behaviour. This review article provides an in-depth examination of the TME, focusing on stromal cells, blood vessels, signaling molecules, and ECM, along with commonly available therapeutic compounds that target these components. Moreover, we explore the TME as a novel strategy for discovering new anti-tumor drugs. The dynamic and adaptive nature of the TME offers opportunities for targeting specific cellular interactions and signaling pathways. We discuss emerging approaches, such as combination therapies that simultaneously target cancer cells and modulate the TME. Finally, we address the challenges and future prospects in targeting the TME. Overcoming drug resistance, improving drug delivery, and identifying new therapeutic targets within the TME are among the challenges discussed. We also highlight the potential of personalized medicine and the integration of emerging technologies, such as immunotherapy and nanotechnology, in TME-targeted therapies. This comprehensive review provides insights into the TME and its therapeutic implications. Understanding the TME's complexity and targeting its components offer promising avenues for the development of novel anti-tumor therapies and improved patient outcomes.
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Affiliation(s)
- Sharav A Desai
- Department of Pharmaceutical Biotechnology, Sanjivani College of Pharmaceutical Education & Research, Kopargaon, India
| | - Vipul P Patel
- Department of Pharmaceutical Biotechnology, Sanjivani College of Pharmaceutical Education & Research, Kopargaon, India
| | - Kunal P Bhosle
- Department of Pharmaceutical Biotechnology, Sanjivani College of Pharmaceutical Education & Research, Kopargaon, India
| | - Sandip D Nagare
- Department of Pharmaceutical Biotechnology, Sanjivani College of Pharmaceutical Education & Research, Kopargaon, India
| | - Kirti C Thombare
- Department of Pharmaceutical Biotechnology, Sanjivani College of Pharmaceutical Education & Research, Kopargaon, India
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Na YJ, Choi KJ, Jung WH, Park SB, Koh B, Hoe KL, Kim KY. Development of 3D Muscle Cell Culture-Based Screening System for Metabolic Syndrome Drug Research. Tissue Eng Part C Methods 2025; 31:53-64. [PMID: 39912898 DOI: 10.1089/ten.tec.2024.0292] [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] [Indexed: 02/07/2025] Open
Abstract
Developing effective drug screening methods for type 2 diabetes requires physiologically relevant models. Traditional 2D cell cultures have limitations in replicating in vivo conditions, leading to challenges in assessing drug efficacy. To overcome these issues, we developed a 3D artificial muscle model that induces insulin resistance, a hallmark of type 2 diabetes. Using C2C12 myoblasts cultured in a scaffold of 1% alginate and 1 mg/mL collagen type 1, we optimized conditions for differentiation and structural stability. Insulin resistance was induced using palmitic acid (PA), and glucose uptake was assessed using the fluorescent glucose analog 2-NBDG. The 3D model demonstrated superior glucose uptake responses compared with 2D cultures, with a threefold increase in insulin-stimulated glucose uptake on days 4 and 8 of differentiation. Induced insulin resistance was observed with 0.1 mM PA, which maintained cell viability and differentiation capacity. The model was validated through comparative drug screening using rosiglitazone and metformin, as well as 165 candidate compounds provided by Korea Chemical Bank. Drug screening revealed that three out of five hit compounds identified in both 2D and 3D models exhibited greater efficacy in 3D cultures, with results consistent with ex vivo assays using mouse soleus muscle. This model closely mimics in vivo conditions, offering a robust platform for type 2 diabetes drug discovery while supporting ethical research practices.
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Affiliation(s)
- Yoon-Ju Na
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
- Department of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea
| | - Kyoung Jin Choi
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
| | - Won Hoon Jung
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
| | - Sung Bum Park
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
| | - Byumseok Koh
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
| | - Kwang-Lae Hoe
- Department of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea
| | - Ki Young Kim
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
- Department of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea
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Huang G, Yin W, Zhao X, Xu M, Wang P, Li R, Zhou L, Tang W, Jiao J. Osteoking inhibits apoptosis of BMSCs in osteoporotic rats via PI3K/AKT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:118961. [PMID: 39653105 DOI: 10.1016/j.jep.2024.118961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 01/04/2025]
Abstract
In China, Osteoking is a commonly used treatment and preventive measure for osteoporosis. The pathophysiology of osteoporosis is closely associated with apoptosis; however, it remains unclear whether the role of Osteoking in promoting bone formation is linked to apoptosis. AIM OF STUDY This study aims to investigate whether Osteoking inhibits apoptosis of BMSCs in osteoporotic rats via the PI3K/AKT signaling pathway and to conduct a detailed exploration of this mechanism. The goal is to provide a theoretical basis for the clinical application of Osteoking in osteoporosis treatment. METHODS A rat model of osteoporosis was established through bilateral ovariectomy (OVX), followed by treatment with Osteoking. After ten weeks of therapy, BMD was evaluated. The biomechanics of the left tibia were measured, the left femur was sequenced, and the right tibia was stained using histomorphometric and Masson's staining methods. Peripheral serum was collected to measure bone-related markers, including E2, PINP, and CTX. RNA-Seq results were verified using the remaining bone samples. Comparative analysis demonstrated the efficacy of Osteoking in treating osteoporosis and provided preliminary insights into the underlying mechanisms. Primary BMSCs were cultured using bone marrow apposition. CCK8 assays were conducted to screen the intervention conditions of Osteoking and LY294002. Various concentrations of Osteoking-containing serum and LY294002 were tested separately to determine the optimal intervention concentration for drug delivery. The impact of Osteoking on lipid formation was also evaluated. Following treatment of BMSCs from OVX rats with Sham serum, OVX serum, OVX + LY294002 serum, and Osteoking + LY294002 serum, the expression of PI3K/AKT/mTOR, osteogenesis-related regulatory factors, and apoptosis-related regulatory factors was assessed. Flow cytometry was employed to evaluate apoptosis in BMSCs. RESULTS Osteoking significantly improved whole-body BMD and bone biomechanical indices in OVX rats. It also significantly elevated the serum levels of E2 and PINP while reducing the level of CTX, which significantly improved bone microstructure and promoted new bone formation. RNA-seq analysis indicated that the therapeutic mechanism involved the PI3K/AKT signaling pathway. Osteoking increased the expression of RUNX2 and decreased the expression of PPAR-γ, a marker of lipogenesis, in OVX rats. Extraction of BMSCs for subsequent studies revealed a significant reduction in proliferation and osteogenic differentiation, along with an increase in lipogenic differentiation, in the OVX group. Osteoking treatment inhibited the expression of PPAR-γ and increased the expression of RUNX2 in BMSCs. Additionally, Osteoking reversed the LY294002-mediated inhibition of PI3K/AKT/mTOR signaling pathway activation, increased the expression of the apoptosis-protecting protein Bcl2, and decreased the expression of apoptosis-associated proteins Caspase3 and Bax. CONCLUSION Osteoking markedly improved bone microstructure, biomechanics, and bone density in OVX rats. Osteoking-containing serum reversed the imbalance in lineage differentiation in OVX rats, characterized by reduced osteogenic differentiation and increased lipid differentiation of BMSCs. Furthermore, Osteoking-containing serum significantly increased BMSC proliferation and prevented apoptosis in OVX rats through the PI3K/AKT signaling pathway.
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Affiliation(s)
- Guijiang Huang
- Department of Science and Education, The First Affiliated Hospital of Kunming Medical University, Kunming, 650600, China; Department of Pharmacy, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650600, China
| | - Wenjie Yin
- Department of Pharmacy, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650600, China
| | - Xin Zhao
- Department of Science and Education, The First Affiliated Hospital of Kunming Medical University, Kunming, 650600, China
| | - Muli Xu
- Kunming Medical University, Kunming, 650600, China
| | - Peijin Wang
- Kunming Medical University, Kunming, 650600, China
| | - Rong Li
- Kunming Medical University, Kunming, 650600, China
| | - Li Zhou
- Department of Pharmacy, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650600, China
| | - Wei Tang
- Department of Science and Education, The First Affiliated Hospital of Kunming Medical University, Kunming, 650600, China.
| | - Jianlin Jiao
- Kunming Medical University, Kunming, 650600, China.
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Wang M, Czernik PJ, Lecka-Czernik B, Xu Y, Hill JW. IGF-1 and insulin receptors in LepRb neurons jointly regulate body growth, bone mass, reproduction, and metabolism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.20.614140. [PMID: 39345425 PMCID: PMC11429997 DOI: 10.1101/2024.09.20.614140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, but whether these functions are mediated via insulin-like growth factor 1 receptor (IGF1R) signaling is unknown. IGF-1 and insulin can bind to each other's receptors, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and simultaneously lacking IGF1R and insulin receptor (IR) in LepRb neurons (IGF1R/IRLepRb mice) and then characterized their body growth, bone morphology, reproductive and metabolic functions. We found that IGF1R and IR in LepRb neurons were required for normal timing of pubertal onset, while IGF1R in LepRb neurons played a predominant role in regulating adult fertility and exerted protective effects against reproductive aging. Accompanying these reproductive deficits, IGF1RLepRb mice and IGF1R/IRLepRb mice had transient growth retardation. Notably, IGF1R in LepRb neurons was indispensable for normal trabecular and cortical bone mass accrual in both sexes. These findings suggest that IGF1R in LepRb neurons is involved in the interaction among body growth, bone development, and reproduction. Though only mild changes in body weight were detected, simultaneous deletion of IGF1R and IR in LepRb neurons caused dramatically increased fat mass composition, decreased lean mass composition, lower energy expenditure, and locomotor activity in both sexes. Male IGF1R/IRLepRb mice exhibited impaired insulin sensitivity. These findings suggest that IGF1R and IR in LepRb neurons jointly regulated body composition, energy balance, and glucose homeostasis. Taken together, our studies identified the sex-dependent complex roles of IGF1R and IR in LepRb neurons in regulating body growth, reproduction, and metabolism.
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Affiliation(s)
- Mengjie Wang
- Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Piotr J Czernik
- Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA
| | - Beata Lecka-Czernik
- Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA
- Department of Orthopedic Surgery, University of Toledo College of Medicine, Toledo, Ohio, USA
| | - Yong Xu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Jennifer W Hill
- Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA
- Department of Obstetrics and Gynecology, University of Toledo College of Medicine, Toledo, Ohio, USA
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Guarnotta V, Emanuele F, Salzillo R, Bonsangue M, Amato C, Mineo MI, Giordano C. Practical therapeutic approach in the management of diabetes mellitus secondary to Cushing's syndrome, acromegaly and neuroendocrine tumours. Front Endocrinol (Lausanne) 2023; 14:1248985. [PMID: 37842314 PMCID: PMC10569460 DOI: 10.3389/fendo.2023.1248985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/28/2023] [Indexed: 10/17/2023] Open
Abstract
Cushing's syndrome, acromegaly and neuroendocrine disorders are characterized by an excess of counterregulatory hormones, able to induce insulin resistance and glucose metabolism disorders at variable degrees and requiring immediate treatment, until patients are ready to undergo surgery. This review focuses on the management of diabetes mellitus in endocrine disorders related to an excess of counterregulatory hormones. Currently, the landscape of approved agents for treatment of diabetes is dynamic and is mainly patient-centred and not glycaemia-centred. In addition, personalized medicine is more and more required to provide a precise approach to the patient's disease. For this reason, we aimed to define a practical therapeutic algorithm for management of diabetes mellitus in patients with glucagonoma, pheochromocytoma, Cushing's syndrome and acromegaly, based on our practical experience and on the physiopathology of the specific endocrine disease taken into account. This document is addressed to all specialists who approach patients with diabetes mellitus secondary to endocrine disorders characterized by an excess of counterregulatory hormones, in order to take better care of these patients. Care and control of diabetes mellitus should be one of the primary goals in patients with an excess of counterregulatory hormones requiring immediate and aggressive treatment.
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Affiliation(s)
| | | | | | | | | | | | - Carla Giordano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Section of Endocrinology, University of Palermo, Piazza delle Cliniche 2, Palermo, Italy
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Bone marrow-derived IGF-1 orchestrates maintenance and regeneration of the adult skeleton. Proc Natl Acad Sci U S A 2023; 120:e2203779120. [PMID: 36577075 PMCID: PMC9910602 DOI: 10.1073/pnas.2203779120] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Insulin-like growth factor I (IGF-1) is a key regulator of tissue growth and development in response to growth hormone stimulation. In the skeletal system, IGF-1 derived from osteoblasts and chondrocytes are essential for normal bone development; however, whether bone marrow (BM)-resident cells provide distinct sources of IGF-1 in the adult skeleton remains elusive. Here, we show that BM stromal cells (BMSCs) and megakaryocytes/platelets (MKs/PLTs) express the highest levels of IGF-1 in adult long bones. Deletion of Igf1 from BMSCs by Lepr-Cre leads to decreased bone formation, impaired bone regeneration, and increased BM adipogenesis. Importantly, reduction of BMSC-derived IGF-1 contributes to fasting-induced marrow fat accumulation. In contrast, deletion of Igf1 from MKs/PLTs by Pf4-Cre leads to reduced bone formation and regeneration without affecting BM adipogenesis. To our surprise, MKs/PLTs are also an important source of systemic IGF-1. Platelet-rich plasma (PRP) from Pf4-Cre; Igf1f/fmice showed compromised osteogenic potential both in vivo and in vitro, suggesting that MK/PLT-derived IGF-1 underlies the therapeutic effects of PRP. Taken together, this study identifies BMSCs and MKs/PLTs as two important sources of IGF-1 that coordinate to maintain and regenerate the adult skeleton, highlighting reciprocal regulation between the hematopoietic and skeletal systems.
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Abstract
Adaptive thermogenesis is a catabolic process that consumes energy-storing molecules and expends that energy as heat in response to environmental changes. This process occurs primarily in brown and beige adipose tissue. Thermogenesis is regulated by many factors, including lipid derived paracrine and endocrine hormones called lipokines. Recently, technologic advances for identifying new lipid biomarkers of thermogenic activity have shed light on a diverse set of lipokines that act through different pathways to regulate energy expenditure. In this review, we highlight a few examples of lipokines that regulate thermogenesis. The biosynthesis, regulation, and effects of the thermogenic lipokines in several families are reviewed, including oloeylethanolamine, endocannabinoids, prostaglandin E2, and 12,13-diHOME. These thermogenic lipokines present potential therapeutic targets to combat states of excess energy storage, such as obesity and related metabolic disorders.
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Affiliation(s)
- Matthew D Lynes
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
| | - Sean D Kodani
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
| | - Yu-Hua Tseng
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
- Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts
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Zhao Q, Yang D, Gao L, Zhao M, He X, Zhu M, Tian C, Liu G, Li L, Hu C. Downregulation of peroxisome proliferator-activated receptor gamma in the placenta correlates to hyperglycemia in offspring at young adulthood after exposure to gestational diabetes mellitus. J Diabetes Investig 2019; 10:499-512. [PMID: 30187673 PMCID: PMC6400209 DOI: 10.1111/jdi.12928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 08/14/2018] [Accepted: 08/28/2018] [Indexed: 01/08/2023] Open
Abstract
AIMS/INTRODUCTION Children who are exposed to gestational diabetes mellitus (GDM) in utero are at high risk of developing related illnesses, such as type 2 diabetes mellitus in young adulthood, but the underlying mechanism and related predictive biomarkers are not known. MATERIALS AND METHODS The present study identified the related biomarkers of hyperglycemia in young adults from the relationship between fetal blood glucose and placental lipid transporters at messenger ribonucleic acid (mRNA) and protein expression levels. We recruited patients from a prospective cohort, and determined the mRNA and protein levels of placental fatty acid transporters. Diet-induced mouse models of GDM were established, and the mRNA and protein levels of the same transporters in placentas were validated. RESULTS Only the mRNA levels of peroxisome proliferator-activated receptor gamma correlated with the levels of neonatal blood glucose in GDM patients using linear regression and Spearman's correlation analyses (r = 0.774, P = 0.001). The mRNA levels of peroxisome proliferator-activated receptor gamma, matrix metalloproteinase-2 and fatty acid transport protein-6 correlated with blood glucose levels in mouse offspring (r = 0.82, P = 0.001, r = 0.737, P = 0.006 and r = -0.891, P = 0.001, respectively) at young adulthood using the same analyses. Notably, we observed significantly higher blood glucose levels in GDM offspring at 12 weeks-of-age compared with the control and rosiglitazone-supplemented groups (P < 0.05). CONCLUSIONS The downregulation of peroxisome proliferator-activated receptor gamma in the placenta might predict hyperglycemia in offspring at young adulthood.
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Affiliation(s)
- Qihong Zhao
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Dong Yang
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Lei Gao
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Mingqiu Zhao
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Xiujie He
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Meng Zhu
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Chaoqing Tian
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Gang Liu
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Li Li
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
| | - Chuanlai Hu
- Department of Nutrition and Food HygieneSchool of Public HealthAnhui Medical UniversityAnhuiHefeiChina
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11
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Hawkes CP, Mostoufi-Moab S. Fat-bone interaction within the bone marrow milieu: Impact on hematopoiesis and systemic energy metabolism. Bone 2019; 119:57-64. [PMID: 29550266 PMCID: PMC6139083 DOI: 10.1016/j.bone.2018.03.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 03/13/2018] [Indexed: 12/23/2022]
Abstract
The relationship between fat, bone and systemic metabolism is a growing area of scientific interest. Marrow adipose tissue is a well-recognized component of the bone marrow milieu and is metabolically distinct from current established subtypes of adipose tissue. Despite recent advances, the functional significance of marrow adipose tissue is still not clearly delineated. Bone and fat cells share a common mesenchymal stem cell (MSC) within the bone marrow, and hormones and transcription factors such as growth hormone, leptin, and peroxisomal proliferator-activated receptor γ influence MSC differentiation into osteoblasts or adipocytes. MSC osteogenic potential is more vulnerable than adipogenic potential to radiation and chemotherapy, and this confers a risk for an abnormal fat-bone axis in survivors following cancer therapy and bone marrow transplantation. This review provides a summary of data from animal and human studies describing the relationship between marrow adipose tissue and hematopoiesis, bone mineral density, bone strength, and metabolic function. The significance of marrow adiposity in other metabolic disorders such as osteoporosis, diabetes mellitus, and estrogen and growth hormone deficiency are also discussed. We conclude that marrow adipose tissue is an active endocrine organ with important metabolic functions contributing to bone energy maintenance, osteogenesis, bone remodeling, and hematopoiesis. Future studies on the metabolic role of marrow adipose tissue may provide the critical insight necessary for selecting targeted therapeutic interventions to improve altered hematopoiesis and augment skeletal remodeling in cancer survivors.
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Affiliation(s)
- C P Hawkes
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, USA
| | - S Mostoufi-Moab
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, USA; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA; Perelman School of Medicine, Department of Pediatrics, University of Pennsylvania, Philadelphia, USA.
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12
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Liu Y, Hu X, Shan X, Chen K, Tang H. Rosiglitazone metformin adduct inhibits hepatocellular carcinoma proliferation via activation of AMPK/p21 pathway. Cancer Cell Int 2019; 19:13. [PMID: 30651718 PMCID: PMC6330460 DOI: 10.1186/s12935-019-0732-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/08/2019] [Indexed: 12/25/2022] Open
Abstract
Background Rosiglitazone metformin adduct (RZM) is a novel compound, synthesized from rosiglitazone (Ros) and metformin (Met) combined at a molar mass ratio of 1:1. Met and Ros are widely used together for treating type 2 diabetes to improve drug effectiveness and reduce adverse drug reactions. Recent studies reported that both Met and Ros may possess antineoplastic properties in several cancers, including hepatocellular carcinoma (HCC). However, the effects of RZM in HCC and its underlying mechanisms remain unknown. Methods RZM was synthesized from Ros and Met at an equal molar ratio and identified by infrared spectroscopy. MTS and colony formation assays were performed to detect proliferative repression of RZM, the mixture, Met and Ros, respectively. Tumorigenesis assay in vivo was used to confirm the anti-tumorigenesis potential of RZM and Met. Moreover, cellular apoptosis caused by RZM was analyzed by hoechst staining assay and flow cytometry. RT-qPCR and western blotting were performed to reveal mechanisms for the function of RZM. Results Both in vitro and in vivo data showed that low doses of RZM enhanced inhibitory effect on HCC cells growth compared with Met. Flow cytometry analysis confirmed that treatment with RZM at 1 mM for 48 h triggered HCC cells apoptosis. RT-qPCR and western blotting analyses showed that p21 was upregulated in response to 1 mM RZM treatment. Furthermore, RZM could increase AMPK activation compared with Met. The increased p21 expression induced by RZM treatment was attenuated by an AMPK inhibitor compound C. Conclusions All these observations demonstrate that RZM increases the antiproliferative effect of Met in HCC via upregulating p21 expression in an AMPK-dependent manner. Our results suggest that RZM has the potential to be an adjuvant for HCC therapy.
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Affiliation(s)
- Yuyang Liu
- 1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016 China
| | - Xiangnan Hu
- 2Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Xuefeng Shan
- 3Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ke Chen
- 1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016 China
| | - Hua Tang
- 1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016 China
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13
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Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomed Pharmacother 2018; 109:1593-1601. [PMID: 30551413 DOI: 10.1016/j.biopha.2018.11.032] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 11/05/2018] [Accepted: 11/07/2018] [Indexed: 01/15/2023] Open
Abstract
The prevalence of diabetes mellitus especially type 2 diabetes mellitus is increasing all over the world. In addition to cardiomyopathy and nephropathy, diabetics are at higher risk of mortality and morbidity due to greater risk of bone fractures and skeletal abnormalities. Patients with diabetes mellitus have lower bone quality in comparison to their non-diabetic counterparts mainly because of hyperglycemia, toxic effects of advanced glycosylation end-products (AGEs) on bone tissue, and impaired bone microvascular system. AGEs may also contribute to the development of osteoarthritis further to osteoporosis. Therefore, glycemic control in diabetic patients is vital for bone health. Metformin, a widely used antidiabetic drug, has been shown to improve bone quality and decrease the risk of fractures in patients with diabetes in addition to glycemic control and improving insulin sensitivity. AMP activated protein kinase (AMPK), the key molecule in metformin antidiabetic mechanism of action, is also effective in signaling pathways involved in bone physiology. This review, discusses the molecules linking diabetes and bone turnover, role of AMPK in bone metabolism, and the effect of metformin as an activator of AMPK on bone disorders and malignancies.
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14
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Stolarczyk A, Sarzyńska S, Gondek A, Cudnoch-Jędrzejewska A. Influence of diabetes on tissue healing in orthopaedic injuries. Clin Exp Pharmacol Physiol 2018; 45:619-627. [PMID: 29570835 DOI: 10.1111/1440-1681.12939] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 02/15/2018] [Accepted: 03/12/2018] [Indexed: 12/22/2022]
Abstract
Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from the defective action or secretion of insulin. Chronic hyperglycaemia can lead to the damage, dysfunction and failure of various organs. In the context of complications of healing and orthopaedic rehabilitation, vascular (microangiopathy) and nerve (neuropathy) disorders deserve particular attention. About 12% of the patients admitted to orthopaedic departments have diabetes. Studies indicate that there is an indisputable link between diabetes and: an increased risk of fractures, the difficult healing of injuries of bones, ligaments and musculotendinous. It appears that one of the main reasons for this is non-enzymatic glycosylation (glycation) of collagen molecules, a phenomenon observed in the elderly and diabetic populations, as it leads to the formation of advanced glycation end products (AGEs). Collagen is one of the major connective tissue components, and is therefore part of ligaments, tendons and bones. AGEs affect the weakening of its structure and biomechanical properties, and thus also affects the weakening of the structure and properties of the above-mentioned tissues. The aim of the study is to undertake an overview of the current knowledge of the impact of diabetes on the risk of some injuries and subsequent healing and rehabilitation of patients following orthopaedic injuries.
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Affiliation(s)
- Artur Stolarczyk
- Department of Clinical Rehabilitation, Second Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Sylwia Sarzyńska
- Department of Orthopaedics and Traumatology, Medical University of Warsaw, Warsaw, Poland
| | - Agata Gondek
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Cudnoch-Jędrzejewska
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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15
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Ponti F, Guerri S, Sassi C, Battista G, Guglielmi G, Bazzocchi A. Imaging of diabetic bone. Endocrine 2017; 58:426-441. [PMID: 28293856 DOI: 10.1007/s12020-017-1278-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 02/24/2017] [Indexed: 01/02/2023]
Abstract
Diabetes is an important concern in terms of medical and socioeconomic costs; a high risk for low-trauma fractures has been reported in patients with both type 1 and type 2 diabetes. The mechanism involved in the increased fracture risk from diabetes is highly complex and still not entirely understood; obesity could play an important role: recent evidence suggests that the influence of fat on bone is mainly dependent on the pattern of regional fat deposition and that an increased amount of visceral adipose tissue negatively affects skeletal health.Correct and timely individuation of people with high fracture risk is critical for both prevention and treatment: Dual-energy X-ray Absorptiometry (currently the "gold standard" for diagnosis of osteoporosis) underestimates fracture risk in diabetic patients and therefore is not sufficient by itself to investigate bone status. This paper is focused on imaging, covering different modalities involved in the evaluation of skeletal deterioration in diabetes, discussing the limitations of conventional methods and exploring the potential of new tools and recent high-resolution techniques, with the intent to provide interesting insight into pathophysiology and fracture risk.
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Affiliation(s)
- Federico Ponti
- Diagnostic and Interventional Radiology, The "Rizzoli" Orthopaedic Institute, Via G. C. Pupilli 1, 40136, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Division of Radiology S.Orsola-Malpighi Hospital, University of Bologna, Via G. Massarenti 9, 40138, Bologna, Italy
| | - Sara Guerri
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Division of Radiology S.Orsola-Malpighi Hospital, University of Bologna, Via G. Massarenti 9, 40138, Bologna, Italy
| | - Claudia Sassi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Division of Radiology S.Orsola-Malpighi Hospital, University of Bologna, Via G. Massarenti 9, 40138, Bologna, Italy
| | - Giuseppe Battista
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Division of Radiology S.Orsola-Malpighi Hospital, University of Bologna, Via G. Massarenti 9, 40138, Bologna, Italy
| | - Giuseppe Guglielmi
- Department of Radiology, University of Foggia, Viale Luigi Pinto 1, 71100, Foggia, Italy
- Department of Radiology, Scientific Institute "Casa Sollievo della Sofferenza" Hospital, Viale Cappuccini 1, 71013, San Giovanni Rotondo, Foggia, Italy
| | - Alberto Bazzocchi
- Diagnostic and Interventional Radiology, The "Rizzoli" Orthopaedic Institute, Via G. C. Pupilli 1, 40136, Bologna, Italy.
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16
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Watts NB. Adverse bone effects of medications used to treat non-skeletal disorders. Osteoporos Int 2017; 28:2741-2746. [PMID: 28752332 DOI: 10.1007/s00198-017-4171-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 07/20/2017] [Indexed: 12/11/2022]
Abstract
There is a growing list of medications used to treat non-skeletal disorders that cause bone loss and/or increase fracture risk. This review discusses glucocorticoids, drugs that reduce sex steroids, antidiabetic agents, acid-reducing drugs, selective serotonin reuptake inhibitors, and heparin. A number of drugs are known to cause bone loss, increase fracture risk, or both. These drugs should be used in the lowest dose necessary to achieve the desired benefit and for the shortest time necessary, but in many cases, long-term treatment is required. Effective countermeasures are available for some.
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Affiliation(s)
- N B Watts
- Mercy Health Osteoporosis and Bone Health Services, 4760 E. Galbraith Rd., Suite 212, Cincinnati, OH, 45236, USA.
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17
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Davidson MA, Mattison DR, Azoulay L, Krewski D. Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future. Crit Rev Toxicol 2017; 48:52-108. [PMID: 28816105 DOI: 10.1080/10408444.2017.1351420] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.
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Affiliation(s)
- Melissa A Davidson
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada
| | - Donald R Mattison
- b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada
| | - Laurent Azoulay
- d Center for Clinical Epidemiology , Lady Davis Research Institute, Jewish General Hospital , Montreal , Canada.,e Department of Oncology , McGill University , Montreal , Canada
| | - Daniel Krewski
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada.,f Faculty of Medicine , University of Ottawa , Ottawa , Canada
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18
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Lindsey RC, Mohan S. Thyroid hormone acting via TRβ induces expression of browning genes in mouse bone marrow adipose tissue. Endocrine 2017; 56:109-120. [PMID: 28229360 PMCID: PMC8745377 DOI: 10.1007/s12020-017-1265-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 02/10/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE Mutant hypothyroid mouse models have recently shown that thyroid hormone is critical for skeletal development during an important prepubertal growth period. Additionally, thyroid hormone negatively regulates total body fat, consistent with the well-established effects of thyroid hormone on energy and fat metabolism. Since bone marrow mesenchymal stromal cells differentiate into both adipocytes and osteoblasts and a relationship between bone marrow adipogenesis and osteogenesis has been predicted, we hypothesized thyroid hormone deficiency during the postnatal growth period increases marrow adiposity in mice. METHODS Marrow adiposity in TH-deficient (Tshr -/-) mice treated with T3/T4, TH receptor β-specific agonist GC-1, or vehicle control was evaluated via dual-energy X-ray absorptiometry and osmium micro-computed tomography. To further examine the mechanism for thyroid hormone regulation of marrow adiposity, we used real-time RT-PCR to measure the effects of thyroid hormone on adipocyte differentiation markers in primary mouse bone marrow mesenchymal stromal cells and two mouse cell lines in vitro and in Tshr -/- mice in vivo. RESULTS Marrow adiposity increased >20% (P < 0.01) in Tshr -/- mice at 3 weeks of age, and treatment with T3/T4 when serum thyroid hormone normally increases (day 5-14) rescued this phenotype. Furthermore, GC-1 rescued this phenotype equally well, suggesting this thyroid hormone effect is in part mediated via TRβ signaling. Treatment of bone marrow mesenchymal stromal or ST2 cells with T3 or GC-1 significantly increased expression of several brown/beige fat markers. Moreover, injection of T3/T4 increased browning-specific markers in white fat of Tshr -/- mice. CONCLUSIONS These data suggest that thyroid hormone regulation of marrow adiposity is mediated at least in part via activation of TRβ signaling.
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Affiliation(s)
- Richard C Lindsey
- Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA
- Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
- Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Subburaman Mohan
- Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA.
- Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
- Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
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19
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Wan X, Wang S, Xu J, Zhuang L, Xing K, Zhang M, Zhu X, Wang L, Gao P, Xi Q, Sun J, Zhang Y, Li T, Shu G, Jiang Q. Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation. PLoS One 2017; 12:e0173174. [PMID: 28257428 PMCID: PMC5336265 DOI: 10.1371/journal.pone.0173174] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 02/16/2017] [Indexed: 02/07/2023] Open
Abstract
Dietary protein or amino acid (AA) is a crucial nutritional factor to regulate hepatic insulin-like growth factor-1 (IGF-1) expression and secretion. However, the underlying intracellular mechanism by which dietary protein or AA induces IGF-1 expression remains unknown. We compared the IGF-1 gene expression and plasma IGF-1 level of pigs fed with normal crude protein (CP, 20%) and low-protein levels (LP, 14%). RNA sequencing (RNA-seq) was performed to detect transcript expression in the liver in response to dietary protein. The results showed that serum concentrations and mRNA levels of IGF-1 in the liver were higher in the CP group than in the LP group. RNA-seq analysis identified a total of 1319 differentially expressed transcripts (667 upregulated and 652 downregulated), among which the terms “oxidative phosphorylation”, “ribosome”, “gap junction”, “PPAR signaling pathway”, and “focal adhesion” were enriched. In addition, the porcine primary hepatocyte and HepG2 cell models also demonstrated that the mRNA and protein levels of IGF-1 and PPARγ increased with the increasing AA concentration in the culture. The PPARγ activator troglitazone increased IGF-1 gene expression and secretion in a dose dependent manner. Furthermore, inhibition of PPARγ effectively reversed the effects of the high AA concentration on the mRNA expression of IGF-1 and IGFBP-1 in HepG2 cells. Moreover, the protein levels of IGF-1 and PPARγ, as well as the phosphorylation of mTOR, significantly increased in HepG2 cells under high AA concentrations. mTOR phosphorylation can be decreased by the mTOR antagonist, rapamycin. The immunoprecipitation results also showed that high AA concentrations significantly increased the interaction of mTOR and PPARγ. In summary, PPARγ plays an important role in the regulation of IGF-1 secretion and gene expression in response to dietary protein.
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Affiliation(s)
- Xiaojuan Wan
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Songbo Wang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Jingren Xu
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Lu Zhuang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Kongping Xing
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Mengyuan Zhang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Xiaotong Zhu
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Lina Wang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Ping Gao
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Qianyun Xi
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Jiajie Sun
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Yongliang Zhang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Tiejun Li
- Key Laboratory of Subtropical Agro-ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, PR China
| | - Gang Shu
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Qingyan Jiang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
- * E-mail:
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20
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Abstract
Diabetes be it type 1 or type 2 is associated with an increased risk of fragility fractures. The mechanisms underlying this increased risk are just being elucidated. Anti-diabetes medications are crucial for maintaining glucose control and for preventing micro- and macrovascular complications in diabetes. However, they may modulate fracture risk in diabetes in different ways. Thiazolidinediones have demonstrated an unfavorable effect on the skeleton, while metformin and sulfonylureas may have a neutral if not beneficial effect on bone. The use of insulin has been associated with an increased risk of fragility fractures though it is not clear whether it is due to direct influence of insulin or whether it is mediated through hypoglycemia and increased falls risk. The overall effect of incretin mimetics appears to be beneficial; however, this has to be elucidated further. The bone effects of pramlintide, a synthetic analog of amylin, have not been explored fully. Finally, issues regarding bone safety of SGLT2 (sodium-dependent glucose transporter 2) inhibitors, the newest anti-diabetic medications on the market are of concern. The purpose of this review is to provide a comprehensive overview of the effect of these medications on bone metabolism and the studies exploring the risk or lack thereof of these medications on bone loss and fragility fractures.
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Affiliation(s)
- Manju Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, ACADEMIA, 20 College Road, Singapore, 169856, Singapore.
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21
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Chen SC, Brooks R, Houskeeper J, Bremner SK, Dunlop J, Viollet B, Logan PJ, Salt IP, Ahmed SF, Yarwood SJ. Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. Mol Cell Endocrinol 2017; 440:57-68. [PMID: 27856330 PMCID: PMC5228588 DOI: 10.1016/j.mce.2016.11.011] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 11/11/2016] [Accepted: 11/12/2016] [Indexed: 02/08/2023]
Abstract
People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARγ, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPβ, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context.
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Affiliation(s)
- Suet Ching Chen
- The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK; Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK
| | - Rebecca Brooks
- The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK
| | - Jessica Houskeeper
- Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK
| | - Shaun K Bremner
- Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK
| | - Julia Dunlop
- Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK
| | - Benoit Viollet
- INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France
| | - Pamela J Logan
- Institute of Cardiovascular and Medical Sciences, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK
| | - Ian P Salt
- Institute of Cardiovascular and Medical Sciences, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK
| | - S Faisal Ahmed
- The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK
| | - Stephen J Yarwood
- Institute of Biological Chemistry, Biophysics and Bioengineering, Edinburgh Campus, Heriot-Watt University, Edinburgh EH14 4AS, UK.
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22
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Marín-Peñalver JJ, Martín-Timón I, Sevillano-Collantes C, del Cañizo-Gómez FJ. Update on the treatment of type 2 diabetes mellitus. World J Diabetes 2016; 7:354-95. [PMID: 27660695 PMCID: PMC5027002 DOI: 10.4239/wjd.v7.i17.354] [Citation(s) in RCA: 366] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/02/2016] [Accepted: 07/20/2016] [Indexed: 02/05/2023] Open
Abstract
To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.
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Iosef Husted C, Valencik M. Insulin-like growth factors and their potential role in cardiac epigenetics. J Cell Mol Med 2016; 20:1589-602. [PMID: 27061217 PMCID: PMC4956935 DOI: 10.1111/jcmm.12845] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/24/2016] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular disease (CVD) constitutes a major public health threat worldwide, accounting for 17.3 million deaths annually. Heart disease and stroke account for the majority of healthcare costs in the developed world. While much has been accomplished in understanding the pathophysiology, molecular biology and genetics underlying the diagnosis and treatment of CVD, we know less about the role of epigenetics and their molecular determinants. The impact of environmental changes and epigenetics in CVD is now emerging as critically important in understanding the origin of disease and the development of new therapeutic approaches to prevention and treatment. This review focuses on the emerging role of epigenetics mediated by insulin like-growth factors-I and -II in major CVDs such as heart failure, cardiac hypertrophy and diabetes.
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Affiliation(s)
- Cristiana Iosef Husted
- Department of Pharmacology, University of Nevada, Reno School of Medicine (UNSOM), Reno, NV, USA
| | - Maria Valencik
- Department of Pharmacology, University of Nevada, Reno School of Medicine (UNSOM), Reno, NV, USA
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24
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The role of bone marrow adipocytes in bone metastasis. J Bone Oncol 2016; 5:121-123. [PMID: 27761371 PMCID: PMC5063230 DOI: 10.1016/j.jbo.2016.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 03/04/2016] [Accepted: 03/07/2016] [Indexed: 11/22/2022] Open
Abstract
Adipocytes are a significant component of the bone marrow microenvironment. Although bone marrow adipocytes were first identified more than 100 years ago, it is only in recent years that an understanding of their complex physiological role is emerging. Bone marrow adipocytes act as local regulators of skeletal biology and homeostasis, with recent studies suggesting that marrow adipose tissue is metabolically active, and can function as an endocrine organ. As such, bone marrow adipocytes have the potential to interact with tumour cells, influencing both tumour growth and bone disease. This review discusses the current evidence for the role of bone marrow adipocytes in tumour growth within the bone marrow microenvironment and the development of the associated bone disease.
Bone marrow adipocytes are a metabolically active source of lipids and adipokines. Marrow adipocytes increase with age, but their role in bone metastasis is ill-defined. Marrow adipocytes have tumour-promoting and -suppressive effects in bone metastasis.
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25
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Morris EV, Edwards CM. Bone Marrow Adipose Tissue: A New Player in Cancer Metastasis to Bone. Front Endocrinol (Lausanne) 2016; 7:90. [PMID: 27471491 PMCID: PMC4943927 DOI: 10.3389/fendo.2016.00090] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 06/29/2016] [Indexed: 01/02/2023] Open
Abstract
The bone marrow is a favored site for a number of cancers, including the hematological malignancy multiple myeloma, and metastasis of breast and prostate cancer. This specialized microenvironment is highly supportive, not only for tumor growth and survival but also for the development of an associated destructive cancer-induced bone disease. The interactions between tumor cells, osteoclasts and osteoblasts are well documented. By contrast, despite occupying a significant proportion of the bone marrow, the importance of bone marrow adipose tissue is only just emerging. The ability of bone marrow adipocytes to regulate skeletal biology and hematopoiesis, combined with their metabolic activity, endocrine functions, and proximity to tumor cells means that they are ideally placed to impact both tumor growth and bone disease. This review discusses the recent advances in our understanding of how marrow adipose tissue contributes to bone metastasis and cancer-induced bone disease.
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Affiliation(s)
- Emma V. Morris
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Claire M. Edwards
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- *Correspondence: Claire M. Edwards,
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26
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Meier C, Schwartz AV, Egger A, Lecka-Czernik B. Effects of diabetes drugs on the skeleton. Bone 2016; 82:93-100. [PMID: 25913633 DOI: 10.1016/j.bone.2015.04.026] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 04/13/2015] [Accepted: 04/16/2015] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes is associated with increased fracture risk and the mechanisms underlying the detrimental effects of diabetes on skeletal health are only partially understood. Antidiabetic drugs are indispensable for glycemic control in most type 2 diabetics, however, they may, at least in part, modulate fracture risk in exposed patients. Preclinical and clinical data clearly demonstrate an unfavorable effect of thiazolidinediones on the skeleton with impaired osteoblast function and activated osteoclastogenesis. The negative effect of thiazolidinediones on osteoblastogenesis includes decreased activity of osteoblast-specific transcription factors (e.g. Runx2, Dlx5, osterix) and decreased activity of osteoblast-specific signaling pathways (e.g. Wnt, TGF-β/BMP, IGF-1). In contrast, metformin has a positive effect on osteoblast differentiation due to increased activity of Runx2 via the AMPK/USF-1/SHP regulatory cascade resulting in a neutral or potentially protective effect on bone. Recently marketed antidiabetic drugs include incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2)-inhibitors. Preclinical studies indicate that incretins (GIP, GLP-1, and GLP-2) play an important role in the regulation of bone turnover. Clinical safety data are limited, however, meta-analyses of trials investigating the glycemic-lowering effect of both, GLP-1 receptor agonists and DPP4-inhibitors, suggest a neutral effect of incretin-based therapies on fracture risk. For SGLT2-inhibitors recent data indicate that due to their mode of action they may alter calcium and phosphate homeostasis (secondary hyperparathyroidism induced by increased phosphate reabsorption) and thereby potentially affect bone mass and fracture risk. Clinical studies are needed to elucidate the effect of SGLT2-inhibitors on bone metabolism. Meanwhile SGLT2-inhibitors should be used with caution in patients with high fracture risk, which is specifically true for the use of thiazolidinediones.
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Affiliation(s)
- Christian Meier
- Division of Endocrinology, Diabetes and Metabolism, University Hospital, Basel, Switzerland.
| | - Ann V Schwartz
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
| | - Andrea Egger
- Division of Endocrinology, Diabetes and Metabolism, University Hospital, Basel, Switzerland
| | - Beata Lecka-Czernik
- Department of Orthopedic Surgery, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, OH, USA; Department of Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, OH, USA
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Effects of Thiazolidinediones on metabolism and cancer: Relative influence of PPARγ and IGF-1 signaling. Eur J Pharmacol 2015; 768:217-25. [DOI: 10.1016/j.ejphar.2015.10.057] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 10/13/2015] [Accepted: 10/30/2015] [Indexed: 12/31/2022]
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Palermo A, D'Onofrio L, Eastell R, Schwartz AV, Pozzilli P, Napoli N. Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int 2015; 26:2073-89. [PMID: 25910746 DOI: 10.1007/s00198-015-3123-0] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 03/24/2015] [Indexed: 12/16/2022]
Abstract
Fracture risk is higher in older adults with type 2 diabetes and may be influenced by treatments for diabetes. Oral anti-diabetic drugs have different effects on bone metabolism. The purpose of this review is to describe the effects of these drugs on bone metabolism and fracture risk. Osteoporosis is a progressive skeletal disorder that is characterized by compromised bone strength and increased risk of fracture. This condition has become an important global health problem, affecting approximately 200 million people worldwide. Another chronic and highly prevalent condition is diabetes mellitus, which affects more than 380 million people; both type 1 and type 2 diabetes are risk factors for fracture. Type 2 diabetes, in particular, is associated with impaired bone strength, although it is characterized by normal or elevated bone mineral density. Several therapeutic strategies are available to achieve the best outcomes in the management of diabetes mellitus but these have different effects on bone metabolism. The purpose of this narrative review is to describe the effects of oral hypoglycemic agents (metformin, sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-dependent glucose transporter 2 inhibitors) on bone metabolism and on the risk of developing fragility fractures in patients with type 2 diabetes. Both diabetes and osteoporosis represent a significant burden in terms of healthcare costs and quality of life. It is very important to choose therapies for diabetes that ensure good metabolic control whilst preserving skeletal health.
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Affiliation(s)
- A Palermo
- Department of Endocrinology and Diabetes, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21-00128, Rome, Italy
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Thiazolidinediones Inhibit Mouse Osteoblastic MC3T3-E1 Cell Proliferation in Part Through the Wnt Signaling Pathway. J Investig Med 2015; 63:758-64. [DOI: 10.1097/jim.0000000000000191] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Obesity and osteoporosis are two of the most common chronic disorders of the 21st century. Both are accompanied by significant morbidity. The only place in the mammalian organism where bone and fat lie adjacent to each other is in the bone marrow. Marrow adipose tissue is a dynamic depot that probably exists as both constitutive and regulated compartments. Adipocytes secrete cytokines and adipokines that either stimulate or inhibit adjacent osteoblasts. The relationship of marrow adipose tissue to other fat depots is complex and might play very distinct parts in modulation of metabolic homoeostasis, haemopoiesis, and osteogenesis. Understanding of the relationship between bone and fat cells that arise from the same progenitor within the bone marrow niche provides insight into the pathophysiology of age-related osteoporosis, diabetes, and obesity.
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Affiliation(s)
| | - Clifford J Rosen
- Maine Medical Center Research Institute, Scarborough, ME 04074, USA
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31
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Kim SY, Kim MS, Lee MK, Kim JS, Yi HK, Nam SY, Lee DY, Hwang PH. PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells. ACTA ACUST UNITED AC 2015; 48:226-33. [PMID: 25590353 PMCID: PMC4381942 DOI: 10.1590/1414-431x20144212] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Accepted: 10/13/2014] [Indexed: 12/23/2022]
Abstract
Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated
transcriptional factor involved in the carcinogenesis of various cancers.
Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor
suppressor gene that has anti-apoptotic activity. The purpose of this study was to
investigate the anticancer mechanism of PPARγ with respect to
IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells
using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed
exhibited growth inhibition, induction of apoptosis, and a significant increase in
IGFBP-3 expression. We investigated the underlying molecular
mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter
system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells,
suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its
expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity
was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795).
This suggests that the critical PPARγ-response region is located within the
p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in
PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53
expression. Taken together, these data suggest that PPARγ exhibits its anticancer
effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor
suppressor.
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Affiliation(s)
- S Y Kim
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - M S Kim
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - M K Lee
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - J S Kim
- Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju, Korea
| | - H K Yi
- Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju, Korea
| | - S Y Nam
- Department of Alternative Therapy, Jeonju University, Jeonju, Korea
| | - D Y Lee
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - P H Hwang
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
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Abstract
In this review, we will first discuss the concept of bone strength and introduce how fat at different locations, including the bone marrow, directly or indirectly regulates bone turnover. We will then review the current literature supporting the mechanistic relationship between marrow fat and bone and our understanding of the relationship between body fat, body weight, and bone with emphasis on its hormonal regulation. Finally, we will briefly discuss the importance and challenges of accurately measuring the fat compartments using non-invasive methods. This review highlights the complex relationship between fat and bone and how these new concepts will impact our diagnostic and therapeutic approaches in the very near future.
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Affiliation(s)
- Richard Kremer
- McGill University, Montreal, QC, Canada
- *Correspondence: Richard Kremer,
| | - Vicente Gilsanz
- Children’s Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
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Abstract
Osteoporosis is a skeletal disease characterized by decreased bone mass and microarchitectural changes in bone tissue that increase the susceptibility to fracture. Secondary osteoporosis is loosely defined as low bone mineral density or increased risk of fragility fracture caused by any factor other than aging or postmenopausal status. The purpose of this review is to discuss the current understanding of the pathophysiology and contribution to fracture risk of many of the more common causes of secondary osteoporosis, as well as diagnostic considerations, outlined by organ system. While not comprehensive, included are a wide array of diseases, conditions, and medications that have been associated with bone loss and susceptibility to fractures. The hope is to highlight the importance to the general clinician of screening for and treating the osteoporosis in these patients, so to limit the resultant increased morbidity associated with fractures.
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Affiliation(s)
- Gregory R Emkey
- Pennsylvania Regional Center for Arthritis & Osteoporosis Research, 1200 Broadcasting Road, Suite 200, Wyomissing, PA 19610, USA.
| | - Sol Epstein
- Mt Sinai School of Medicine, I Gustave Levy Place New York, New York, NY, USA
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Bonnet N, Somm E, Rosen CJ. Diet and gene interactions influence the skeletal response to polyunsaturated fatty acids. Bone 2014; 68:100-7. [PMID: 25088402 PMCID: PMC4266596 DOI: 10.1016/j.bone.2014.07.024] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 07/09/2014] [Accepted: 07/22/2014] [Indexed: 11/16/2022]
Abstract
Diets rich in omega-3s have been thought to prevent both obesity and osteoporosis. However, conflicting findings are reported, probably as a result of gene by nutritional interactions. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor that improves insulin sensitivity but causes weight gain and bone loss. Fish oil is a natural agonist for PPARγ and thus may exert its actions through the PPARγ pathway. We examined the role of PPARγ in body composition changes induced by a fish or safflower oil diet using two strains of C57BL/6J (B6); i.e. B6.C3H-6T (6T) congenic mice created by backcrossing a small locus on Chr 6 from C3H carrying 'gain of function' polymorphisms in the Pparγ gene onto a B6 background, and C57BL/6J mice. After 9months of feeding both diets to female mice, body weight, percent fat and leptin levels were less in mice fed the fish oil vs those fed safflower oil, independent of genotype. At the skeletal level, fish oil preserved vertebral bone mineral density (BMD) and microstructure in B6 but not in 6T mice. Moreover, fish oil consumption was associated with an increase in bone marrow adiposity and a decrease in BMD, cortical thickness, ultimate force and plastic energy in femur of the 6T but not the B6 mice. These effects paralleled an increase in adipogenic inflammatory and resorption markers in 6T but not B6. Thus, compared to safflower oil, fish oil (high ratio omega-3/-6) prevents weight gain, bone loss, and changes in trabecular microarchitecture in the spine with age. These beneficial effects are absent in mice with polymorphisms in the Pparγ gene (6T), supporting the tenet that the actions of n-3 fatty acids on bone microstructure are likely to be genotype dependent. Thus caution must be used in interpreting dietary intervention trials with skeletal endpoints in mice and in humans.
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MESH Headings
- Adipose Tissue, Brown/anatomy & histology
- Adipose Tissue, Brown/drug effects
- Adipose Tissue, Brown/metabolism
- Adipose Tissue, White/anatomy & histology
- Adipose Tissue, White/drug effects
- Adipose Tissue, White/metabolism
- Adiposity/drug effects
- Adiposity/physiology
- Animals
- Biomarkers/metabolism
- Biomechanical Phenomena/drug effects
- Body Composition/drug effects
- Bone Density/drug effects
- Bone Marrow/drug effects
- Bone Marrow/physiology
- Bone and Bones/drug effects
- Bone and Bones/metabolism
- Cell Count
- Diet
- Dietary Supplements
- Fatty Acids, Omega-3/pharmacology
- Fatty Acids, Omega-6/pharmacology
- Female
- Femur/anatomy & histology
- Femur/drug effects
- Femur/physiology
- Fish Oils/pharmacology
- Gene Expression Regulation/drug effects
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Organ Size/drug effects
- Osteoclasts/cytology
- Osteoclasts/drug effects
- Spine/anatomy & histology
- Spine/drug effects
- Spine/physiology
- Tibia/anatomy & histology
- Tibia/drug effects
- Tibia/physiology
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Affiliation(s)
- Nicolas Bonnet
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital & Faculty of Medicine, Geneva 14, Switzerland.
| | - Emmanuel Somm
- Service of Endocrinology, Diabetology, and Metabolism, Centre Hospitalier Universitaire Vaudois/Department of Physiology, Lausanne CH-1005, Switzerland; Division of Development and Growth, Department of Paediatrics, University of Geneva School of Medicine, 1211 Geneva 14, Switzerland
| | - Clifford J Rosen
- Maine Medical Center Research Institute, Scarborough, ME 04074, USA
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Jöhrer K, Ploner C, Thangavadivel S, Wuggenig P, Greil R. Adipocyte-derived players in hematologic tumors: useful novel targets? Expert Opin Biol Ther 2014; 15:61-77. [PMID: 25308972 DOI: 10.1517/14712598.2015.970632] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Adipocytes and their products play essential roles in tumor establishment and progression. As the main cellular component of the bone marrow, adipocytes may contribute to the development of hematologic tumors. AREAS COVERED This review summarizes experimental data on adipocytes and their interaction with various cancer cells. Special focus is set on the interactions of bone marrow adipocytes and normal and transformed cells of the hematopoietic system such as myeloma and leukemia cells. Current in vitro and in vivo data are summarized and the potential of novel therapeutic targets is critically discussed. EXPERT OPINION Targeting lipid metabolism of cancer cells and adipocytes in combination with standard therapeutics might open novel therapeutic avenues in these cancer entities. Adipocyte-derived products such as free fatty acids and specific adipokines such as adiponectin may be vital anti-cancer targets in hematologic malignancies. However, available data on lipid metabolism is currently mostly referring to peripheral fat cell/cancer cell interactions and results need to be evaluated specifically for the bone marrow niche.
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Affiliation(s)
- Karin Jöhrer
- Tyrolean Cancer Research Institute , Innrain 66, 6020 Innsbruck , Austria
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RUI MINGZHONG, HUANG ZHANPING, LIU YING, WANG ZIYAN, LIU RUI, FU JINXIANG, HUANG HAIWEN. Rosiglitazone suppresses angiogenesis in multiple myeloma via downregulation of hypoxia-inducible factor-1α and insulin-like growth factor-1 mRNA expression. Mol Med Rep 2014; 10:2137-43. [DOI: 10.3892/mmr.2014.2407] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 04/14/2014] [Indexed: 11/06/2022] Open
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Correlation of Circulating Acid-Labile Subunit Levels with Insulin Sensitivity and Serum LDL Cholesterol in Patients with Type 2 Diabetes: Findings from a Prospective Study with Rosiglitazone. PPAR Res 2014; 2014:917823. [PMID: 24966876 PMCID: PMC4055636 DOI: 10.1155/2014/917823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Revised: 04/15/2014] [Accepted: 04/29/2014] [Indexed: 12/26/2022] Open
Abstract
Silencing of acid-labile subunit (ALS) improved glucose metabolism in animal models. The aim of this study is to evaluate the effects of rosiglitazone (RSG) on ALS levels in individuals with type 2 diabetes. A randomized, double-blind, placebo-controlled trial was conducted. Subjects with type 2 diabetes mellitus were randomly distributed to an RSG-treated (n = 30) or a placebo (n = 31) group. Patients were evaluated prior to treatment at baseline and at 12 and 24 weeks after treatment. At baseline, ALS levels were negatively associated with low-density lipoprotein cholesterol (LDLc) levels and homeostatic model assessment version 2 insulin sensitivity (HOMA2-%S). Over 24 weeks, there was a significantly greater reduction in ALS levels in the nonobese RSG-treated individuals than placebo-treated group. The effect of RSG on ALS was not significant in obese individuals. Fasting plasma glucose and hemoglobin A1c were reduced, but total cholesterol and LDLc were increased, in patients on RSG. Change in ALS levels predicted changes in total cholesterol and HOMA2-%S over time. This study suggested a BMI-dependent effect of RSG treatment on ALS levels. Reduction of ALS by RSG increases the risk of atherosclerosis in individuals with type 2 diabetes.
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Montagnani A, Gonnelli S. Antidiabetic therapy effects on bone metabolism and fracture risk. Diabetes Obes Metab 2013; 15:784-91. [PMID: 23368527 DOI: 10.1111/dom.12077] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Revised: 09/25/2012] [Accepted: 01/21/2013] [Indexed: 12/22/2022]
Abstract
Patients with diabetes are at greater risk of fractures mostly due to not only to extraskeletal factors, such as propensity to fall, but also to bone quality alteration, which reduces bone strength. In people with diabetes, insulin deficiency and hyperglycaemia seem to play a role in determining bone formation alteration by advanced glycation end product (AGE) accumulation or AGE/RAGE (receptors for AGE) axis imbalance, which directly influence osteoblast activity. Moreover, hyperglycaemia and oxidative stress are able to negatively influence osteocalcin production and the Wnt signalling pathways with an imbalance of osteoblast/osteoclast activity leading to bone quality reduction as global effect. In addition, other factors such as insulin growth factors and peroxisome proliferator-activated receptor-γ pathways seem to have an important role in the pathophysiology of osteoporosis in diabetes. Although there are conflicting data in literature, adequate glycaemic control with hypoglycaemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 diabetes. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycaemic control. Finally, preliminary data on animals and in humans suggest the hypothesis that incretins and dipeptidyl peptidase-4 inhibitors could have a positive effect on bone metabolism by a direct effect on bone cells; however, such issue needs further investigations.
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Affiliation(s)
- A Montagnani
- Metabolic Bone Diseases and Osteoporosis Ambulatory, Internal Medicine Unit, Misericordia Hospital, Grosseto, Italy.
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Sadie-Van Gijsen H, Crowther NJ, Hough FS, Ferris WF. The interrelationship between bone and fat: from cellular see-saw to endocrine reciprocity. Cell Mol Life Sci 2013; 70:2331-49. [PMID: 23178849 PMCID: PMC11113730 DOI: 10.1007/s00018-012-1211-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 10/05/2012] [Accepted: 11/07/2012] [Indexed: 01/03/2023]
Abstract
The number of mature osteoblasts and marrow adipocytes in bone is influenced by the differentiation of the common mesenchymal progenitor cell towards one phenotype and away from the other. Consequently, factors which promote adipogenesis not only lead to fatty marrow but also inhibit osteoblastogenesis, resulting in decreased osteoblast numbers, diminished bone formation and, potentially, inadequate bone mass and osteoporosis. In addition to osteoblast and bone adipocyte numbers being influenced by this skewing of progenitor cell differentiation towards one phenotype, mature osteoblasts and adipocytes secrete factors which may evoke changes in the cell fate and function of each other. This review examines the endogenous factors, such as PPAR-γ2, Wnt, IGF-1, GH, FGF-2, oestrogen, the GP130 signalling cytokines, vitamin D and glucocorticoids, which regulate the selection between osteoblastogenesis and adipogenesis and the interrelationship between fat and bone. The role of adipokines on bone, such as adiponectin and leptin, as well as adipose-derived oestrogen, is reviewed and the role of bone as an energy regulating endocrine organ is discussed.
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Affiliation(s)
- H. Sadie-Van Gijsen
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Francie van Zijl Drive, Tygerberg, 7505 South Africa
| | - N. J. Crowther
- Department of Chemical Pathology, National Health Laboratory Services, University of Witwatersrand Medical School, 7 York Road, Parktown, 2193 South Africa
| | - F. S. Hough
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Francie van Zijl Drive, Tygerberg, 7505 South Africa
| | - W. F. Ferris
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Francie van Zijl Drive, Tygerberg, 7505 South Africa
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Abstract
INTRODUCTION The treatment of acromegaly aims at normalizing growth hormone (GH) and insulin-like growth factor (IGF-I) levels and controlling tumor growth. The approaches to therapy are essentially three: surgery and pharmacotherapy, alone or in combination, and radiotherapy, generally used in more aggressive tumors. AREAS COVERED This review focuses on the novel drug formulations being developed for medical therapy of acromegaly. Even though many efficient treatments have been made available to manage acromegaly in the last two decades, a significant number of patients remain still uncontrolled. Medical therapy represents an important therapeutic option and can be used as the first-line treatment in many patients. However, roughly 25% of patients might be considered as poor responsive or resistant to conventional long-acting somatostatin analogs (SSA) treatment. Therefore, new longer-acting SSA, oral SSA formulations, new combined therapies with weekly doses of pegvisomant, combination therapy with pegvisomant (PEG) and cabergoline (CAB) or SSA and new approaches have been proposed. New molecules are currently under investigation in clinical trials, such as the SSA multi-receptor ligand, pasireotide, which represents a promising option therapy, especially in patients not adequately controlled with currently available SSA. Further, temozolomide has been suggested as an efficient drug for treating GH-aggressive pituitary tumors resistant to conventional therapy. EXPERT OPINION All these novel SSA formulations and new molecules implement the available options in therapies of acromegaly to improve disease control. However, further studies are needed to define the exact role of these newer agents. The predicting factors for response to these new therapies should also be determined.
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Affiliation(s)
- Ludovica F S Grasso
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, via S. Pansini 5, 80131 Naples, Italy
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Smith SS, Kessler CB, Shenoy V, Rosen CJ, Delany AM. IGF-I 3' untranslated region: strain-specific polymorphisms and motifs regulating IGF-I in osteoblasts. Endocrinology 2013; 154:253-62. [PMID: 23183171 PMCID: PMC3529377 DOI: 10.1210/en.2012-1476] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 11/06/2012] [Indexed: 12/12/2022]
Abstract
Reduced IGF-I is associated with low bone mass in humans and mice. C3H/He/J (C3H) mice have higher skeletal IGF-I and greater bone mass than C57BL/6J (B6). We hypothesized that strain-related genotypic differences in Igf1 affected skeletal function. The Igf1 coding region is nonpolymorphic, but its 3' untranslated region (UTR) is polymorphic between C3H and B6. Luciferase-Igf1 3' UTR reporter constructs showed that these polymorphic regions did not affect UTR function. IGF-I splice variants give rise to a common mature IGF-I peptide, but different E peptides. We identified two splice products, exon 4+6 (Ea) and exon 4+5+6 (Eb, mechano-growth factor) and found that their abundance was unchanged during osteoblastic differentiation. The Igf1 3' UTR encoded by exon 6 contains alternative polyadenylation sites. Proximal site use produces a short 3' UTR of approximately 195 bases, whereas distal site usage results in an approximately 6300-base UTR. Although Igf1 mRNA levels did not change during osteoblastic differentiation, distal polyadenylation site usage was increased in B6 cells but not in C3H. The resulting long Igf1 RNA isoform is less stable and has decreased translation efficiency, which may be one mechanism contributing to decreased IGF-I in B6 vs. C3H mice. Although the long UTR contains a conserved [GU](18) repeat, which is a positive regulator of UTR activity, it is also targeted by negative regulators, miR-29 and miR-365. These microRNAs are increased in B6 and C3H cells during osteoblastic differentiation. Differential expression of the long Igf1 3' UTR isoform may be a possible mechanism for enhanced IGF-I regulation in B6 vs. C3H mice.
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Affiliation(s)
- Spenser S Smith
- Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
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Woeckel V, Bruedigam C, Koedam M, Chiba H, van der Eerden B, van Leeuwen J. 1α,25-Dihydroxyvitamin D3 and rosiglitazone synergistically enhance osteoblast-mediated mineralization. Gene 2013; 512:438-43. [DOI: 10.1016/j.gene.2012.07.051] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Revised: 07/26/2012] [Accepted: 07/30/2012] [Indexed: 11/28/2022]
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SUN LIJUN, WANG HAOYU, XU HAO, WEI JINHONG, SHI LIANG, LIU XIAOGANG, ZHANG JIANBAO. EFFECTS OF FLUID SHEAR STRESS AND CIGLITAZONE ON OSTEOBLASTS. J MECH MED BIOL 2012. [DOI: 10.1142/s0219519412005022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Long-term use of thiazolidinedione (TZD) antidiabetic agents in patients with type 2 diabetes mellitus has been shown to increase the incidence of osteoporosis. Mechanical loading can enhance bone mass by promoting bone formation and suppressing bone resorption, which may be beneficial to patients with TZD-induced osteoporosis. In this study, we examined the cooperative effect of fluid shear stress (FSS) and ciglitazone (CIG), a type of TZD, on osteoblasts. The proliferation, osteoblast differentiation-related mRNA expression and translocation of nuclear factor κB (NFκB) of osteoblasts were assessed. The results show that CIG significantly decreased the proliferation of osteoblasts, inhibited the translocation of NFκB to the nucleus and reduced the mRNA expression of COX-2, IGF, Runx2 and OCN. At the same time, CIG also increased the mRNA expression of PPARγ. Conversely, FSS significantly increased the proliferation of osteoblasts, promoted the translocation of NFκB to the nucleus and increased the mRNA expression of COX-2, IGF, Runx2 and OCN but decreased the mRNA expression of PPARγ. When FSS and CIG were combined, FSS counteracted the effects of CIG on osteoblasts. Taken together, the current results suggest that FSS is able to arrest the effects of CIG on the proliferation and differentiation of osteoblasts.
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Affiliation(s)
- LIJUN SUN
- The Key Laboratory of Biomedical Information, Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China
| | - HAOYU WANG
- The Key Laboratory of Biomedical Information, Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China
| | - HAO XU
- The Key Laboratory of Biomedical Information, Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China
| | - JINHONG WEI
- The Key Laboratory of Biomedical Information, Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China
| | - LIANG SHI
- The Key Laboratory of Biomedical Information, Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China
| | - XIAOGANG LIU
- The Key Laboratory of Biomedical Information, Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China
| | - JIANBAO ZHANG
- The Key Laboratory of Biomedical Information, Engineering of Ministry of Education, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, 710049, China
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Fang XL, Shu G, Zhang ZQ, Wang SB, Zhu XT, Gao P, Xi QY, Zhang YL, Jiang QY. Roles of α-linolenic acid on IGF-I secretion and GH/IGF system gene expression in porcine primary hepatocytes. Mol Biol Rep 2012; 39:10987-96. [DOI: 10.1007/s11033-012-2000-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2012] [Accepted: 10/01/2012] [Indexed: 11/30/2022]
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Kim DDW, Goh J, Panossian Z, Gamble G, Holdaway I, Grey A. Pioglitazone in acromegaly - an open-label, prospective study. Clin Endocrinol (Oxf) 2012; 77:575-8. [PMID: 22512403 DOI: 10.1111/j.1365-2265.2012.04411.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE Preclinical studies demonstrate that thiazolidinediones (TZDs) decrease growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, suggesting that they might be effective treatments for acromegaly. This study investigated the effect of pioglitazone on biochemical indices of disease activity in acromegaly. DESIGN AND PARTICIPANTS This was a 4-month open-label prospective study in 16 patients with active acromegaly who were attending public hospital endocrinology clinics. METHODS The intervention was pioglitazone 45 mg/day. The primary outcome was change in serum IGF-1; the secondary outcome was change in area under the curve of glucose-suppressed GH. RESULTS Serum IGF-1 did not change during treatment with pioglitazone (P = 0·95). After 4 months, the mean (95% CI) change from baseline was -1 μg/l (-51, 49). GH levels following oral glucose loading were unchanged during pioglitazone therapy. After 4 months, the mean (95% CI) change from baseline in area under curve for glucose-suppressed GH was 31 μg/l (-75, 138, P = 0·54). CONCLUSIONS Short-term treatment with conventional doses of pioglitazone did not improve biochemical measures of disease activity in acromegaly.
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Affiliation(s)
- David D W Kim
- Department of Endocrinology, Auckland City Hospital, Auckland, New Zealand
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Idealized PPARγ-Based Therapies: Lessons from Bench and Bedside. PPAR Res 2012; 2012:978687. [PMID: 22745632 PMCID: PMC3382399 DOI: 10.1155/2012/978687] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Accepted: 04/23/2012] [Indexed: 01/07/2023] Open
Abstract
The incidence of type 2 (T2D) diabetes and other chronic conditions associated with insulin resistance is increasing at an alarming rate, underscoring the need for effective and safe therapeutic strategies. Peroxisome-proliferator-activated receptor gamma (PPARγ) has emerged as a critical regulator of glucose homeostasis, lipid homeostasis, and vascular inflammation. Currently marketed drugs targeting this receptor, the thiazolidinediones (TZDs), have proven benefits on insulin resistance and hyperglycemia associated with T2D. Unfortunately, they have been associated with long-term unfavorable effects on health, such as weight gain, plasma volume expansion, bone loss, cardiovascular toxicity, and possibly cancer, and these safety concerns have led to reduced interest for many PPARγ ligands. However, over the last years, data from human genetic studies, animal models, and studies with ligands have increased our understanding of PPARγ's actions and provided important insights into how ligand development strategies could be optimized to increase effectiveness and safety of PPARγ-based therapies.
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Gimble JM, Nuttall ME. The relationship between adipose tissue and bone metabolism. Clin Biochem 2012; 45:874-9. [PMID: 22429519 DOI: 10.1016/j.clinbiochem.2012.03.006] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 02/28/2012] [Accepted: 03/01/2012] [Indexed: 01/06/2023]
Abstract
OBJECTIVES The authors have set out to evaluate the literature relevant to the dynamic regulation of adipogenesis and osteogenesis. DESIGN AND METHODS A detailed search of the past and recent literature was conducted on Pubmed using a combination of keywords including: adipogenesis, bone marrow, hematopoiesis, mesenchymal stromal/stem cell, and osteogenesis. RESULTS Throughout one's lifespan, the bone marrow microenvironment provides a unique niche for mesenchymal stromal/stem cells (BMSCs) and hematopoietic stem cells (HSCs). The marrow changes as a function of biological age and pathophysiology. Historically, clinical biochemistry has observed these changes from an HSC and hematological perspective. Nevertheless, these changes also reflect the balance between BMSC adipogenic and osteogenic processes which can display an inverse or reciprocal relationship. Multiple hormonal factors and nuclear hormone receptor ligands and drugs are responsible for BMSC lineage selection. Data from a number of laboratories now implicates endocrine feedback loops between extramedullary adipose depots and the central nervous system. CONCLUSIONS This concise review provides a perspective on the mechanisms regulating BMSC differentiation in the context of biological aging, obesity, and osteoporosis.
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Affiliation(s)
- Jeffrey M Gimble
- Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
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Oxidative stress and heme oxygenase-1 regulated human mesenchymal stem cells differentiation. Int J Hypertens 2012; 2012:890671. [PMID: 22518296 PMCID: PMC3296285 DOI: 10.1155/2012/890671] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Revised: 11/09/2011] [Accepted: 11/14/2011] [Indexed: 12/21/2022] Open
Abstract
This paper describes the effect of increased expression of HO-1 protein and increased levels of HO activity on differentiation of bone-marrow-derived human MSCs. MSCs are multipotent cells that proliferate and differentiate into many different cell types including adipocytes and osteoblasts. HO, the rate-limiting enzyme in heme catabolism, plays an important role during MSCs differentiation. HO catalyzes the stereospecific degradation of heme to biliverdin, with the concurrent release of iron and carbon monoxide. Upregulation of HO-1 expression and increased HO activity are essential for MSC growth and differentiation to the osteoblast lineage consistent with the role of HO-1 in hematopoietic stem cell differentiation. HO-1 participates in the MSC differentiation process shifting the balance of MSC differentiation in favor of the osteoblast lineage by decreasing PPARγ and increasing osteogenic markers such as alkaline phosphatase and BMP-2. In this paper, we define HO-1 as a target molecule in the modulation of adipogenesis and osteogenesis from MSCs and examine the role of the HO system in diabetes, inflammation, osteoporosis, hypertension, and other pathologies, a burgeoning area of research.
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Abstract
Osteoporosis and diabetic disease have reached epidemic proportion and create significant public health concerns. The prevalence of these diseases is alarming, and indicates that in the US, 50% of elderly individuals are osteoporotic and almost 20% of population has either diabetic or prediabetic conditions (Centers for Disease Control and Prevention; http://www.cdc.gov). Osteoporosis and diabetes share many features including genetic predispositions and molecular mechanisms. The linkage between these two chronic diseases, which stems from overlapping molecular controls involved in bone homeostasis and energy metabolism, creates a possibility that certain anti-diabetic therapies may affect bone. This concurs with recent findings indicating that bone status is closely linked to regulation of energy metabolism and insulin sensitivity. Indeed, bone and energy homeostasis are under the control of the same regulatory factors, including insulin, peroxisome proliferator activated receptor gamma (PPARγ), gastrointestinal hormones such as glucose inhibitory protein (GIP) and glucagon inhibitory peptide (GLP), and bone derived hormone osteocalcin. These factors and related mechanisms control glucose homeostasis and fatty acids metabolism in fat tissue, pancreas and intestine, which are pharmacological targets for anti-diabetic therapies. The same factors contribute to the bone quality by their effect on bone cell differentiation and bone remodeling process. This implies that bone should be considered as a vital target for therapies which modulate energy metabolism. This review is summarizing available data on the skeletal effects of clinically approved anti-diabetic therapies.
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Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone 2012; 50:534-9. [PMID: 21757043 PMCID: PMC3197966 DOI: 10.1016/j.bone.2011.06.032] [Citation(s) in RCA: 132] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 06/24/2011] [Accepted: 06/25/2011] [Indexed: 12/25/2022]
Abstract
Recent advances in understanding the role of bone in the systemic regulation of energy metabolism indicate that bone marrow cells, adipocytes and osteoblasts, are involved in this process. Marrow adipocytes store significant quantities of fat and produce adipokines, leptin and adiponectin, which are known for their role in the regulation of energy metabolism, whereas osteoblasts produce osteocalcin, a bone-specific hormone that has a potential to regulate insulin production in the pancreas and adiponectin production in fat tissue. Both osteoblasts and marrow adipocytes express insulin receptor and respond to insulin-sensitizing anti-diabetic TZDs in a manner, which tightly links bone with the energy metabolism system. Metabolic profile of marrow fat resembles that of both, white and brown fat, which is reflected by its plasticity in acquiring different functions including maintenance of bone micro-environment. Marrow fat responds to physiologic and pathologic changes in energy metabolism status by changing volume and metabolic activity. This review summarizes available information on the metabolic function of marrow fat and provides hypothesis that this fat depot may acquire multiple roles depending on the local and perhaps systemic demands. These functions may include a role in bone energy maintenance and endocrine activities to serve osteogenesis during bone remodeling and bone healing.
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Affiliation(s)
- Beata Lecka-Czernik
- Department of Orthopaedic Surgery, University of Toledo Health Sciences Campus, Toledo, OH 43614, USA.
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