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Hewitt‐Dedman CL, Kershaw LE, Schwarz T, Del‐Pozo J, Duncan J, Daniel CR, Cillán‐García E, Pressanto MC, Taylor SE. Preliminary study of proton magnetic resonance spectroscopy to assess bone marrow adiposity in the third metacarpus or metatarsus in Thoroughbred racehorses. Equine Vet J 2025; 57:471-479. [PMID: 38699829 PMCID: PMC11807939 DOI: 10.1111/evj.14086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 03/07/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND Magnetic resonance spectroscopy (MRS) has been used to investigate metabolic changes within human bone. It may be possible to use MRS to investigate bone metabolism and fracture risk in the distal third metacarpal/tarsal bone (MC/MTIII) in racehorses. OBJECTIVES To determine the feasibility of using MRS as a quantitative imaging technique in equine bone by using the 1H spectra for the MC/MTIII to calculate fat content (FC). STUDY DESIGN Observational cross-sectional study. METHODS Limbs from Thoroughbred racehorses were collected from horses that died or were subjected to euthanasia on racecourses. Each limb underwent magnetic resonance imaging (MRI) at 3 T followed by single-voxel MRS at three regions of interest (ROI) within MC/MTIII (lateral condyle, medial condyle, proximal bone marrow [PBM]). Percentage FC was calculated at each ROI. Each limb underwent computed tomography (CT) and bone mineral density (BMD) was calculated for the same ROIs. All MR and CT images were graded for sclerosis. Histology slides were graded for sclerosis and proximal marrow space was calculated. Pearson or Spearman correlations were used to assess the relationship between BMD, FC and marrow space. Kruskal-Wallis tests were used to check for differences between sclerosis groups for BMD or FC. RESULTS Eighteen limbs from 10 horses were included. A negative correlation was identified for mean BMD and FC for the lateral condyle (correlation coefficient = -0.60, p = 0.01) and PBM (correlation coefficient = -0.5, p = 0.04). There was a significant difference between median BMD for different sclerosis grades in the condyles on both MRI and CT. A significant difference in FC was identified between sclerosis groups in the lateral condyle on MRI and CT. MAIN LIMITATIONS Small sample size. CONCLUSIONS 1H Proton MRS is feasible in the equine MC/MTIII. Further work is required to evaluate the use of this technique to predict fracture risk in racehorses.
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Affiliation(s)
| | - Lucy E. Kershaw
- BHF Centre for Cardiovascular Science and Edinburgh ImagingUniversity of EdinburghEdinburghUK
| | - Tobias Schwarz
- Royal (Dick) School of Veterinary Studies and Roslin InstituteThe University of EdinburghRoslinUK
| | - Jorge Del‐Pozo
- Royal (Dick) School of Veterinary Studies and Roslin InstituteThe University of EdinburghRoslinUK
| | - Juliet Duncan
- Royal (Dick) School of Veterinary Studies and Roslin InstituteThe University of EdinburghRoslinUK
| | - Carola R. Daniel
- Royal (Dick) School of Veterinary Studies and Roslin InstituteThe University of EdinburghRoslinUK
| | - Eugenio Cillán‐García
- Royal (Dick) School of Veterinary Studies and Roslin InstituteThe University of EdinburghRoslinUK
| | - Maria Chiara Pressanto
- Royal (Dick) School of Veterinary Studies and Roslin InstituteThe University of EdinburghRoslinUK
| | - Sarah E. Taylor
- Royal (Dick) School of Veterinary Studies and Roslin InstituteThe University of EdinburghRoslinUK
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Wang YW, Luo CW. Unveiling the signal valve specifically tuning the TGF-β1 suppression of osteogenesis: mediation through a SMAD1-SMAD2 complex. Cell Commun Signal 2025; 23:38. [PMID: 39844165 PMCID: PMC11752969 DOI: 10.1186/s12964-025-02051-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 01/16/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND TGF-β1 is the most abundant cytokine in bone, in which it serves as a vital factor to interdict adipogenesis and osteogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, how TGF-β1 concurrently manipulates differentiation into these two distinct lineages remains elusive. METHODS Treatments with ligands or inhibitors followed by biochemical characterization, reporter assay, quantitative PCR and induced differentiation were applied to MSC line or primary BM-MSCs for signaling dissection. In vivo adipogenesis and ex vivo culture of bone explants were used to verify the functions of different SMAD complexes. Ingenuity Pathway Analysis, and analysis of transcriptomic datasets from human BM-MSCs in combination with hierarchical clustering and STRING assay were used to decipher the interplaying co-repressors. Mouse models of chronic and acute bone loss followed by biochemical assays and micro-computed tomography demonstrated the bone effects when functionally blocking the critical co-repressor HDAC1. RESULTS Distinct from the TGF-β1 inhibition on adipogenesis through canonical SMAD2/3 signaling, we clarified that TGF-β1 suppresses osteogenesis by inducing the formation of previously unidentified mixed SMADs mainly composed of SMAD1 and SMAD2, in which SMAD2 recruits more TGF-β1-induced co-repressors including HDAC1, TGIF1 and ATF3, whereas SMAD1 allows directing the whole transcriptional suppression complex to the cis-elements of osteogenic genes. Depletion of the cross-activation to the mixed SMADs dismantled specifically the TGF-β1 suppression on osteogenesis without affecting its inhibition on adipogenesis. Such phenomena can be reproduced via knockdown of co-repressors such as Hdac1 or addition of HDAC1 inhibitors in TGF-β1-treated MSCs. In either the chronic or the acute bone loss model, we demonstrated that the TGF-β signaling was augmented in the bone niche during osteolysis, whereas administration of HDAC1 inhibitors significantly improved bone quality. CONCLUSION This study identifies a new signal valve through which TGF-β1 can inhibit osteogenesis specifically. Functional interruption of this valve can tilt the seesaw balance of BM-MSC differentiation towards osteogenesis, highlighting the interplaying co-repressors, such as HDAC1, as promising therapeutic targets to combat diverse degenerative orthopedic diseases.
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Affiliation(s)
- Ying-Wen Wang
- Department of Life Sciences, Institute of Genome Sciences, National Yang Ming Chiao Tung University, 155 Li-Nong Street, Section 2, Beitou, Taipei, 112, Taiwan
| | - Ching-Wei Luo
- Department of Life Sciences, Institute of Genome Sciences, National Yang Ming Chiao Tung University, 155 Li-Nong Street, Section 2, Beitou, Taipei, 112, Taiwan.
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Nishida R, Fukui T, Niikura T, Kumabe Y, Yoshikawa R, Takase K, Yamamoto Y, Kuroda R, Oe K. Preventive effects of transcutaneous CO 2 application on disuse osteoporosis and muscle atrophy in a rat hindlimb suspension model. Bone 2024; 189:117262. [PMID: 39303931 DOI: 10.1016/j.bone.2024.117262] [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: 07/26/2024] [Revised: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
We previously demonstrated that transcutaneous CO2 application promotes muscle fiber-type switching, fracture healing, and osteogenesis by increasing blood flow and angiogenesis. Here, we aimed to investigate the preventive effects of transcutaneous CO2 application on disuse osteoporosis and muscle atrophy in a rat hindlimb suspension model. Eleven-week-old male Sprague-Dawley rats were divided into hindlimb suspension (HS), HS with transcutaneous CO2 application (HSCO2), and control groups. HSCO2 rats were administered transcutaneous 100 % CO2 gas in their bilateral hindlimbs, five times a week for 20 min. After 3 weeks, we harvested the gastrocnemius, femur, and tibia for assessment. Histological analysis revealed a significant decrease in the gastrocnemius myofiber cross-sectional area in HS rats compared to the control rats, whereas HSCO2 rats exhibited a significant increase compared to HS rats. Micro-computed tomography showed significant bone atrophy in the trabecular and cortical bones of the femur in HS rats compared to those of the control rats, whereas significant improvement was noted in HSCO2 rats. Histological analysis of the proximal tibia revealed more marrow adipose tissue in the HS rats than in the control rats. However, in the HSCO2 rats, fewer marrow adipose tissue and osteoclasts were observed. Moreover, HSCO2 rats had more osteoblasts and higher expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and vascular endothelial growth factor (VEGF) than the HS rats. The gastrocnemius and distal femur of HSCO2 rats also exhibited elevated PGC-1α and VEGF expression and upregulation of the myogenesis markers and osteogenesis markers compared to those of HS rats. This treatment effectively prevented disuse osteoporosis and muscle atrophy by promoting local angiogenesis and blood flow. PGC-1α is crucial for promoting this angiogenic pathway. Transcutaneous CO2 application may be a novel preventive procedure for disuse osteoporosis and muscle atrophy, complementing medication and rehabilitation.
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Affiliation(s)
- Ryota Nishida
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Tomoaki Fukui
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Yohei Kumabe
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Ryo Yoshikawa
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Kyohei Takase
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Yuya Yamamoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Keisuke Oe
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan.
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Kaneguchi A, Yamaoka K, Ozawa J. Effects of Weight Bearing on Marrow Adipose Tissue and Trabecular Bone after Anterior Cruciate Ligament Reconstruction in the Rat Proximal Tibial Epiphysis. Acta Histochem Cytochem 2024; 57:15-24. [PMID: 38463204 PMCID: PMC10918432 DOI: 10.1267/ahc.23-00060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 01/11/2024] [Indexed: 03/12/2024] Open
Abstract
The effects of mechanical unloading after anterior cruciate ligament (ACL) reconstruction on bone and marrow adipose tissue (MAT) are unclear. We investigated weight bearing effects on bone and MAT after ACL reconstruction. Rats underwent unilateral knee ACL transection and reconstruction, followed by hindlimb unloading (non-weight bearing), no intervention (low-weight bearing, the hindlimb standing time ratio (STR; operated/contralateral) during treadmill locomotion ranging from 0.55 to 0.91), or sustained morphine administration (moderate-weight bearing, STR ranging from 0.80 to 0.95). Untreated rats were used as controls. At 7 or 14 days after surgery, changes in trabecular bone and MAT in the proximal tibial were assessed histologically. Histological assessments at 7 or 14 days after surgery showed that ACL reconstruction without post-operative intervention did not significantly change trabecular bone and MAT areas. Hindlimb unloading after ACL reconstruction induced MAT accumulation with adipocyte hyperplasia and hypertrophy within 14 days, but did not significantly affect trabecular bone area. Increased weight bearing through morphine administration did not affect trabecular bone and MAT parameters. Our results suggest that early weight bearing after ACL reconstruction is important in reducing MAT accumulation, and that reduction in weight bearing alone is not sufficient to induce bone loss early after ACL reconstruction.
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Affiliation(s)
- Akinori Kaneguchi
- Department of Rehabilitation, Faculty of Rehabilitation, Hiroshima International University, Kurose-Gakuendai 555-36, Higashi-Hiroshima, Hiroshima, Japan
| | - Kaoru Yamaoka
- Department of Rehabilitation, Faculty of Rehabilitation, Hiroshima International University, Kurose-Gakuendai 555-36, Higashi-Hiroshima, Hiroshima, Japan
| | - Junya Ozawa
- Department of Rehabilitation, Faculty of Rehabilitation, Hiroshima International University, Kurose-Gakuendai 555-36, Higashi-Hiroshima, Hiroshima, Japan
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Yan L, Guo L. Exercise-regulated white adipocyte differentitation: An insight into its role and mechanism. J Cell Physiol 2023; 238:1670-1692. [PMID: 37334782 DOI: 10.1002/jcp.31056] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 06/20/2023]
Abstract
White adipocytes play a key role in the regulation of fat mass amount and energy balance. An appropriate level of white adipocyte differentiation is important for maintaining metabolic homeostasis. Exercise, an important way to improve metabolic health, can regulate white adipocyte differentiation. In this review, the effect of exercise on the differentiation of white adipocytes is summarized. Exercise could regulate adipocyte differentiation in multiple ways, such as exerkines, metabolites, microRNAs, and so on. The potential mechanism underlying the role of exercise in adipocyte differentiation is also reviewed and discussed. In-depth investigation of the role and mechanism of exercise in white adipocyte differentiation would provide new insights into exercise-mediated improvement of metabolism and facilitate the application of exercise-based strategy against obesity.
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Affiliation(s)
- Linjing Yan
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences (Shanghai University of Sport), Ministry of Education, Shanghai, China
| | - Liang Guo
- School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China
- Key Laboratory of Exercise and Health Sciences (Shanghai University of Sport), Ministry of Education, Shanghai, China
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Buettmann EG, Goldscheitter GM, Hoppock GA, Friedman MA, Suva LJ, Donahue HJ. Similarities Between Disuse and Age-Induced Bone Loss. J Bone Miner Res 2022; 37:1417-1434. [PMID: 35773785 PMCID: PMC9378610 DOI: 10.1002/jbmr.4643] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 06/17/2022] [Accepted: 06/24/2022] [Indexed: 11/07/2022]
Abstract
Disuse and aging are known risk factors associated with low bone mass and quality deterioration, resulting in increased fracture risk. Indeed, current and emerging evidence implicate a large number of shared skeletal manifestations between disuse and aging scenarios. This review provides a detailed overview of current preclinical models of musculoskeletal disuse and the clinical scenarios they seek to recapitulate. We also explore and summarize the major similarities between bone loss after extreme disuse and advanced aging at multiple length scales, including at the organ/tissue, cellular, and molecular level. Specifically, shared structural and material alterations of bone loss are presented between disuse and aging, including preferential loss of bone at cancellous sites, cortical thinning, and loss of bone strength due to enhanced fragility. At the cellular level bone loss is accompanied, during disuse and aging, by increased bone resorption, decreased formation, and enhanced adipogenesis due to altered gap junction intercellular communication, WNT/β-catenin and RANKL/OPG signaling. Major differences between extreme short-term disuse and aging are discussed, including anatomical specificity, differences in bone turnover rates, periosteal modeling, and the influence of subject sex and genetic variability. The examination also identifies potential shared mechanisms underlying bone loss in aging and disuse that warrant further study such as collagen cross-linking, advanced glycation end products/receptor for advanced glycation end products (AGE-RAGE) signaling, reactive oxygen species (ROS) and nuclear factor κB (NF-κB) signaling, cellular senescence, and altered lacunar-canalicular connectivity (mechanosensation). Understanding the shared structural alterations, changes in bone cell function, and molecular mechanisms common to both extreme disuse and aging are paramount to discovering therapies to combat both age-related and disuse-induced osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Evan G Buettmann
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Galen M Goldscheitter
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Gabriel A Hoppock
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Michael A Friedman
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Larry J Suva
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Henry J Donahue
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
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Marrow adipose tissue accumulation and dysgenesis of the trabecular bone after anterior cruciate ligament transection and reconstruction in the rat proximal tibial epiphysis. Acta Histochem 2022; 124:151891. [PMID: 35367815 DOI: 10.1016/j.acthis.2022.151891] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/07/2022] [Accepted: 03/24/2022] [Indexed: 11/23/2022]
Abstract
The accumulation of marrow adipose tissue (MAT) is frequently associated with bone loss. Although anterior cruciate ligament (ACL) injury induces bone loss, MAT accumulation after ACL injury has not been evaluated. In addition, no information about changes in MAT after ACL reconstruction is available. In this study, we aimed to examine (1) the effects of ACL transection on the amounts of trabecular bone and MAT present, and (2) whether ACL reconstruction inhibits the changes in the trabecular bone and MAT that are induced by ACL transection. ACL transection alone or with immediate reconstruction was performed on the right knees of rats. Untreated left knees were used as controls. Histomorphological changes in the trabecular bone and MAT in the proximal tibial epiphysis were examined prior to surgery and at one, four, and 12 weeks postsurgery. The trabecular bone area on the untreated side increased in a time-dependent manner. However, after ACL transection, the trabecular bone area did not increase during the experimental period, indicating dysgenesis of the bone (bone loss). Dysgenesis of the trabecular bone after ACL transection was attenuated by ACL reconstruction. MAT accumulation due to adipocyte hyperplasia and hypertrophy had been induced by ACL transection by four weeks postsurgery. This ACL transection-induced MAT accumulation was not prevented by ACL reconstruction. Based on these results, we conclude that (1) dysgenesis of the bone in the proximal tibia following ACL transection is accompanied by MAT accumulation, and (2) ACL reconstruction attenuates dysgenesis of the trabecular bone but cannot prevent MAT accumulation.
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Recent advances in smart stimuli-responsive biomaterials for bone therapeutics and regeneration. Bone Res 2022; 10:17. [PMID: 35197462 PMCID: PMC8866424 DOI: 10.1038/s41413-021-00180-y] [Citation(s) in RCA: 192] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 07/26/2021] [Accepted: 09/17/2021] [Indexed: 02/05/2023] Open
Abstract
Bone defects combined with tumors, infections, or other bone diseases are challenging in clinical practice. Autologous and allogeneic grafts are two main traditional remedies, but they can cause a series of complications. To address this problem, researchers have constructed various implantable biomaterials. However, the original pathological microenvironment of bone defects, such as residual tumors, severe infection, or other bone diseases, could further affect bone regeneration. Thus, the rational design of versatile biomaterials with integrated bone therapy and regeneration functions is in great demand. Many strategies have been applied to fabricate smart stimuli-responsive materials for bone therapy and regeneration, with stimuli related to external physical triggers or endogenous disease microenvironments or involving multiple integrated strategies. Typical external physical triggers include light irradiation, electric and magnetic fields, ultrasound, and mechanical stimuli. These stimuli can transform the internal atomic packing arrangements of materials and affect cell fate, thus enhancing bone tissue therapy and regeneration. In addition to the external stimuli-responsive strategy, some specific pathological microenvironments, such as excess reactive oxygen species and mild acidity in tumors, specific pH reduction and enzymes secreted by bacteria in severe infection, and electronegative potential in bone defect sites, could be used as biochemical triggers to activate bone disease therapy and bone regeneration. Herein, we summarize and discuss the rational construction of versatile biomaterials with bone therapeutic and regenerative functions. The specific mechanisms, clinical applications, and existing limitations of the newly designed biomaterials are also clarified.
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Louvet L, Leterme D, Delplace S, Miellot F, Marchandise P, Gauthier V, Hardouin P, Chauveau C, Ghali Mhenni O. Sirtuin 1 deficiency decreases bone mass and increases bone marrow adiposity in a mouse model of chronic energy deficiency. Bone 2020; 136:115361. [PMID: 32289519 DOI: 10.1016/j.bone.2020.115361] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 11/16/2022]
Abstract
Sirtuin of type 1 (Sirt1), a class III HDAC, is known to be involved in the regulation of differentiation of skeletal stem cells (SSCs) into osteoblasts and adipocytes. In caloric restriction, it has been shown that the expression and activity of Sirt1 is a tissue-dependent regulation. However, at present, no study has focused on the link between Sirt1, bone marrow adiposity (BMA) and osteoporosis related to anorexia nervosa (AN). Thus, the aims of this work were to (i) determine BMA and bone changes in a mouse model replicating the phenotypes of AN (separation-based anorexia model (SBA)); (ii) determine the expression of Sirt1 in bone marrow stromal cells (BMSCs) extracted from these mice and identify their differentiation capacities; (iii) study the effects of pharmacological activation and inhibition of Sirt1 on the osteoblastogenesis and adipogenesis of these cells and (iiii) delineate the molecular mechanism by which Sirt1 could regulate osteogenesis in an SBA model. Our results demonstrated that SBA protocol induces an increase in BMA and alteration of bone architecture. In addition, BMSCs from restricted mice present a down-regulation of Sirt1 which is accompanied by an increase in adipogenesis at expense of osteogenesis. After a 10-day organotypic culture, tibias from SBA mice displayed low levels of Sirt1 mRNA which are restored by resveratrol treatment. Interestingly, this recovery of Sirt1 levels also returned the BMA, BV/TV and Tb.Th in cultured tibias from SBA mice to normal levels. In contrast of down-regulation of Sirt1 expression induced by sirtinol treatment, stimulation of Sirt1 expression by resveratrol lead to a decrease in adipogenesis and increase in osteogenesis. Finally, to investigate the molecular mechanisms by which Sirt1 could regulate osteogenesis in the SBA model, the acetylation levels of Runx2 and Foxo1 transcription factors were determined. Our data show that this chronic energy deficiency in female mice causes a decrease in BMSC activity, resulting in critical changes to Runx2 and Foxo1 acetylation levels and thus to their activity. Altogether, these data suggest that Sirt1 could be considered as a potential therapeutic target in osteoporosis related to AN.
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Affiliation(s)
- Loïc Louvet
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Damien Leterme
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Séverine Delplace
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Flore Miellot
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Pierre Marchandise
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Véronique Gauthier
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Pierre Hardouin
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Christophe Chauveau
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Olfa Ghali Mhenni
- Marrow Adiposity and Bone Lab (MABLab, ex-PMOI) ULR4490, Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France.
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Bone marrow fat fraction assessment in regard to physical activity: KORA FF4-3-T MR imaging in a population-based cohort. Eur Radiol 2020; 30:3417-3428. [PMID: 32086579 DOI: 10.1007/s00330-019-06612-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/31/2019] [Accepted: 12/06/2019] [Indexed: 01/03/2023]
Abstract
OBJECTIVES To establish the effect of different degrees and kinds of physical activity on bone marrow fat (BMAT) content at different anatomical locations in a population-based cohort study undergoing whole-body MR imaging. METHODS Subjects of the KORA FF4 study without known cardiovascular disease underwent BMAT fat fraction (FF) quantification in L1 and L2 vertebrae and femoral heads/necks (hip) via a 2-point T1-weighted VIBE Dixon sequence. BMAT-FF was calculated as mean value (fat image) divided by mean value (fat + water image). Physical activity was determined by self-assessment questionnaire regarding time spent exercising, non-exercise walking, non-exercise cycling, and job-related physical activity. RESULTS A total of 385 subjects (96% of 400 available; 56 ± 9.1 years; 58% male) were included in the analysis. Exercise was distributed quite evenly (29% > 2 h/week; 31% ~ 1 h/week (regularly); 15% ~ 1 h/week (irregularly); 26% no physical activity). BMAT-FF was 52.6 ± 10.2% in L1, 56.2 ± 10.3% in L2, 87.4 ± 5.9% in the right hip, and 87.2 ± 5.9% in the left hip (all p < 0.001). Correlation of BMAT-FF between spine and hip was only moderate (r 0.42 to 0.46). Spinal BMAT-FF, but not hip BMAT-FF, was inversely associated with exercise > 2 h/week (p ≤ 0.02 vs. p ≥ 0.35, respectively). These associations remained significant after adjusting for age, gender, waist circumference, and glucose tolerance. No coherent association was found between BMAT-FF and physical activity in the less active groups. CONCLUSIONS In our study, exercise was inversely correlated with vertebral BMAT-FF, but not hip BMAT-FF, when exercising for more than 2 h per week. Physical activity seems to affect the spine at least preferentially compared to the hip. KEY POINTS • In our population-based cohort, at least 2 h of physical activity per week were required to show lower levels of bone marrow adipose tissue fat fraction in MRI. • Physical activity seems to affect bone marrow adipose tissue at least preferentially at the spine in contrast to the proximal femur.
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Trudel G, Melkus G, Sheikh A, Ramsay T, Laneuville O. Marrow adipose tissue gradient is preserved through high protein diet and bed rest. A randomized crossover study. Bone Rep 2019; 11:100229. [PMID: 31799339 PMCID: PMC6883331 DOI: 10.1016/j.bonr.2019.100229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022] Open
Abstract
CONTEXT Marrow adipose tissue (MAT) has a peripheral to central distribution in adults, higher in peripheral bones. Similarly, the spine has a caudal to cephalad MAT distribution, higher in lumbar vertebras. Diet and the level of physical activities are known modulators of MAT with significant impact on bone; however, whether these can modulate the MAT gradient is unknown. OBJECTIVE To measure the effect of high protein diet and bed rest interventions on the lumbar MAT gradient. DESIGN PARTICIPANTS INTERVENTION In a prospective randomized crossover trial, 10 healthy men participated in 2 consecutive campaigns of 21days head-down-tilt-bed-rest (HDTBR). They received either whey protein and potassium bicarbonate-supplemented or control diet separated by a 4-month washout period. MAIN OUTCOME MEASURES Ten serial MRI measures of lumbar vertebral fat fraction (VFF) were performed at baseline, 10days and 20days of HDTBR and 3 and 28days after HDTBR of each bed rest campaign. RESULTS The mean L5-L1 VFF difference of 4.2 ± 1.2 percentage point higher at L5 (p = 0.008) constituted a caudal to cephalad lumbar MAT gradient. High protein diet did not alter the lumbar VFF differences during both HDTBR campaigns (all time points p > 0.05). Similarly, 2 campaigns of 21days of HDTBR did not change the lumbar VFF differences (all time points p > 0.05). CONCLUSIONS This pilot study established that the lumbar vertebral MAT gradient was not altered by a high protein nor by 2 × 21days bed rest interventions. These findings demonstrated that this lack of mechanical stimulus was not an important modulator of the lumbar MAT gradient. The highly preserved MAT gradient needs to be measured in more situations of health and disease and may potentially serve to detect pathological situations.
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Key Words
- BDC, baseline data collection
- Bed rest study
- DLR, German Aerospace Center
- FOV, field of view
- HDT, head-down tilt
- HDTBR, head-down-tilt-bed-rest
- IOP, in-phase and out-phase imaging
- Lumbar vertebral fat fraction
- MAT, marrow adipose tissue
- MEP, whey protein study
- MR, magnetic resonance
- Magnetic resonance imaging
- Marrow adipose tissue
- PDFF, proton-density fat fraction
- R, recovery
- ROI, region of interest
- TR, repetition time
- VFF, vertebral fat fraction
- Whey protein
- in-phase, echo time 1 (TE1)
- out-phase, echo time 2 (TE2)
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Affiliation(s)
- Guy Trudel
- Bone and Joint Research Laboratory, Department of Physical Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ontario, Canada
| | - Gerd Melkus
- The Ottawa Hospital Research Institute, Ontario, Canada
- Department of Radiology, University of Ottawa, Ontario, Canada
| | - Adnan Sheikh
- The Ottawa Hospital Research Institute, Ontario, Canada
- Department of Radiology, University of Ottawa, Ontario, Canada
| | - Tim Ramsay
- The Ottawa Hospital Research Institute, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ontario, Canada
| | - Odette Laneuville
- Bone and Joint Research Laboratory, Department of Physical Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada
- Department of Biology, Faculty of Science, University of Ottawa, Ontario, Canada
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12
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Keune JA, Branscum AJ, Wong CP, Iwaniec UT, Turner RT. Effect of Leptin Deficiency on the Skeletal Response to Hindlimb Unloading in Adult Male Mice. Sci Rep 2019; 9:9336. [PMID: 31249331 PMCID: PMC6597714 DOI: 10.1038/s41598-019-45587-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 06/06/2019] [Indexed: 12/29/2022] Open
Abstract
Based on body weight, morbidly obese leptin-deficient ob/ob mice have less bone than expected, suggesting that leptin plays a role in the skeletal response to weight bearing. To evaluate this possibility, we compared the skeletal response of wild type (WT) and ob/ob mice to hindlimb unloading (HU). Mice were individually housed at 32 °C (thermoneutral) from 4 weeks of age (rapidly growing) to 16 weeks of age (approaching skeletal maturity). Mice were then randomized into one of 4 groups (n = 10/group): (1) WT control, (2) WT HU, (3) ob/ob control, and (4) ob/ob HU and the results analyzed by 2-way ANOVA. ob/ob mice pair-fed to WT mice had normal cancellous bone volume fraction (BV/TV) in distal femur, lower femur length and total bone area, mineral content (BMC) and density (BMD), and higher cancellous bone volume fraction in lumbar vertebra (LV). HU resulted in lower BMC and BMD in total femur, and lower BV/TV in distal femur and LV in both genotypes. Cancellous bone loss in femur in both genotypes was associated with increases in osteoclast-lined bone perimeter. In summary, leptin deficiency did not attenuate HU-induced osteopenia in male mice, suggesting that leptin is not required for bone loss induced by unweighting.
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Affiliation(s)
- Jessica A. Keune
- 0000 0001 2112 1969grid.4391.fSkeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR 97331 USA
| | - Adam J. Branscum
- 0000 0001 2112 1969grid.4391.fBiostatistics Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR 97331 USA
| | - Carmen P. Wong
- 0000 0001 2112 1969grid.4391.fSkeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR 97331 USA
| | - Urszula T. Iwaniec
- 0000 0001 2112 1969grid.4391.fSkeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR 97331 USA ,0000 0001 2112 1969grid.4391.fCenter for Healthy Aging Research, Oregon State University, Corvallis, OR 97331 USA
| | - Russell T. Turner
- 0000 0001 2112 1969grid.4391.fSkeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR 97331 USA ,0000 0001 2112 1969grid.4391.fCenter for Healthy Aging Research, Oregon State University, Corvallis, OR 97331 USA
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13
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Souza Gomes TP, Veloso FLDM, Antunes Filho J, Mourão FC, Nascif NHT, Loures EDA, Labronici PJ, Mendes Júnior AF. Obesidade, Diabetes Mellitus tipo 2 e fragilidade óssea: uma revisão narrativa. HU REVISTA 2019. [DOI: 10.34019/1982-8047.2018.v44.14058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Durante anos a obesidade foi vista como um fator protetor para fraturas e osteoporose. Diversos estudos, no entanto, contestam esta tese, descrevendo que a obesidade na verdade afeta negativamente o sistema esquelético, em especial a homeostase óssea, diminuindo a rigidez do tecido ósseo e aumentando o risco de fraturas. A obesidade e o diabetes estão frequentemente associados no mesmo paciente, e a compreensão da alteração do tecido ósseo nestas duas condições clínicas é fundamental para o melhor cuidado destes pacientes, principalmente devido ao risco aumentado de fraturas, que estão associadas a maior número de complicações no seu tratamento. O presente estudo, em revisão narrativa, descreve a relação entre obesidade e homeostase óssea, a fragilidade óssea nos pacientes obesos, diabéticos ou não, e a relação entre obesidade e fraturas.
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14
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Li Y, Meng Y, Yu X. The Unique Metabolic Characteristics of Bone Marrow Adipose Tissue. Front Endocrinol (Lausanne) 2019; 10:69. [PMID: 30800100 PMCID: PMC6375842 DOI: 10.3389/fendo.2019.00069] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 01/24/2019] [Indexed: 02/05/2023] Open
Abstract
Bone marrow adipose tissue (MAT) is distinct from white adipose tissue (WAT) or brown adipose tissue (BAT) for its location, feature and function. As a largely ignored adipose depot, it is situated in bone marrow space and resided with bone tissue side-by-side. MAT is considered not only as a regulator of bone metabolism through paracrine, but also as a functionally particular adipose tissue that may contribute to global metabolism. Adipokines, inflammatory factors and other molecules derived from bone marrow adipocytes may exert systematic effects. In this review, we summary the evidence from several aspects including development, distribution, histological features and phenotype to elaborate the basic characteristics of MAT. We discuss the association between bone metabolism and MAT, and highlight our current understanding of this special adipose tissue. We further demonstrate the probable relationship between MAT and energy metabolism, as well as glucose metabolism. On the basis of preliminary results from animal model and clinical studies, we propose that MAT has its unique secretory and metabolic function, although there is no in-depth study at present.
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Affiliation(s)
- Yujue Li
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Meng
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xijie Yu ;
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15
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Abstract
Bone marrow adipocytes (BMA-) constitute an original and heterogeneous fat depot whose development appears interlinked with bone status throughout life. The gradual replacement of the haematopoietic tissue by BMA arises in a well-ordered way during childhood and adolescence concomitantly to bone growth and continues at a slower rate throughout the adult life. Importantly, BM adiposity quantity is found well associated with bone mineral density (BMD) loss at different skeletal sites in primary osteoporosis such as in ageing or menopause but also in secondary osteoporosis consecutive to anorexia nervosa. Since BMA and osteoblasts originate from a common mesenchymal stem cell, adipogenesis is considered as a competitive process that disrupts osteoblastogenesis. Besides, most factors secreted by bone and bone marrow cells (ligands and antagonists of the WNT/β-catenin pathway, BMP and others) reciprocally regulate the two processes. Hormones such as oestrogens, glucocorticoids, parathyroid and growth hormones that control bone remodelling also modulate the differentiation and the activity of BMA. Actually, BMA could also contribute to bone loss through the release of paracrine factors altering osteoblast and/or osteoclast formation and function. Based on clinical and fundamental studies, this review aims at presenting and discussing these current arguments that support but also challenge the involvement of BMA in the bone mass integrity.
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Affiliation(s)
- Tareck Rharass
- Littoral Côte d’Opale University, Lille University, EA 4490, PMOI, Physiopathologie des Maladies Osseuses Inflammatoires, Lille, F-59000, France
| | - Stéphanie Lucas
- Littoral Côte d’Opale University, Lille University, EA 4490, PMOI, Physiopathologie des Maladies Osseuses Inflammatoires, Lille, F-59000, France
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16
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Lu Y, Wang Z, Chen L, Wang J, Li S, Liu C, Sun D. The In Vitro Differentiation of GDNF Gene-Engineered Amniotic Fluid-Derived Stem Cells into Renal Tubular Epithelial-Like Cells. Stem Cells Dev 2018; 27:590-599. [PMID: 29649411 DOI: 10.1089/scd.2017.0120] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Ying Lu
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Zhuojun Wang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Lu Chen
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jia Wang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Shulin Li
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Caixia Liu
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Dong Sun
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Department of Internal Medicine and Diagnostics, Xuzhou Medical University, Xuzhou, China
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17
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Belavy DL, Quittner MJ, Ridgers ND, Shiekh A, Rantalainen T, Trudel G. Specific Modulation of Vertebral Marrow Adipose Tissue by Physical Activity. J Bone Miner Res 2018; 33:651-657. [PMID: 29336053 DOI: 10.1002/jbmr.3357] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 11/23/2017] [Accepted: 12/02/2017] [Indexed: 11/09/2022]
Abstract
Marrow adipose tissue (MAT) accumulation with normal aging impacts the bone, hemopoiesis, and metabolic pathways. We investigated whether exercise was associated with lower MAT, as measured by vertebral marrow fat fraction (VFF) on magnetic resonance imaging. A total of 101 healthy individuals (54 females) aged 25 to 35 years without spine or bone disease but with distinct exercise histories were studied. Long-distance runners (67 km/wk, n = 25) exhibited lower mean lumbar VFF (27.9% [8.6%] versus 33.5% [6.0%]; p = 0.0048) than non-sporting referents (n = 24). In habitual joggers (28 km/wk, n = 30), mean lumbar VFF was 31.3% (9.0%) (p = 0.22 versus referents) and 6.0 percentage points lower than referents at vertebrae T10 , T11 , and T12 (p ≤ 0.023). High-volume road cycling (275 km/wk, n = 22) did not impact VFF. 3D accelerations corresponding to faster walking, slow jogging, and high-impact activities correlated with lower VFF, whereas low-impact activities and sedentary time correlated with higher mean lumbar VFF (all p ≤ 0.05). Given an estimated adipose bone marrow conversion of 7% per decade of life, long distance runners, with 5.6 percentage points lower VFF, showed an estimated 8-year younger vertebral marrow adipose tissue phenotype. Regression analysis showed a 0.7 percentage point reduction in mean lumbar VFF with every 9.4 km/wk run (p = 0.002). This study presents the first evidence in humans or animals that specific volumes and types of exercise may influence the age-determined adipose marrow conversion and result in low MAT. These results identify a potentially modifiable risk factor for prevalent chronic conditions related to bone metabolism, hemopoietic production, and other metabolic functions with potential global health applications. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Daniel L Belavy
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Australia
| | - Matthew J Quittner
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Australia
| | - Nicola D Ridgers
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Australia
| | - Adnan Shiekh
- Department of Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, Canada
| | - Timo Rantalainen
- Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Australia
| | - Guy Trudel
- Department of Medicine, Division of Physical Medicine and Rehabilitation, Bone and Joint Research Laboratory, University of Ottawa, Ottawa, Canada
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18
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Frechette DM, Krishnamoorthy D, Pamon T, Chan ME, Patel V, Rubin CT. Mechanical signals protect stem cell lineage selection, preserving the bone and muscle phenotypes in obesity. Ann N Y Acad Sci 2017; 1409:33-50. [PMID: 28891202 DOI: 10.1111/nyas.13442] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/19/2017] [Accepted: 06/28/2017] [Indexed: 12/18/2022]
Abstract
The incidence of obesity is rapidly rising, increasing morbidity and mortality rates worldwide. Associated comorbidities include type 2 diabetes, heart disease, fatty liver disease, and cancer. The impact of excess fat on musculoskeletal health is still unclear, although it is associated with increased fracture risk and a decline in muscular function. The complexity of obesity makes understanding the etiology of bone and muscle abnormalities difficult. Exercise is an effective and commonly prescribed nonpharmacological treatment option, but it can be difficult or unsafe for the frail, elderly, and morbidly obese. Exercise alternatives, such as low-intensity vibration (LIV), have potential for improving musculoskeletal health, particularly in conditions with excess fat. LIV has been shown to influence bone marrow mesenchymal stem cell differentiation toward higher-order tissues (i.e., bone) and away from fat. While the exact mechanisms are not fully understood, recent studies utilizing LIV both at the bench and in the clinic have demonstrated some efficacy. Here, we discuss the current literature investigating the effects of obesity on bone, muscle, and bone marrow and how exercise and LIV can be used as effective treatments for combating the negative effects in the presence of excess fat.
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Affiliation(s)
- Danielle M Frechette
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Divya Krishnamoorthy
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Tee Pamon
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - M Ete Chan
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Vihitaben Patel
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Clinton T Rubin
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
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19
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The effects of knee immobilization on marrow adipocyte hyperplasia and hypertrophy at the proximal rat tibia epiphysis. Acta Histochem 2017; 119:759-765. [PMID: 28967429 DOI: 10.1016/j.acthis.2017.09.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 09/15/2017] [Accepted: 09/21/2017] [Indexed: 12/25/2022]
Abstract
Marrow adipose deposition is observed during aging and in association with extended periods of immobility. The objective of this study was to determine the contribution of adipocyte hypertrophy and hyperplasia to bone marrow fat deposition induced by immobilization of the rat knee joint for 2, 4, 16 or 32 weeks. Histomorphometric analyses compared immobilized to sham-operated proximal tibia from age and gender matched rats to assess the contribution of aging and duration of immobilization on the number and size of marrow adipocytes. Results indicated that marrow adipose tissue increased with the duration of immobilization and was significant larger at 16 weeks compared to the sham-operated group (0.09956±0.13276mm2 vs 0.01990±0.01100mm2, p=0.047). The marrow adipose tissue was characterized by hyperplasia of adipocytes with a smaller average size after 2 and 4 weeks of immobilization (at 2 weeks hyperplasia: 68.86±33.62 vs 43.57±24.47 adipocytes/mm2, p=0.048; at 4 weeks hypotrophy: 0.00036±0.00019 vs 0.00046±0.00023mm2, p=0.027), and by adipocyte hypertrophy after 16 weeks of immobilization (0.00083±0.00049 vs 0.00046±0.00028mm2, p=0.027) compared to sham-operated. Both immobilized and sham-operated groups showed marrow adipose conversion with age; immobilized (p=0.008; sham: p=0.003). Overall, fat deposition in the bone marrow of the proximal rat tibia epiphysis and induced by knee joint immobilization was characterized by hyperplasia of small adipocytes in the early phase and by adipocyte hypertrophy in the later phase. Mediators of marrow fat deposition after immobilization and preventive countermeasures need to be investigated.
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20
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Towards human exploration of space: the THESEUS review series on muscle and bone research priorities. NPJ Microgravity 2017. [PMID: 28649630 PMCID: PMC5445590 DOI: 10.1038/s41526-017-0013-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Without effective countermeasures, the musculoskeletal system is altered by the microgravity environment of long-duration spaceflight, resulting in atrophy of bone and muscle tissue, as well as in deficits in the function of cartilage, tendons, and vertebral disks. While inflight countermeasures implemented on the International Space Station have evidenced reduction of bone and muscle loss on low-Earth orbit missions of several months in length, important knowledge gaps must be addressed in order to develop effective strategies for managing human musculoskeletal health on exploration class missions well beyond Earth orbit. Analog environments, such as bed rest and/or isolation environments, may be employed in conjunction with large sample sizes to understand sex differences in countermeasure effectiveness, as well as interaction of exercise with pharmacologic, nutritional, immune system, sleep and psychological countermeasures. Studies of musculoskeletal biomechanics, involving both human subject and computer simulation studies, are essential to developing strategies to avoid bone fractures or other injuries to connective tissue during exercise and extravehicular activities. Animal models may be employed to understand effects of the space environment that cannot be modeled using human analog studies. These include studies of radiation effects on bone and muscle, unraveling the effects of genetics on bone and muscle loss, and characterizing the process of fracture healing in the mechanically unloaded and immuno-compromised spaceflight environment. In addition to setting the stage for evidence-based management of musculoskeletal health in long-duration space missions, the body of knowledge acquired in the process of addressing this array of scientific problems will lend insight into the understanding of terrestrial health conditions such as age-related osteoporosis and sarcopenia.
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21
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Eiras S, Varela-Román A, Andrade MC, Castro A, González-Ferreiro R, Viñuela JE, Fernández-Trasancos Á, Carreira MC, Álvarez E, Casanueva FF, González-Juanatey JR. Non classical Monocytes Levels, Increased by Subcutaneous Fat-Secretome, Are Associated with Less Rehospitalization after Heart Failure Admission. J Cardiovasc Transl Res 2017; 10:16-26. [PMID: 28035653 DOI: 10.1007/s12265-016-9724-y] [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: 10/24/2016] [Accepted: 12/15/2016] [Indexed: 02/04/2023]
Abstract
Differential monocyte subsets are increased in obesity and heart failure (HF). We studied their role as predictors of rehospitalization for HF and their regulation by adipose tissue. Monocyte subsets and body fat composition were determined from 136 patients at the discharge after HF admission. Regulation of monocytes by SAT secretomes from obese/non-obese patients with HF was studied in a cell culture method. Proteomic analysis of secretome SAT was performed by LC-MALDI TOF/TOF. High CD14-CD16+ monocyte levels indicated less rehospitalization for HF (p = 0.018). SAT secretomes from obese patients increased the CD14-CD16+monocytes (11.8 ± 5.3 vs 3.9 ± 2.6%; p < 0.01). Differential proteins were determined between obese and non-obese patients with HF. High levels of CD14-CD16+ monocytes are associated with less rehospitalization for HF. This phenotype is upregulated by SAT secretome from obese patients with HF. This mechanism might help us to understand the obesity paradox in HF.
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Affiliation(s)
- Sonia Eiras
- Cardiology Group, Health Research Institute, Santiago de Compostela, Spain.
- Laboratorio 6. IDIS. Planta-2, C/Choupana s/n, Complejo Hospitalario Universitario de Santiago de Compostela, 15706, Santiago de Compostela, Spain.
| | - Alfonso Varela-Román
- Cardiology Group, Health Research Institute, Santiago de Compostela, Spain
- Cardiovascular Area and Coronary Unit, University Clinical Hospital, Santiago de Compostela, Spain
| | | | - Ana Castro
- Laboratory of Molecular and Cellular Endocrinology, Health Research Institute of Santiago de Compostela and CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío González-Ferreiro
- Cardiovascular Area and Coronary Unit, University Clinical Hospital, Santiago de Compostela, Spain
| | - Juan E Viñuela
- Immunology Unit, University Clinical Hospital, Santiago de Compostela, Spain
| | | | - Marcos C Carreira
- Laboratory of Molecular and Cellular Endocrinology, Health Research Institute of Santiago de Compostela and CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Ezequiel Álvarez
- Cardiology Group, Health Research Institute, Santiago de Compostela, Spain
| | - Felipe F Casanueva
- Laboratory of Molecular and Cellular Endocrinology, Health Research Institute of Santiago de Compostela and CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - José R González-Juanatey
- Cardiology Group, Health Research Institute, Santiago de Compostela, Spain
- Cardiovascular Area and Coronary Unit, University Clinical Hospital, Santiago de Compostela, Spain
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Shapses SA, Pop LC, Wang Y. Obesity is a concern for bone health with aging. Nutr Res 2017; 39:1-13. [PMID: 28385284 DOI: 10.1016/j.nutres.2016.12.010] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/16/2016] [Accepted: 12/27/2016] [Indexed: 02/08/2023]
Abstract
Accumulating evidence supports a complex relationship between adiposity and osteoporosis in overweight/obese individuals, with local interactions and endocrine regulation by adipose tissue on bone metabolism and fracture risk in elderly populations. This review was conducted to summarize existing evidence to test the hypothesis that obesity is a risk factor for bone health in aging individuals. Mechanisms by which obesity adversely affects bone health are believed to be multiple, such as an alteration of bone-regulating hormones, inflammation, oxidative stress, the endocannabinoid system, that affect bone cell metabolism are discussed. In addition, evidence on the effect of fat mass and distribution on bone mass and quality is reviewed together with findings relating energy and fat intake with bone health. In summary, studies indicate that the positive effects of body weight on bone mineral density cannot counteract the detrimental effects of obesity on bone quality. However, the exact mechanism underlying bone deterioration in the obese is not clear yet and further research is required to elucidate the effect of adipose depots on bone and fracture risk in the obese population.
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Affiliation(s)
- Sue A Shapses
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ.
| | - L Claudia Pop
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ
| | - Yang Wang
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ
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23
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Ghali O, Al Rassy N, Hardouin P, Chauveau C. Increased Bone Marrow Adiposity in a Context of Energy Deficit: The Tip of the Iceberg? Front Endocrinol (Lausanne) 2016; 7:125. [PMID: 27695438 PMCID: PMC5025430 DOI: 10.3389/fendo.2016.00125] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 08/30/2016] [Indexed: 12/17/2022] Open
Abstract
Elevated bone marrow adiposity (BMA) is defined as an increase in the proportion of the bone marrow (BM) cavity volume occupied by adipocytes. This can be caused by an increase in the size and/or number of adipocytes. BMA increases with age in a bone-site-specific manner. This increase may be linked to certain pathophysiological situations. Osteoporosis or compromised bone quality is frequently associated with high BMA. The involvement of BM adipocytes in bone loss may be due to commitment of mesenchymal stem cells to the adipogenic pathway rather than the osteogenic pathway. However, adipocytes may also act on their microenvironment by secreting factors with harmful effects for the bone health. Here, we review evidence that in a context of energy deficit (such as anorexia nervosa (AN) and restriction rodent models) bone alterations can occur in the absence of an increase in BMA. In severe cases, bone alterations are even associated with gelatinous BM transformation. The relationship between BMA and energy deficit and the potential regulators of this adiposity in this context are also discussed. On the basis of clinical studies and preliminary results on animal model, we propose that competition between differentiation into osteoblasts and differentiation into adipocytes might trigger bone loss at least in moderate-to-severe AN and in some calorie restriction models. Finally, some of the main questions resulting from this hypothesis are discussed.
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Affiliation(s)
- Olfa Ghali
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université de Lille, Boulogne-sur-Mer, France
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université du Littoral Côte d’Opale, Boulogne-sur-Mer, France
| | - Nathalie Al Rassy
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université de Lille, Boulogne-sur-Mer, France
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université du Littoral Côte d’Opale, Boulogne-sur-Mer, France
| | - Pierre Hardouin
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université de Lille, Boulogne-sur-Mer, France
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université du Littoral Côte d’Opale, Boulogne-sur-Mer, France
| | - Christophe Chauveau
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université de Lille, Boulogne-sur-Mer, France
- Laboratoire de Physiopathologie des Maladies Osseuses Inflammatoires, Université du Littoral Côte d’Opale, Boulogne-sur-Mer, France
- *Correspondence: Christophe Chauveau,
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Pagnotti GM, Styner M. Exercise Regulation of Marrow Adipose Tissue. Front Endocrinol (Lausanne) 2016; 7:94. [PMID: 27471493 PMCID: PMC4943947 DOI: 10.3389/fendo.2016.00094] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Accepted: 07/04/2016] [Indexed: 12/20/2022] Open
Abstract
Despite association with low bone density and skeletal fractures, marrow adipose tissue (MAT) remains poorly understood. The marrow adipocyte originates from the mesenchymal stem cell (MSC) pool that also gives rise to osteoblasts, chondrocytes, and myocytes, among other cell types. To date, the presence of MAT has been attributed to preferential biasing of MSC into the adipocyte rather than osteoblast lineage, thus negatively impacting bone formation. Here, we focus on understanding the physiology of MAT in the setting of exercise, dietary interventions, and pharmacologic agents that alter fat metabolism. The beneficial effect of exercise on musculoskeletal strength is known: exercise induces bone formation, encourages growth of skeletally supportive tissues, inhibits bone resorption, and alters skeletal architecture through direct and indirect effects on a multiplicity of cells involved in skeletal adaptation. MAT is less well studied due to the lack of reproducible quantification techniques. In recent work, osmium-based 3D quantification shows a robust response of MAT to both dietary and exercise intervention in that MAT is elevated in response to high-fat diet and can be suppressed following daily exercise. Exercise-induced bone formation correlates with suppression of MAT, such that exercise effects might be due to either calorie expenditure from this depot or from mechanical biasing of MSC lineage away from fat and toward bone, or a combination thereof. Following treatment with the anti-diabetes drug rosiglitazone - a PPARγ-agonist known to increase MAT and fracture risk - mice demonstrate a fivefold higher femur MAT volume compared to the controls. In addition to preventing MAT accumulation in control mice, exercise intervention significantly lowers MAT accumulation in rosiglitazone-treated mice. Importantly, exercise induction of trabecular bone volume is unhindered by rosiglitazone. Thus, despite rosiglitazone augmentation of MAT, exercise significantly suppresses MAT volume and induces bone formation. That exercise can both suppress MAT volume and increase bone quantity, notwithstanding the skeletal harm induced by rosiglitazone, underscores exercise as a powerful regulator of bone remodeling, encouraging marrow stem cells toward the osteogenic lineage to fulfill an adaptive need for bone formation. Thus, exercise represents an effective strategy to mitigate the deleterious effects of overeating and iatrogenic etiologies on bone and fat.
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Affiliation(s)
- Gabriel M. Pagnotti
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
| | - Maya Styner
- Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
- *Correspondence: Maya Styner,
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Tencerova M, Kassem M. The Bone Marrow-Derived Stromal Cells: Commitment and Regulation of Adipogenesis. Front Endocrinol (Lausanne) 2016; 7:127. [PMID: 27708616 PMCID: PMC5030474 DOI: 10.3389/fendo.2016.00127] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 09/05/2016] [Indexed: 12/13/2022] Open
Abstract
Bone marrow (BM) microenvironment represents an important compartment of bone that regulates bone homeostasis and the balance between bone formation and bone resorption depending on the physiological needs of the organism. Abnormalities of BM microenvironmental dynamics can lead to metabolic bone diseases. BM stromal cells (also known as skeletal or mesenchymal stem cells) [bone marrow stromal stem cell (BMSC)] are multipotent stem cells located within BM stroma and give rise to osteoblasts and adipocytes. However, cellular and molecular mechanisms of BMSC lineage commitment to adipocytic lineage and regulation of BM adipocyte formation are not fully understood. In this review, we will discuss recent findings pertaining to identification and characterization of adipocyte progenitor cells in BM and the regulation of differentiation into mature adipocytes. We have also emphasized the clinical relevance of these findings.
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Affiliation(s)
- Michaela Tencerova
- Department of Molecular Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
- Danish Diabetes Academy, Novo Nordisk Foundation, Odense, Denmark
- *Correspondence: Michaela Tencerova,
| | - Moustapha Kassem
- Department of Molecular Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
- Danish Diabetes Academy, Novo Nordisk Foundation, Odense, Denmark
- Stem Cell Unit, Department of Anatomy, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
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Li J, Liu X, Zuo B, Zhang L. The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis. Aging Dis 2015; 7:514-25. [PMID: 27493836 DOI: 10.14336/ad.2015.1206] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 12/06/2015] [Indexed: 01/08/2023] Open
Abstract
In the adult bone marrow, osteoblasts and adipocytes share a common precursor called mesenchymal stem cells (MSCs). The plasticity between the two lineages has been confirmed over the past decades, and has important implications in the etiology of bone diseases such as osteoporosis, which involves an imbalance between osteoblasts and adipocytes. The commitment and differentiation of bone marrow (BM) MSCs is tightly controlled by the local environment that maintains a balance between osteoblast lineage and adipocyte. However, pathological conditions linked to osteoporosis can change the BM microenvironment and shift the MSC fate to favor adipocytes over osteoblasts, and consequently decrease bone mass with marrow fat accumulation. This review discusses the changes that occur in the BM microenvironment under pathological conditions, and how these changes affect MSC fate. We suggest that manipulating local environments could have therapeutic implications to avoid bone loss in diseases like osteoporosis.
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Affiliation(s)
- Jiao Li
- 1Department of Cell Biology, Zunyi Medical College, Zunyi, China
| | - Xingyu Liu
- 1Department of Cell Biology, Zunyi Medical College, Zunyi, China
| | - Bin Zuo
- 2Department of Orthopedic Surgery, Xinhua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Li Zhang
- 3Department of Orthopedics, Tenth People's Hospital, Shanghai Tong Ji University, School of Medicine, Shanghai, China
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Li R, Liang L, Dou Y, Huang Z, Mo H, Wang Y, Yu B. Mechanical stretch inhibits mesenchymal stem cell adipogenic differentiation through TGFβ1/Smad2 signaling. J Biomech 2015; 48:3665-71. [PMID: 26341460 DOI: 10.1016/j.jbiomech.2015.08.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 08/10/2015] [Accepted: 08/13/2015] [Indexed: 12/28/2022]
Abstract
Mesenchymal stem cells (MSCs) are the common precursors of several functionally disparate cell lineages. A plethora of chemical and physical stimuli contribute to lineage decisions and guidance, including mechanical stretch concomitant with physical movement. Here, we examined how stretch regulates MSC differentiation into adipocytes and the intracellular signaling pathways involved. MSCs were cultured under adipogenic conditions and divided into a control and an experimental group. Cultures in the experimental group were subjected to a sinusoidal stretch regimen delivered via flexible culture bottoms (5% magnitude, 10 times per min, 6h/day, 3 or 5 days). Expression levels of the adipocyte markers PPARγ-2, adiponectin, and C/EBPα were measured as indices of differentiation. Compared to controls, MSCs exposed to mechanical stretch exhibited downregulated PPARγ-2, adiponectin, and C/EBPα mRNA expression. Alternatively, stretch upregulated phosphorylation of Smad2. This stretch-induced increase in Smad2 phosphorylation was suppressed by pretreatment with the TGFβ1/Smad2 pathway antagonist SB-431542. Pretreatment with the TGFβ1/Smad2 signaling agonist TGFβ1 facilitated the inhibitory effect of stretch on the expression levels of PPARγ-2, adiponectin, and C/EBPα proteins, while pretreatment with SB-431542 reversed the inhibitory effects of subsequent stretch on the expression levels of these markers. These results strongly suggest that the anti-adipogenic effects of mechanical stretch on MSCs are mediated, at least in part, by activation of the TGFβ1/Smad2 signaling pathway.
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Affiliation(s)
- Runguang Li
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Huiqiao Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Liang Liang
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yonggang Dou
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zeping Huang
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Huiting Mo
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yaning Wang
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bin Yu
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Tou JC. Evaluating resveratrol as a therapeutic bone agent: preclinical evidence from rat models of osteoporosis. Ann N Y Acad Sci 2015. [PMID: 26200189 DOI: 10.1111/nyas.12840] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Resveratrol (RSV) is a naturally occurring plant polyphenol that has potential to attenuate osteoporosis with distinct pathologies. This review evaluates preclinical evidence regarding the efficacy and safety of RSV as a therapeutic bone agent using different rat models. Limitations of these animal models are discussed, and suggestions for strengthening the experimental design of future studies are provided. The ovariectomized rat model of postmenopausal osteoporosis reported that RSV supplementation attenuated estrogen deficiency-induced bone loss and trabecular structural deterioration. RSV safety was indicated by the absence of stimulation of estrogen-sensitive tissue. Providing RSV to rats aged >6 months attenuated age-related bone mass loss and structural deterioration but produced inconsistent effects on bones in rats aged <6 months. The hindlimb-suspension rat model of disuse osteoporosis reported that RSV attenuated bone loss in old rats, but higher doses and longer duration supplementation before mechanical loading were required for younger rats. Limitations common to studies using rat models of osteoporosis include requirements to include animals that are skeletally mature, longer study durations, and to adjust for potential confounding effects due to altered body weight and endocrine function. Strengthening experimental design can contribute to translation of animal results to clinically relevant recommendations for humans.
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Affiliation(s)
- Janet C Tou
- Human Nutrition and Foods, Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, West Virginia
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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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30
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Lee SY, Li MH, Chen YL, Lin KT, Hsu SW, Chen YH. TAZ is Associated with Poor Osteoblast Differentiation of Mesenchymal Stem Cells Under Simulated Microgravity. JOURNAL OF MEDICAL SCIENCES 2015. [DOI: 10.4103/1011-4564.172997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Lescale C, Schenten V, Djeghloul D, Bennabi M, Gaignier F, Vandamme K, Strazielle C, Kuzniak I, Petite H, Dosquet C, Frippiat JP, Goodhardt M. Hind limb unloading, a model of spaceflight conditions, leads to decreased B lymphopoiesis similar to aging. FASEB J 2014; 29:455-63. [PMID: 25376832 DOI: 10.1096/fj.14-259770] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure induced by a ground-based model of spaceflight, hind limb unloading (HU), could affect B lymphopoiesis. To this end, we analyzed both bone parameters and the frequency of early hematopoietic precursors and cells of the B lineage after 3, 6, 13, and 21 d of HU. We found that limb disuse leads to a decrease in both bone microstructure and the frequency of B-cell progenitors in the bone marrow. Although multipotent hematopoietic progenitors were not affected by HU, a decrease in B lymphopoiesis was observed as of the common lymphoid progenitor (CLP) stage with a major block at the progenitor B (pro-B) to precursor B (pre-B) cell transition (5- to 10-fold decrease). The modifications in B lymphopoiesis were similar to those observed in aged mice and, as with aging, decreased B-cell generation in HU mice was associated with reduced expression of B-cell transcription factors, early B-cell factor (EBF) and Pax5, and an alteration in STAT5-mediated IL-7 signaling. These findings demonstrate that mechanical unloading of hind limbs results in a decrease in early B-cell differentiation resembling age-related modifications in B lymphopoiesis.
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Affiliation(s)
- Chloé Lescale
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Véronique Schenten
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Dounia Djeghloul
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Meriem Bennabi
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Fanny Gaignier
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Katleen Vandamme
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Catherine Strazielle
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Isabelle Kuzniak
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Hervé Petite
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Christine Dosquet
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Jean-Pol Frippiat
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
| | - Michele Goodhardt
- *Institut Universitaire d'Hématologie, Université Paris 7 Denis Diderot, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-940, Paris, France; EA7300, Stress Immunity Pathogens Laboratory, Lorraine University, Vandœuvre-lès-Nancy, France; and UMR CNRS 7052, Biomécanique et Biomatériaux Ostéo-articulaires, Faculté de Médecine Lariboisière, Paris, France
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Lee EJ, Song DH, Kim YJ, Choi B, Chung YH, Kim SM, Koh JM, Yoon SY, Song Y, Kang SW, Chang EJ. PTX3 stimulates osteoclastogenesis by increasing osteoblast RANKL production. J Cell Physiol 2014; 229:1744-52. [PMID: 24664887 DOI: 10.1002/jcp.24626] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 03/20/2014] [Indexed: 12/15/2022]
Abstract
Pentraxin-3 (PTX3), also known as tumor necrosis factor-stimulated gene 14 (TSG-14), is produced by immune and vascular cells in response to pro-inflammatory signals and is therefore a multipotent inflammatory mediator. The present study showed that during human osteoblast (OB) differentiation, precursor OBs (pOBs), but not mature OB, highly expressed PTX3. TNFα treatment elevated the PTX3 expression of pOBs. When mice were injected with lipopolysaccharide, which induces an inflammatory osteolytic condition characterized by trabecular bone destruction and high osteoclastogenesis, their bone marrow cells expressed elevated levels of PTX3 protein. Exogenous PTX3 did not directly affect osteoclast (OC) or OB differentiation. However, when pOBs and precursor OCs were co-cultured, exogenous PTX3 significantly increased the number of tartrate-resistant acid phosphatase-positive multinucleated cells (i.e., OC cells) by increasing the pOB mRNA expression and protein secretion of RANK ligand (RANKL). This was accompanied with increased Runt-related transcription factor 2 (Runx2) expression in the pOBs. Knock-down of endogenous PTX3 with small-interfering RNA did not change the osteogenic potential of pOBs but suppressed their production of RANKL and reduced osteoclastogenesis. Finally, TNFα treatment of the co-culture elevated PTX3 expression by the pOBs and increased OC formation. This effect was suppressed by PTX3 knock-down by decreasing RANKL expression. Thus, the PTX3-driven increase in the osteoclastogenic potential of pOBs appears to be mediated by the effect of PTX3 on pOB RANKL production. These findings suggest that PTX3 is an inflammatory mediator that contributes to the deteriorating osteolytic condition of inflamed bone. J. Cell. Physiol. 229: 1744-1752, 2014. © 2014 Wiley Periodicals, Inc.
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Affiliation(s)
- Eun-Jin Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; Department of Anatomy and Cell Biology, Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul, Korea
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Abstract
Bones adapt to accommodate the physical forces they experience through changes in architecture and mass. Stem cells differentiate into bone-forming osteoblasts, and mechanical stimulation is involved in this process. Various studies have applied controlled mechanical stimulation to stem cells and investigated the effects on osteogenic lineage commitment. These studies demonstrate that physical stimuli can induce osteogenic lineage commitment. Tension, fluid shear stress, substrate material properties, and cell shape are all factors that influence osteogenic differentiation. In particular, the level of tension is important. Also, rigid substrates with stiffness similar to collagenous bone induce osteogenic differentiation, while softer substrates induce other lineages. Finally, cells allowed to adhere over a larger area are able to differentiate towards the osteogenic lineage while cells adhering to a smaller area are restricted to the adipogenic lineage. Stem cells are able to sense their mechanical environments through various mechanosensors, including the cytoskeleton, focal adhesions, and primary cilia. The cytoskeleton provides a structural frame for the cell, and myosin interacts with actin to generate cytoskeletal tension, which is important for mechanically induced osteogenesis of stem cells. Adapter proteins link the cytoskeleton to integrins, which attach the cell to the substrate, forming a focal adhesion. A variety of signaling proteins are also associated with focal adhesions. Forces are transmitted to the substrate at these sites, and an intact focal adhesion is important for mechanically induced osteogenesis. The primary cilium is a single, immotile, antenna-like structure that extends from the cell into the extracellular space. It has emerged as an important signaling center, acting as a microdomain to facilitate biochemical signaling. Mechanotransduction is the process by which physical stimuli are converted into biochemical responses. When potential mechanosensors are disrupted, the activities of components of mechanotransduction pathways are also inhibited, preventing mechanically induced osteogenesis. Calcium, mitogen-activated protein kinase/extracellular signal-regulated kinase, Wnt, Yes-associated protein/transcriptional coactivator with PDZ-binding motif and RhoA/Rho kinase signaling are some of the mechanotransduction pathways proposed to be important. In this review, types of mechanical stimuli, mechanosensors, and key pathways involved in mechanically induced osteogenesis of stem cells are discussed.
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34
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Marie PJ. Bone cell senescence: mechanisms and perspectives. J Bone Miner Res 2014; 29:1311-21. [PMID: 24496911 DOI: 10.1002/jbmr.2190] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 01/24/2014] [Accepted: 01/27/2014] [Indexed: 12/15/2022]
Abstract
Age-related bone loss is in large part the consequence of senescence mechanisms that impact bone cell number and function. In recent years, progress has been made in the understanding of the molecular mechanisms underlying bone cell senescence that contributes to the alteration of skeletal integrity during aging. These mechanisms can be classified as intrinsic senescence processes, alterations in endogenous anabolic factors, and changes in local support. Intrinsic senescence mechanisms cause cellular dysfunctions that are not tissue specific and include telomere shortening, accumulation of oxidative damage, impaired DNA repair, and altered epigenetic mechanisms regulating gene transcription. Aging mechanisms that are more relevant to the bone microenvironment include alterations in the expression and signaling of local growth factors and altered intercellular communications. This review provides an integrated overview of the current concepts and interacting mechanisms underlying bone cell senescence during aging and how they could be targeted to reduce the negative impact of senescence in the aging skeleton.
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Affiliation(s)
- Pierre J Marie
- Inserm UMR-1132, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France
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35
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Hu M, Qin YX. Dynamic fluid flow stimulation on cortical bone and alterations of the gene expressions of osteogenic growth factors and transcription factors in a rat functional disuse model. Arch Biochem Biophys 2014; 545:154-61. [PMID: 24486201 DOI: 10.1016/j.abb.2014.01.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 01/17/2014] [Accepted: 01/21/2014] [Indexed: 12/31/2022]
Abstract
Recently we have developed a dynamic hydraulic stimulation (DHS) as a loading modality to induce anabolic responses in bone. To further study the functional process of DHS regulated bone metabolism, the objective of this study was to evaluate the effects of DHS on cortical bone and its alterations on gene expressions of osteogenic growth factors and transcription factors as a function of time. Using a model system of 5-month-old hindlimb suspended (HLS) female Sprague-Dawley rats, DHS was applied to the right tibiae of the stimulated rats with a loading frequency of 2Hz with 30mmHg (p-p) dynamic pressure, 5days/week, for a total of 28days. Midshafts of the tibiae were analyzed using μCT and histology. Total RNA was analyzed using RT-PCR on selected osteogenic genes (RUNX2, β-catenin, osteopontin, VEGF, BMP2, IGF-1, and TGF-β) on 3-, 7-, 14- , and 21-day. Results showed increased Cort.Th and Ct.BV/TV as well as a time-dependent fashion of gradual changes in mRNA levels upon DHS. While DHS-driven fold changes of the mRNA levels remained low before Day-7, its fold changes started to elevate by Day-14 and then dropped by Day-21. This study further delineates the underlying molecular mechanism of DHS-derived mechanical signals, and its time-dependent optimization.
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Affiliation(s)
- Minyi Hu
- Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States
| | - Yi-Xian Qin
- Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States.
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36
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Spyropoulou A, Basdra EK. Mechanotransduction in bone: Intervening in health and disease. World J Exp Med 2013; 3:74-86. [DOI: 10.5493/wjem.v3.i4.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/06/2013] [Accepted: 11/03/2013] [Indexed: 02/06/2023] Open
Abstract
Mechanotransduction has been proven to be one of the most significant variables in bone remodeling and its alterations have been shown to result in a variety of bone diseases. Osteoporosis, Paget’s disease, orthopedic disorders, osteopetrosis as well as hyperparathyroidism and hyperthyroidism all comprise conditions which have been linked with deregulated bone remodeling. Although the significance of mechanotransduction for bone health and disease is unquestionable, the mechanisms behind this important process have not been fully understood. This review will discuss the molecules that have been found to be implicated in mechanotransduction, as well as the mechanisms underlying bone health and disease, emphasizing on what is already known as well as new molecules potentially taking part in conveying mechanical signals from the cell surface towards the nucleus under physiological or pathologic conditions. It will also focus on the model systems currently used in mechanotransduction studies, like osteoblast-like cells as well as three-dimensional constructs and their applications among others. It will also examine the role of mechanostimulatory techniques in preventing and treating bone degenerative diseases and consider their applications in osteoporosis, craniofacial development, skeletal deregulations, fracture treatment, neurologic injuries following stroke or spinal cord injury, dentistry, hearing problems and bone implant integration in the near future.
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Sadie-Van Gijsen H, Hough FS, Ferris WF. Determinants of bone marrow adiposity: the modulation of peroxisome proliferator-activated receptor-γ2 activity as a central mechanism. Bone 2013; 56:255-65. [PMID: 23800517 DOI: 10.1016/j.bone.2013.06.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 06/04/2013] [Accepted: 06/12/2013] [Indexed: 12/23/2022]
Abstract
Although the presence of adipocytes in the bone marrow is a normal physiological phenomenon, the role of these cells in bone homeostasis and during pathological states has not yet been fully delineated. As osteoblasts and adipocytes originate from a common progenitor, with an inverse relationship existing between osteoblastogenesis and adipogenesis, bone marrow adiposity often negatively correlates with osteoblast number and bone mineral density. Bone adiposity can be affected by several physiological and pathophysiological factors, with abnormal, elevated marrow fat resulting in a pathological state. This review focuses on the regulation of bone adiposity by physiological factors, including aging, mechanical loading and growth factor expression, as well as the pathophysiological factors, including diseases such as anorexia nervosa and dyslipidemia, and pharmacological agents such as thiazolidinediones and statins. Although these factors regulate bone marrow adiposity via a plethora of different intracellular signaling pathways, these diverse pathways often converge on the modulation of the expression and/or activity of the pro-adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)-γ2, suggesting that any factor that affects PPAR-γ2 may have an impact on the fat content of bone.
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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.
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38
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Berendsen AD, Olsen BR. Osteoblast-adipocyte lineage plasticity in tissue development, maintenance and pathology. Cell Mol Life Sci 2013; 71:493-7. [PMID: 23934155 DOI: 10.1007/s00018-013-1440-z] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/22/2013] [Accepted: 07/25/2013] [Indexed: 12/13/2022]
Abstract
Osteoblasts and adipocytes share a common precursor in adult bone marrow and there is a degree of plasticity between the two cell lineages. This has important implications for the etiology of not only osteoporosis but also several other diseases involving an imbalance between osteoblasts and adipocytes. Understanding the process of differentiation of osteoblasts and adipocytes and their trans-differentiation is crucial in order to identify genes and other factors that may contribute to the pathophysiology of such diseases. Several transcriptional regulators have been shown to control osteoblast and adipocyte differentiation and function. Regulation of cell commitment occurs at the level of the progenitor cell through cross talk between complex signaling pathways and epigenetic mechanisms such as DNA methylation, chromatin remodeling, and microRNAs. Here we review the complex precursor cell microenvironment controlling osteoblastogenesis and adipogenesis during tissue development, maintenance, and pathology.
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Affiliation(s)
- Agnes D Berendsen
- Department of Developmental Biology, REB 413, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA, 02115, USA,
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39
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Spatz JM, Ellman R, Cloutier AM, Louis L, van Vliet M, Suva LJ, Dwyer D, Stolina M, Ke HZ, Bouxsein ML. Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. J Bone Miner Res 2013; 28:865-74. [PMID: 23109229 PMCID: PMC4076162 DOI: 10.1002/jbmr.1807] [Citation(s) in RCA: 123] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 10/08/2012] [Accepted: 10/17/2012] [Indexed: 12/13/2022]
Abstract
Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11-17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU-SclAbII were at or above values of CON-VEH mice. For example, hindlimb bone mineral density (BMD) decreased -9.2% ± 1.0% in HLU-VEH, whereas it increased 4.2% ± 0.7%, 13.1% ± 1.0%, and 30.6% ± 3.0% in CON-VEH, HLU-SclAbII, and CON-SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro-computed tomography (µCT) imaging of the distal femur, was lower in HLU-VEH versus CON-VEH (p < 0.05), and was 2- to 3-fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three-point bending, and distal femoral strength, assessed by micro-finite element analysis (µFEA), were significantly higher in SclAbII versus VEH-groups in both loading conditions. Serum sclerostin was higher in HLU-VEH (134 ± 5 pg/mL) compared to CON-VEH (116 ± 6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse-induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments.
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Affiliation(s)
- Jordan M Spatz
- Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology (HST), Bioastronautics Program, Cambridge, MA, USA
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40
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Zhang P, Wu Y, Dai Q, Fang B, Jiang L. p38-MAPK signaling pathway is not involved in osteogenic differentiation during early response of mesenchymal stem cells to continuous mechanical strain. Mol Cell Biochem 2013; 378:19-28. [PMID: 23435958 DOI: 10.1007/s11010-013-1589-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 02/08/2013] [Indexed: 12/31/2022]
Abstract
Mechanical stimuli play a significant role in the regulation of bone remodeling during orthodontic tooth movement. However, the correlation between mechanical strain and bone remodeling is still poorly understood. In this study, we used a model of continuous mechanical strain (CMS) on bone mesenchymal stem cells (BMSCs) to investigate the proliferation and osteogenic differentiation of BMSCs and the mechanism of mechano-transduction. A CMS of 10 % at 1 Hz suppressed the proliferation of BMSCs and induced early osteogenic differentiation within 48 h by activating Runx2 and increasing alkaline phosphatase (ALP) activity and mRNA expression of osteogenesis-related genes (ALP, collagen type I, and osteopontin). Regarding mitogen-activated protein kinase (MAPK) activation, CMS induced phased phosphorylation of p38 consisting of a rapid induction of p38 MAPK at 10 min and a rapid decay after 1 h. Furthermore, the potent p38 inhibitor SB203580 blocked the induction of p38 MAPK signaling, but had little effect on subsequent osteogenic events. These results demonstrate that mechanical strain may act as a stimulator to induce the differentiation of BMSCs into osteoblasts, which is a vital function for bone formation in orthodontic tooth movement. However, activation of the p38 signaling pathway may not be involved in this process.
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Affiliation(s)
- Peng Zhang
- Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Science, Shanghai 9th People's Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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41
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Galea GL, Meakin LB, Sugiyama T, Zebda N, Sunters A, Taipaleenmaki H, Stein GS, van Wijnen AJ, Lanyon LE, Price JS. Estrogen receptor α mediates proliferation of osteoblastic cells stimulated by estrogen and mechanical strain, but their acute down-regulation of the Wnt antagonist Sost is mediated by estrogen receptor β. J Biol Chem 2013; 288:9035-48. [PMID: 23362266 PMCID: PMC3610976 DOI: 10.1074/jbc.m112.405456] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Mechanical strain and estrogens both stimulate osteoblast proliferation through estrogen receptor (ER)-mediated effects, and both down-regulate the Wnt antagonist Sost/sclerostin. Here, we investigate the differential effects of ERα and -β in these processes in mouse long bone-derived osteoblastic cells and human Saos-2 cells. Recruitment to the cell cycle following strain or 17β-estradiol occurs within 30 min, as determined by Ki-67 staining, and is prevented by the ERα antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride. ERβ inhibition with 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-β]pyrimidin-3-yl] phenol (PTHPP) increases basal proliferation similarly to strain or estradiol. Both strain and estradiol down-regulate Sost expression, as does in vitro inhibition or in vivo deletion of ERα. The ERβ agonists 2,3-bis(4-hydroxyphenyl)-propionitrile and ERB041 also down-regulated Sost expression in vitro, whereas the ERα agonist 4,4′,4″-[4-propyl-(1H)-pyrazol-1,3,5-triyl]tris-phenol or the ERβ antagonist PTHPP has no effect. Tamoxifen, a nongenomic ERβ agonist, down-regulates Sost expression in vitro and in bones in vivo. Inhibition of both ERs with fulvestrant or selective antagonism of ERβ, but not ERα, prevents Sost down-regulation by strain or estradiol. Sost down-regulation by strain or ERβ activation is prevented by MEK/ERK blockade. Exogenous sclerostin has no effect on estradiol-induced proliferation but prevents that following strain. Thus, in osteoblastic cells the acute proliferative effects of both estradiol and strain are ERα-mediated. Basal Sost down-regulation follows decreased activity of ERα and increased activity of ERβ. Sost down-regulation by strain or increased estrogens is mediated by ERβ, not ERα. ER-targeting therapy may facilitate structurally appropriate bone formation by enhancing the distinct ligand-independent, strain-related contributions to proliferation of both ERα and ERβ.
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Affiliation(s)
- Gabriel L Galea
- School of Veterinary Sciences, University of Bristol, Bristol BS40 5DU, United Kingdom.
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42
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Ko CY, Kang H, Ryu Y, Jung B, Kim H, Jeong D, Shin HI, Lim D, Kim HS. The effects of minimally invasive laser needle system on suppression of trabecular bone loss induced by skeletal unloading. Lasers Med Sci 2013; 28:1495-502. [PMID: 23324954 DOI: 10.1007/s10103-013-1265-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 01/02/2013] [Indexed: 10/27/2022]
Abstract
This study was aimed to evaluate the effects of low-level laser therapy (LLLT) in the treatment of trabecular bone loss induced by skeletal unloading. Twelve mice have taken denervation operation. At 2 weeks after denervation, LLLT (wavelength, 660 nm; energy, 3 J) was applied to the right tibiae of 6 mice (LASER) for 5 days/week over 2 weeks by using a minimally invasive laser needle system (MILNS) which consists of a 100 μm optical fiber in a fine needle (diameter, 130 μm) [corrected]. Structural parameters and histograms of bone mineralization density distribution (BMDD) were obtained before LLLT and at 2 weeks after LLLT. In addition, osteocyte, osteoblast, and osteoclast populations were counted. Two weeks after LLLT, bone volume fraction, trabeculae number, and trabeculae thickness were significantly increased and trabecular separations, trabecular bone pattern factor, and structure model index were significantly decreased in LASER than SHAM (p < 0.05). BMDD in LASER was maintained while that in SHAM was shifted to lower mineralization. Osteocyte and osteoblast populations were significantly increased but osteoclast population was significantly decreased in LASER when compared with those in SHAM (p < 0.05). The results indicate that LLLT with the MILNS may enhance bone quality and bone homeostasis associated with enhancement of bone formation and suppression of bone resorption.
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Affiliation(s)
- Chang-Yong Ko
- Research Team, Korea Orthopedics and Rehabilitation Engineering Center, Incheon, 403-712, Republic of Korea
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43
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Abstract
Excess body weight due to obesity has traditionally been considered to have a positive effect on bone; however, more recent findings suggest that bone quality is compromised. Both obesity and caloric restriction increase fracture risk and are regulated by endocrine factors and cytokines that have direct and indirect effects on bone and calcium absorption. Weight reduction will decrease bone mass and mineral density, but this varies by the individual's age, gender, and adiposity. Dietary modifications, exercise, and medications have been shown to attenuate the bone loss associated with weight reduction. Future obesity and weight loss trials would benefit from assessment of key hormones, adipokine and gut peptides that regulate calcium absorption, and bone mineral density and quality by using sensitive techniques in high-risk populations.
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Affiliation(s)
- Sue A Shapses
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey 08901, USA.
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44
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Song L, Liu M, Ono N, Bringhurst FR, Kronenberg HM, Guo J. Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes. J Bone Miner Res 2012; 27:2344-58. [PMID: 22729939 PMCID: PMC3474875 DOI: 10.1002/jbmr.1694] [Citation(s) in RCA: 203] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Wnt signaling is essential for osteogenesis and also functions as an adipogenic switch, but it is not known if interrupting wnt signaling via knockout of β-catenin from osteoblasts would cause bone marrow adiposity. Here, we determined whether postnatal deletion of β-catenin in preosteoblasts, through conditional cre expression driven by the osterix promoter, causes bone marrow adiposity. Postnatal disruption of β-catenin in the preosteoblasts led to extensive bone marrow adiposity and low bone mass in adult mice. In cultured bone marrow-derived cells isolated from the knockout mice, adipogenic differentiation was dramatically increased, whereas osteogenic differentiation was significantly decreased. As myoblasts, in the absence of wnt/β-catenin signaling, can be reprogrammed into the adipocyte lineage, we sought to determine whether the increased adipogenesis we observed partly resulted from a cell-fate shift of preosteoblasts that had to express osterix (lineage-committed early osteoblasts), from the osteoblastic to the adipocyte lineage. Using lineage tracing both in vivo and in vitro we showed that the loss of β-catenin from preosteoblasts caused a cell-fate shift of these cells from osteoblasts to adipocytes, a shift that may at least partly contribute to the bone marrow adiposity and low bone mass in the knockout mice. These novel findings indicate that wnt/β-catenin signaling exerts control over the fate of lineage-committed early osteoblasts, with respect to their differentiation into osteoblastic versus adipocytic populations in bone, and thus offers potential insight into the origin of bone marrow adiposity.
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Affiliation(s)
- Lige Song
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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45
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Siu WS, Wong HL, Lau CP, Shum WT, Wong CW, Gao S, Fung KP, Lau CBS, Hung LK, Ko CH, Leung PC. The Effects of an Antiosteoporosis Herbal Formula Containing Epimedii Herba, Ligustri Lucidi Fructus and Psoraleae Fructus on Density and Structure of Rat Long Bones Under Tail-Suspension, and its Mechanisms of Action. Phytother Res 2012; 27:484-92. [DOI: 10.1002/ptr.4743] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 04/13/2012] [Accepted: 05/02/2012] [Indexed: 11/08/2022]
Affiliation(s)
| | - Hing-Lok Wong
- Jockey Club Centre for Osteoporosis Care and Control; The Chinese University of Hong Kong; Shatin; New Territories; Hong Kong
| | | | | | | | | | | | | | - Leung-Kim Hung
- Department of Orthopaedics and Traumatology; The Chinese University of Hong Kong; Shatin; New Territories; Hong Kong
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46
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Ko CY, Seo DH, Kim HS. Deterioration of bone quality in the tibia and fibula in growing mice during skeletal unloading: gender-related differences. J Biomech Eng 2012; 133:111003. [PMID: 22168735 DOI: 10.1115/1.4005350] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Skeletal unloading causes bone loss in both men and women; however, only a few studies have been performed on the effects of gender differences on bone quality during skeletal unloading. Moreover, although the fibula also plays an important role in load bearing and ankle stability, the effects of unloading on the fibula have been rarely investigated. The present study aimed to investigate the effects of skeletal unloading on bone quality of the tibia and fibula in growing animals and to determine whether differences existed between genders. Six-week-old female and male mice were randomly allocated into two groups. The right hindlimb of each mouse in the skeletal unloading group was subjected to sciatic neurectomy. After two weeks of skeletal unloading, the structural characteristics of the tibia and fibula in both genders were worsened. In addition, the bone mineralization density distribution (MDD) of the tibia and fibula in both genders were altered. However, the magnitude of deterioration and alteration of the MDD in the bones of females were larger than in those of males. These results demonstrate that skeletal unloading diminishes bone quality in the tibia and fibula, leading to an increase in bone fracture risks, particularly in females.
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Affiliation(s)
- Chang-Yong Ko
- Inspection and Diagnosis Methods, Fraunhofer Institute for Nondestructive Testing, Dresden 01109, Germany
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47
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Slade JM, Coe LM, Meyer RA, McCabe LR. Human bone marrow adiposity is linked with serum lipid levels not T1-diabetes. J Diabetes Complications 2012; 26:1-9. [PMID: 22257906 DOI: 10.1016/j.jdiacomp.2011.11.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 09/08/2011] [Accepted: 11/02/2011] [Indexed: 02/07/2023]
Abstract
Increased marrow adiposity is often associated with bone loss. Little is known about the regulation of marrow adiposity in humans. Marrow adiposity is increased in several mouse models including type I (T1)-diabetic mice, which also display bone loss. However, the impact of metabolic disease on marrow adiposity in humans has yet to be examined. This study measured bone marrow adiposity levels with iterative decomposition of water and fat with echo asymmetry and least-squares estimation magnetic resonance imaging and determined their relationship with T1-diabetes, bone mineral density (BMD), and serum lipid levels. Participants were adult T1-diabetic patients (glycosylated hemoglobin averaging 7.70%±0.4%) and age- and body-mass-index-matched nondiabetic subjects. Consistent with previous reports, serum osteocalcin levels were lower in subjects with T1-diabetes compared to controls (reaching statistical significance in females) and negatively correlated with disease duration (r=-0.50, P<.01). Furthermore, femur neck BMD inversely correlated with diabetes severity (r=-0.417, P<.05). While marrow adiposity was not altered by T1-diabetes, there was a striking positive correlation between vertebral, femur, and tibia marrow adiposity and serum lipid levels (low-density lipoprotein, total cholesterol, cholesterol:high-density lipoprotein ratio, and triglyceride; r≥0.383), reaching a significance of P<.001 in some comparisons. Marrow adiposity also displayed strong intrasubject correlations at multiple bone sites (r≥0.411, P<.05), increased with age (r=0.410, P<.05 at vertebral sites), and was reciprocally related to bone density (r≥-0.378, P<.05). Taken together, our data suggest that marrow adiposity may be an indicator of elevated serum lipid levels and decreased bone density.
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Affiliation(s)
- Jill M Slade
- Department of Radiology, Michigan State University, East Lansing, MI 48824, USA.
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48
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Huang ZY, Hong LQ, Na N, Luo Y, Miao B, Chen J. Infusion of mesenchymal stem cells overexpressing GDNF ameliorates renal function in nephrotoxic serum nephritis. Cell Biochem Funct 2011; 30:139-44. [PMID: 22105543 DOI: 10.1002/cbf.1827] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Revised: 09/20/2011] [Accepted: 09/30/2011] [Indexed: 01/08/2023]
Abstract
Nephrotoxic serum nephritis (NSN) is a well-established animal model of glomerulonephritis, a frequent clinical condition with a high mortality rate owing to the ineffectiveness of current therapies. Mesenchymal stem cells (MSCs) are adult stem cells with potential as novel therapies in regenerative medicine owing to the absence of allogenic rejection. Glial cell-derived neurotrophic factor (GDNF) acts as a morphogen in kidney development. The therapeutic effectiveness of bone marrow MSCs overexpressing GDNF (GDNF-MSCs) was evaluated in an NSN rat model. An adenoviral vector was used to transduce MSCs with GDNF and a green fluorescent protein reporter gene. Then, GDNF-MSCs were injected into NSN rats via the renal artery. The influence of GDNF on renal injury was assessed. The location of GDNF-MSCs in kidneys was detected using fluorescence microscopy, cells were counted, and kidney function was measured. Infusion of GNDF-MSCs enhanced the recovery of renal function in NSN rats. MSCs were detected in the kidney cortex after injection. Compared with control MSCs, GDNF-MSCs led to significantly better renal function and injury recovery in NSN rats. GDNF has a positive effect on MSC differentiation in renal tissue. Owing to their highly renoprotective capacity, GDNF-MSCs represent a possible novel cell-based paradigm for treatment of glomerulonephritis.
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Affiliation(s)
- Zheng-Yu Huang
- Department of Kidney Transplantation, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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49
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Swift JM, Swift SN, Nilsson MI, Hogan HA, Bouse SD, Bloomfield SA. Cancellous bone formation response to simulated resistance training during disuse is blunted by concurrent alendronate treatment. J Bone Miner Res 2011; 26:2140-50. [PMID: 21509821 DOI: 10.1002/jbmr.407] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The purpose of this study was to assess the effectiveness of simulated resistance training (SRT) exercise combined with alendronate (ALEN) in mitigating or preventing disuse-associated losses in cancellous bone microarchitecture and formation. Sixty male Sprague-Dawley rats (6 months old) were randomly assigned to either cage control (CC), hind limb unloading (HU), HU plus either ALEN (HU + ALEN), SRT (HU + SRT), or a combination of ALEN and SRT (HU + SRT/ALEN) for 28 days. HU + SRT and HU + SRT/ALEN rats were anesthetized and subjected to muscle contractions once every 3 days during HU (four sets of five repetitions, 1000 ms isometric + 1000 ms eccentric). Additionally, HU + ALEN and HU + SRT/ALEN rats received 10 µg/kg of body weight of ALEN three times per week. HU reduced cancellous bone-formation rate (BFR) by 80%, with no effect of ALEN treatment (-85% versus CC). SRT during HU significantly increased cancellous BFR by 123% versus CC, whereas HU + SRT/ALEN inhibited the anabolic effect of SRT (-70% versus HU + SRT). SRT increased bone volume and trabecular thickness by 19% and 9%, respectively, compared with CC. Additionally, osteoid surface (OS/BS) was significantly greater in HU + SRT rats versus CC (+32%). Adding ALEN to SRT during HU reduced Oc.S/BS (-75%), Ob.S/BS (-72%), OS/BS (-61%), and serum TRACP5b (-36%) versus CC. SRT and ALEN each independently suppressed a nearly twofold increase in adipocyte number evidenced with HU and inhibited increases in osteocyte apoptosis. These results demonstrate the anabolic effect of a low volume of high-intensity muscle contractions during disuse and suggest that both bone resorption and bone formation are suppressed when SRT is combined with bisphosphonate treatment.
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Affiliation(s)
- Joshua M Swift
- Departments of Health and Kinesiology, Texas A&M University, College Station, TX 77843-4243, USA
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50
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Cho SW, Yang JY, Her SJ, Choi HJ, Jung JY, Sun HJ, An JH, Cho HY, Kim SW, Park KS, Kim SY, Baek WY, Kim JE, Yim M, Shin CS. Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice. J Bone Miner Res 2011; 26:1939-52. [PMID: 21351141 DOI: 10.1002/jbmr.366] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
PPARγ has critical role in the differentiation of mesenchymal stem cells into adipocytes while suppressing osteoblastic differentiation. We generated transgenic mice that overexpress PPARγ specifically in osteoblasts under the control of a 2.3-kb procollagen type 1 promoter (Col.1-PPARγ). Bone mineral density (BMD) of 6- to 14-week-old Col.1 - PPARγ male mice was 8% to 10% lower than that of their wild-type littermates, whereas no difference was noticed in Col.1-PPARγ female mice. Col.1-PPARγ male mice exhibited decreased bone volume (45%), trabecular thickness (23%), and trabecular number (27%), with a reciprocal increase in trabecular spacing (51%). Dynamic histomorphometric analysis also revealed that bone-formation rate (42%) and mineral apposition rate (32%) were suppressed significantly in Col.1-PPARγ male mice compared with their wild-type littermates. Interestingly, osteoclast number and surface also were decreased by 40% and 58%, respectively, in Col.1-PPARγ male mice. In vitro whole-marrow culture for osteoclastogenesis also showed a significant decrease in osteoclast formation (approximately 35%) with the cells from Col.1-PPARγ male mice, and OPG/RANKL ratio was reduced in stromal cells from Col.1-PPARγ male mice. Although there was no significant difference in BMD in Col.1-PPARγ female mice up to 30 weeks, bone loss was accelerated after ovariectomy compared with wild-type female mice (-3.9% versus -6.8% at 12 weeks after ovariectomy, p < .01), indicating that the effects of PPARγ overexpression becomes more evident in an estrogen-deprived state in female mice. In conclusion, in vivo osteoblast-specific overexpression of PPARγ negatively regulates bone mass in male mice and accelerates estrogen-deficiency-related bone loss in female mice.
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Affiliation(s)
- Sun Wook Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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