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Komori T. Regulation of Skeletal Development and Maintenance by Runx2 and Sp7. Int J Mol Sci 2024; 25:10102. [PMID: 39337587 PMCID: PMC11432631 DOI: 10.3390/ijms251810102] [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: 07/29/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Runx2 (runt related transcription factor 2) and Sp7 (Sp7 transcription factor 7) are crucial transcription factors for bone development. The cotranscription factor Cbfb (core binding factor beta), which enhances the DNA-binding capacity of Runx2 and stabilizes the Runx2 protein, is necessary for bone development. Runx2 is essential for chondrocyte maturation, and Sp7 is partly involved. Runx2 induces the commitment of multipotent mesenchymal cells to osteoblast lineage cells and enhances the proliferation of osteoprogenitors. Reciprocal regulation between Runx2 and the Hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathways and Dlx5 (distal-less homeobox 5) plays an important role in these processes. The induction of Fgfr2 (Fgf receptor 2) and Fgfr3 expression by Runx2 is important for the proliferation of osteoblast lineage cells. Runx2 induces Sp7 expression, and Runx2+ osteoprogenitors become Runx2+Sp7+ preosteoblasts. Sp7 induces the differentiation of preosteoblasts into osteoblasts without enhancing their proliferation. In osteoblasts, Runx2 is required for bone formation by inducing the expression of major bone matrix protein genes, including Col1a1 (collagen type I alpha 1), Col1a2, Spp1 (secreted phosphoprotein 1), Ibsp (integrin binding sialoprotein), and Bglap (bone gamma carboxyglutamate protein)/Bglap2. Bglap/Bglap2 (osteocalcin) regulates the alignment of apatite crystals parallel to collagen fibrils but does not function as a hormone that regulates glucose metabolism, testosterone synthesis, and muscle mass. Sp7 is also involved in Co1a1 expression and regulates osteoblast/osteocyte process formation, which is necessary for the survival of osteocytes and the prevention of cortical porosity. SP7 mutations cause osteogenesis imperfecta in rare cases. Runx2 is an important pathogenic factor, while Runx1, Runx3, and Cbfb are protective factors in osteoarthritis development.
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Affiliation(s)
- Toshihisa Komori
- Department of Molecular Tumor Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
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Fu Y, Zhou J, Schroyen M, Zhang H, Wu S, Qi G, Wang J. Decreased eggshell strength caused by impairment of uterine calcium transport coincide with higher bone minerals and quality in aged laying hens. J Anim Sci Biotechnol 2024; 15:37. [PMID: 38439110 PMCID: PMC10910863 DOI: 10.1186/s40104-023-00986-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 12/28/2023] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Deteriorations in eggshell and bone quality are major challenges in aged laying hens. This study compared the differences of eggshell quality, bone parameters and their correlations as well as uterine physiological characteristics and the bone remodeling processes of hens laying eggs of different eggshell breaking strength to explore the mechanism of eggshell and bone quality reduction and their interaction. A total of 240 74-week-old Hy-line Brown laying hens were selected and allocated to a high (HBS, 44.83 ± 1.31 N) or low (LBS, 24.43 ± 0.57 N) eggshell breaking strength group. RESULTS A decreased thickness, weight and weight ratio of eggshells were observed in the LBS, accompanied with ultrastructural deterioration and total Ca reduction. Bone quality was negatively correlated with eggshell quality, marked with enhanced structures and increased components in the LBS. In the LBS, the mammillary knobs and effective layer grew slowly. At the initiation stage of eggshell calcification, a total of 130 differentially expressed genes (DEGs, 122 upregulated and 8 downregulated) were identified in the uterus of hens in the LBS relative to those in the HBS. These DEGs were relevant to apoptosis due to the cellular Ca overload. Higher values of p62 protein level, caspase-8 activity, Bax protein expression and lower values of Bcl protein expression and Bcl/Bax ratio were seen in the LBS. TUNEL assay and hematoxylin-eosin staining showed a significant increase in TUNEL-positive cells and tissue damages in the uterus of the LBS. Although few DEGs were identified at the growth stage, similar uterine tissue damages were also observed in the LBS. The expressions of runt-related transcription factor 2 and osteocalcin were upregulated in humeri of the LBS. Enlarged diameter and more structural damages of endocortical bones and decreased ash were observed in femurs of the HBS. CONCLUSION The lower eggshell breaking strength may be attributed to a declined Ca transport due to uterine tissue damages, which could affect eggshell calcification and lead to a weak ultrastructure. Impaired uterine Ca transport may result in reduced femoral bone resorption and increased humeral bone formation to maintain a higher mineral and bone quality in the LBS.
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Affiliation(s)
- Yu Fu
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
- Precision Livestock and Nutrition Laboratory, Gembloux Agro-Bio Tech, TERRA Teaching and Research Centre, University of Liège, Gembloux, B-5030, Belgium
| | - Jianmin Zhou
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Martine Schroyen
- Precision Livestock and Nutrition Laboratory, Gembloux Agro-Bio Tech, TERRA Teaching and Research Centre, University of Liège, Gembloux, B-5030, Belgium
| | - Haijun Zhang
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Shugeng Wu
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Guanghai Qi
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Jing Wang
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
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Zhang Z, Huang Z, Awad M, Elsalanty M, Cray J, Ball LE, Maynard JC, Burlingame AL, Zeng H, Mansky KC, Ruan HB. O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors. eLife 2023; 12:e85464. [PMID: 36861967 PMCID: PMC10032655 DOI: 10.7554/elife.85464] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/01/2023] [Indexed: 03/03/2023] Open
Abstract
In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBPβ-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.
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Affiliation(s)
- Zengdi Zhang
- Department of Integrative Biology and Physiology, University of Minnesota Medical SchoolMinneapolisUnited States
| | - Zan Huang
- Department of Integrative Biology and Physiology, University of Minnesota Medical SchoolMinneapolisUnited States
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural UniversityNanjingChina
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural UniversityNanjingChina
| | - Mohamed Awad
- Department of Medical Anatomical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health SciencesPomonaUnited States
| | - Mohammed Elsalanty
- Department of Medical Anatomical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health SciencesPomonaUnited States
| | - James Cray
- Department of Biomedical Education and Anatomy, The Ohio State University College of Medicine, and Division of Biosciences, The Ohio State University College of DentistryColumbusUnited States
| | - Lauren E Ball
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South CarolinaCharlestonUnited States
| | - Jason C Maynard
- Department of Pharmaceutical Chemistry, University of California, San FranciscoSan FranciscoUnited States
| | - Alma L Burlingame
- Department of Pharmaceutical Chemistry, University of California, San FranciscoSan FranciscoUnited States
| | - Hu Zeng
- Division of Rheumatology, Department of Internal Medicine, Mayo ClinicRochesterUnited States
- Department of Immunology, Mayo ClinicRochesterUnited States
| | - Kim C Mansky
- Department of Developmental and Surgical Sciences, School of Dentistry, University of MinnesotaMinneapolisUnited States
| | - Hai-Bin Ruan
- Department of Integrative Biology and Physiology, University of Minnesota Medical SchoolMinneapolisUnited States
- Center for Immunology, University of Minnesota Medical SchoolMinneapolisUnited States
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Whole Aspect of Runx2 Functions in Skeletal Development. Int J Mol Sci 2022; 23:ijms23105776. [PMID: 35628587 PMCID: PMC9144571 DOI: 10.3390/ijms23105776] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/18/2022] [Accepted: 05/20/2022] [Indexed: 11/29/2022] Open
Abstract
Runt-related transcription factor 2 (Runx2) is a fundamental transcription factor for bone development. In endochondral ossification, Runx2 induces chondrocyte maturation, enhances chondrocyte proliferation through Indian hedgehog (Ihh) induction, and induces the expression of vascular endothelial growth factor A (Vegfa), secreted phosphoprotein 1 (Spp1), integrin-binding sialoprotein (Ibsp), and matrix metallopeptidase 13 (Mmp13) in the terminal hypertrophic chondrocytes. Runx2 inhibits the apoptosis of the terminal hypertrophic chondrocytes and induces their transdifferentiation into osteoblasts and osteoblast progenitors. The transdifferentiation is required for trabecular bone formation during embryonic and newborn stages but is dispensable for acquiring normal bone mass in young and adult mice. Runx2 enhances the proliferation of osteoblast progenitors and induces their commitment to osteoblast lineage cells through the direct regulation of the expressions of a hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathway genes and distal-less homeobox 5 (Dlx5), which all regulate Runx2 expression and/or protein activity. Runx2, Sp7, and Wnt signaling further induce osteoblast differentiation. In immature osteoblasts, Runx2 regulates the expression of bone matrix protein genes, including Col1a1, Col1a2, Spp1, Ibsp, and bone gamma carboxyglutamate protein (Bglap)/Bglap2, and induces osteoblast maturation. Osteocalcin (Bglap/Bglap2) is required for the alignment of apatite crystals parallel to the collagen fibers; however, it does not physiologically work as a hormone that regulates glucose metabolism, testosterone synthesis, or muscle mass. Thus, Runx2 exerts multiple functions essential for skeletal development.
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Qin X, Jiang Q, Komori H, Sakane C, Fukuyama R, Matsuo Y, Ito K, Miyazaki T, Komori T. Runt-related transcription factor-2 (Runx2) is required for bone matrix protein gene expression in committed osteoblasts in mice. J Bone Miner Res 2021; 36:2081-2095. [PMID: 34101902 DOI: 10.1002/jbmr.4386] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/29/2021] [Accepted: 06/02/2021] [Indexed: 12/13/2022]
Abstract
Runt-related transcription factor-2 (Runx2) is an essential transcription factor for osteoblast differentiation. However, its functions after the commitment into osteoblasts are controversial and remain to be clarified. We generated enhanced green fluorescent protein (EGFP)-Cre transgenic mice driven by the 2.3-kilobase (kb) Col1a1 promoter, and Runx2 was deleted in osteoblasts and odontoblasts in Runx2fl/flCre mice. The sutures and fontanelles were more widely opened in Runx2fl/flCre newborns than in Runx2fl/fl newborns. Runx2fl/flCre mice exhibited dwarfism with shorter incisors and 37% had irregularly aligned incisors. The volume of trabecular bone in femurs and vertebrae and their bone mineral density (BMD), in addition to the cortical thickness and BMD were reduced in Runx2fl/flCre mice compared with Runx2fl/fl mice in both sexes. The bone formation of both trabecular and cortical bone, osteoblast number, osteoclast surface, osteoblast proliferation, and the serum levels of procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase 5b (TRAP5b), and C-terminal cross-linked telopeptide of type 1 collagen (CTX1) were reduced in Runx2fl/flCre mice. The expression of major bone matrix protein genes, including Col1a1, Col1a2, Spp1, Ibsp, and Bglap&Bglap2, and of Tnfsf11 was lower in Runx2fl/flCre mice than in Runx2fl/fl mice. The expression of Runx2 target genes, including Ihh, Fgfr1, Fgfr2, Fgfr3, Tcf7, Wnt10b, Pth1r, Sp7, and Dlx5, was also reduced. Osteoblasts in Runx2fl/fl mice were cuboidal and contained abundant type I collagen α1 (Col1a1), whereas those in Runx2fl/flCre mice were deflated and contained a small amount of Col1a1. Runx2 activated the reporter activity of the 2.3-kb Col1a1 promoter and bound the region around the Col1a1 transcription start site. The deletion of Runx2 by Cre-expressing adenovirus in Runx2fl/fl primary osteoblasts impaired osteoblast differentiation and the expression of genes encoding major bone matrix proteins, and osteoclastogenesis was inhibited due to the reduction of Tnfsf11 expression in the osteoblasts. This study demonstrated that Runx2 is required for the expression of the major bone matrix protein genes and Tnfsf11 after commitment into osteoblasts in mice. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Xin Qin
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.,Japan Society for the Promotion of Science International Research Fellow, Tokyo, Japan
| | - Qing Jiang
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hisato Komori
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Chiharu Sakane
- Division of Comparative Medicine, Life Science Support Center, Nagasaki University, Nagasaki, Japan
| | - Ryo Fukuyama
- Laboratory of Pharmacology, Hiroshima International University, Kure, Japan
| | - Yuki Matsuo
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kosei Ito
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Toshihiro Miyazaki
- Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Toshihisa Komori
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Dumortier C, Danopoulos S, Velard F, Al Alam D. Bone Cells Differentiation: How CFTR Mutations May Rule the Game of Stem Cells Commitment? Front Cell Dev Biol 2021; 9:611921. [PMID: 34026749 PMCID: PMC8139249 DOI: 10.3389/fcell.2021.611921] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 04/12/2021] [Indexed: 12/30/2022] Open
Abstract
Cystic fibrosis (CF)-related bone disease has emerged as a significant comorbidity of CF and is characterized by decreased bone formation and increased bone resorption. Both osteoblast and osteoclast differentiations are impacted by cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The defect of CFTR chloride channel or the loss of CFTRs ability to interact with other proteins affect several signaling pathways involved in stem cell differentiation and the commitment of these cells toward bone lineages. Specifically, TGF-, nuclear factor-kappa B (NF-B), PI3K/AKT, and MAPK/ERK signaling are disturbed by CFTR mutations, thus perturbing stem cell differentiation. High inflammation in patients changes myeloid lineage secretion, affecting both myeloid and mesenchymal differentiation. In osteoblast, Wnt signaling is impacted, resulting in consequences for both bone formation and resorption. Finally, CFTR could also have a direct role in osteoclasts resorptive function. In this review, we summarize the existing literature on the role of CFTR mutations on the commitment of induced pluripotent stem cells to bone cells.
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Affiliation(s)
- Claire Dumortier
- Division of Neonatology, Department of Pediatrics, Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, United States.,Universit de Reims Champagne-Ardenne, BIOS EA 4691, Reims, France
| | - Soula Danopoulos
- Division of Neonatology, Department of Pediatrics, Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, United States
| | - Frdric Velard
- Universit de Reims Champagne-Ardenne, BIOS EA 4691, Reims, France
| | - Denise Al Alam
- Division of Neonatology, Department of Pediatrics, Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, United States
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Goel D, Vohora D. Liver X receptors and skeleton: Current state-of-knowledge. Bone 2021; 144:115807. [PMID: 33333244 DOI: 10.1016/j.bone.2020.115807] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/26/2020] [Accepted: 12/11/2020] [Indexed: 12/25/2022]
Abstract
The liver X receptors (LXR) is a nuclear receptor that acts as a prominent regulator of lipid homeostasis and inflammatory response. Its therapeutic effectiveness against various diseases like Alzheimer's disease and atherosclerosis has been investigated in detail. Emerging pieces of evidence now reveal that LXR is also a crucial modulator of bone remodeling. However, the molecular mechanisms underlying the pharmacological actions of LXR on the skeleton and its role in osteoporosis are poorly understood. Therefore, in the current review, we highlight LXR and its actions through different molecular pathways modulating skeletal homeostasis. The studies described in this review propound that LXR in association with estrogen, PTH, PPARγ, RXR hedgehog, and canonical Wnt signaling regulates osteoclastogenesis and bone resorption. It regulates RANKL-induced expression of c-Fos, NFATc1, and NF-κB involved in osteoclast differentiation. Additionally, several studies suggest suppression of RANKL-induced osteoclast differentiation by synthetic LXR ligands. Given the significance of modulation of LXR in various physiological and pathological settings, our findings indicate that therapeutic targeting of LXR might potentially prevent or treat osteoporosis and improve bone quality.
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Affiliation(s)
- Divya Goel
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India.
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Yavropoulou MP, Anastasilakis AD, Makras P, Papatheodorou A, Rauner M, Hofbauer LC, Tsourdi E. Serum Profile of microRNAs Linked to Bone Metabolism During Sequential Treatment for Postmenopausal Osteoporosis. J Clin Endocrinol Metab 2020; 105:5855767. [PMID: 32521543 DOI: 10.1210/clinem/dgaa368] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/06/2020] [Indexed: 12/15/2022]
Abstract
CONTEXT Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment. OBJECTIVE To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis. DESIGN Observational, open label, nonrandomized clinical trial. SETTING A single-center outpatient clinic. PATIENTS AND INTERVENTIONS Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6). MAIN OUTCOME MEASURES Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment. RESULTS Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P < 0.001) and 6 months (FC 0.34, P < 0.001), and miR-338-3p and miR-2861 at 6 months (FC 0.31, P = 0.041; FC 0.52, P = 0.016, respectively) in the whole cohort. In subgroup analyses, Dmab decreased the relative expression of miR-21a-5p, miR-29a-3p, miR-338-3p, and miR-2861 at 3 months (FC 0.13, P < 0.001; FC 0.68, P = 0.044; FC 0.46, P = 0.012; and FC 0.16, P < 0.001, respectively) and 6 months (FC 0.1, P < 0.001; FC 0.52, P < 0.001; FC 0.04, P = 0.006; and FC 0.2, P < 0.001, respectively) only within the TPTD group. CONCLUSIONS TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction.
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Affiliation(s)
- Maria P Yavropoulou
- Endocrinology Unit, 1st Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Department of Medical Research, 251 Air Force General Hospital, Athens, Greece
| | | | - Polyzois Makras
- Department of Medical Research, 251 Air Force General Hospital, Athens, Greece
| | | | - Martina Rauner
- Department of Medicine III, Technische Universität Dresden Medical Centre, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden Medical Centre, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III, Technische Universität Dresden Medical Centre, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden Medical Centre, Dresden, Germany
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Elena Tsourdi
- Department of Medicine III, Technische Universität Dresden Medical Centre, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden Medical Centre, Dresden, Germany
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Physical Activity-Dependent Regulation of Parathyroid Hormone and Calcium-Phosphorous Metabolism. Int J Mol Sci 2020; 21:ijms21155388. [PMID: 32751307 PMCID: PMC7432834 DOI: 10.3390/ijms21155388] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/09/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022] Open
Abstract
Exercise perturbs homeostasis, alters the levels of circulating mediators and hormones, and increases the demand by skeletal muscles and other vital organs for energy substrates. Exercise also affects bone and mineral metabolism, particularly calcium and phosphate, both of which are essential for muscle contraction, neuromuscular signaling, biosynthesis of adenosine triphosphate (ATP), and other energy substrates. Parathyroid hormone (PTH) is involved in the regulation of calcium and phosphate homeostasis. Understanding the effects of exercise on PTH secretion is fundamental for appreciating how the body adapts to exercise. Altered PTH metabolism underlies hyperparathyroidism and hypoparathyroidism, the complications of which affect the organs involved in calcium and phosphorous metabolism (bone and kidney) and other body systems as well. Exercise affects PTH expression and secretion by altering the circulating levels of calcium and phosphate. In turn, PTH responds directly to exercise and exercise-induced myokines. Here, we review the main concepts of the regulation of PTH expression and secretion under physiological conditions, in acute and chronic exercise, and in relation to PTH-related disorders.
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Abstract
Parathyroid hormone is an essential regulator of extracellular calcium and phosphate. PTH enhances calcium reabsorption while inhibiting phosphate reabsorption in the kidneys, increases the synthesis of 1,25-dihydroxyvitamin D, which then increases gastrointestinal absorption of calcium, and increases bone resorption to increase calcium and phosphate. Parathyroid disease can be an isolated endocrine disorder or part of a complex syndrome. Genetic mutations can account for diseases of parathyroid gland formulation, dysregulation of parathyroid hormone synthesis or secretion, and destruction of the parathyroid glands. Over the years, a number of different options are available for the treatment of different types of parathyroid disease. Therapeutic options include surgical removal of hypersecreting parathyroid tissue, administration of parathyroid hormone, vitamin D, activated vitamin D, calcium, phosphate binders, calcium-sensing receptor, and vitamin D receptor activators to name a few. The accurate assessment of parathyroid hormone also provides essential biochemical information to properly diagnose parathyroid disease. Currently available immunoassays may overestimate or underestimate bioactive parathyroid hormone because of interferences from truncated parathyroid hormone fragments, phosphorylation of parathyroid hormone, and oxidation of amino acids of parathyroid hormone.
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Affiliation(s)
- Edward Ki Yun Leung
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, United States; Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States.
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Komori T. Molecular Mechanism of Runx2-Dependent Bone Development. Mol Cells 2020; 43:168-175. [PMID: 31896233 PMCID: PMC7057844 DOI: 10.14348/molcells.2019.0244] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 12/03/2019] [Indexed: 01/09/2023] Open
Abstract
Runx2 is an essential transcription factor for skeletal development. It is expressed in multipotent mesenchymal cells, osteoblast-lineage cells, and chondrocytes. Runx2 plays a major role in chondrocyte maturation, and Runx3 is partly involved. Runx2 regulates chondrocyte proliferation by directly regulating Ihh expression. It also determines whether chondrocytes become those that form transient cartilage or permanent cartilage, and functions in the pathogenesis of osteoarthritis. Runx2 is essential for osteoblast differentiation and is required for the proliferation of osteoprogenitors. Ihh is required for Runx2 expression in osteoprogenitors, and hedgehog signaling and Runx2 induce the differentiation of osteoprogenitors to preosteoblasts in endochondral bone. Runx2 induces Sp7 expression, and Runx2, Sp7, and canonical Wnt signaling are required for the differentiation of preosteoblasts to immature osteoblasts. It also induces the proliferation of osteoprogenitors by directly regulating the expression of Fgfr2 and Fgfr3. Furthermore, Runx2 induces the proliferation of mesenchymal cells and their commitment into osteoblast-lineage cells through the induction of hedgehog (Gli1, Ptch1, Ihh), Fgf (Fgfr2, Fgfr3), Wnt (Tcf7, Wnt10b), and Pthlh (Pth1r) signaling pathway gene expression in calvaria, and more than a half-dosage of Runx2 is required for their expression. This is a major cause of cleidocranial dysplasia, which is caused by heterozygous mutation of RUNX2. Cbfb, which is a co-transcription factor that forms a heterodimer with Runx2, enhances DNA binding of Runx2 and stabilizes Runx2 protein by inhibiting its ubiquitination. Thus, Runx2/Cbfb regulates the proliferation and differentiation of chondrocytes and osteoblast-lineage cells by activating multiple signaling pathways and via their reciprocal regulation.
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Affiliation(s)
- Toshihisa Komori
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
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Agas D, Amaroli A, Lacava G, Yanagawa T, Sabbieti MG. Loss of p62 impairs bone turnover and inhibits PTH-induced osteogenesis. J Cell Physiol 2020; 235:7516-7529. [PMID: 32100883 DOI: 10.1002/jcp.29654] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 02/12/2020] [Indexed: 12/17/2022]
Abstract
The p62 (also named sequestosome1/SQSTM1) is multidomain and multifunctional protein associated with several physiological and pathological conditions. A number of studies evidenced an involvement of p62 on the disruptive bone scenarios due to its participation in the inflammatory/osteoclastogenic pathways. However, so far, information regarding the function of p62 in the fine-tuned processes underpinning the bone physiology are not well-defined and are sometime discordant. We, previously, demonstrated that the intramuscular administration of a plasmid coding for p62 was able to contrast bone loss in a mouse model of osteopenia. Here, in vitro findings showed that the p62 overexpression in murine osteoblasts precursors enhanced their maturation while the p62 depletion by a specific siRNA, decreased osteoblasts differentiation. Consistently, the activity of osteoblasts from p62-/- mice was reduced compared with wild-type. Also, morphometric analyses of bone from p62 knockout mice revealed a pathological phenotype characterized by a lower turnover that could be explained by the poor Runx2 protein synthesis in absence of p62. Furthermore, we demonstrated that the parathyroid hormone (PTH) regulates p62 expression and that the osteogenic effects of this hormone were totally abrogated in osteoblasts from p62-deficient mice. Therefore, these findings, for the first time, highlight the important role of p62 both for the basal and for PTH-stimulated bone remodeling.
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Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Andrea Amaroli
- Department of Surgical and Diagnostic Sciences, Laser Therapy Center, University of Genoa, Genoa, Italy
| | - Giovanna Lacava
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Toru Yanagawa
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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Pal S, Porwal K, Singh H, Malik MY, Rashid M, Kulkarni C, Khan Y, Jagavelu K, Wahajuddin M, Chattopadhyay N. Reversal of Osteopenia in Ovariectomized Rats by Pentoxifylline: Evidence of Osteogenic and Osteo-Angiogenic Roles of the Drug. Calcif Tissue Int 2019; 105:294-307. [PMID: 31175387 DOI: 10.1007/s00223-019-00567-4] [Citation(s) in RCA: 17] [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: 01/17/2019] [Accepted: 05/23/2019] [Indexed: 02/05/2023]
Abstract
Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor and is used for the management of intermittent claudication. We tested whether PTX has oral efficacy in stimulating new bone formation. Rat calvarial osteoblasts (RCO) were used to study the effect of PTX on osteoblast differentiation and angiogenesis. Pharmacokinetic and pharmacodynamic studies were carried out in rats to determine an oral dose of PTX. In ovariectomized (OVX) rats with osteopenia, the effect of PTX on various skeletal parameters was studied, and compared with teriparatide. Effect of PTX on angiogenic signaling was studied by immunoblotting and relevant pharmacologic inhibitors. Bone vascularity was measured by intravenous injection of polystyrene fluorospheres followed by in vivo imaging, and angiogenesis was studied in vitro by tubulogenesis of endothelial cells and in vivo by Matrigel plug assay. Effective concentration (EC50) of PTX in RCO was 8.2 nM and plasma PTX level was 7 nM/mL after single oral dosing of 25 mg/kg, which was 1/6th the clinically used dose. At this dose, PTX enhanced bone regeneration at femur osteotomy site and completely restored bone mass, microarchitecture, and strength in OVX rats. Furthermore, PTX increased surface referent bone formation parameters and serum bone formation marker (PINP) without affecting the resorption marker (CTX-1). PTX increased the expression of vascular endothelial growth factor and its receptor in bones and osteoblasts. PTX also increased skeletal vascularity, tubulogenesis of endothelial cells and in vivo angiogenesis. Taken together, our study suggested that PTX at 16% of adult human oral dose completely reversed osteopenia in OVX rats by osteogenic and osteo-angiogenic mechanisms.
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Affiliation(s)
- Subhashis Pal
- Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India
| | - Konica Porwal
- Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India
| | - Himalaya Singh
- Division of Pharmacology, CSIR-CDRI, Lucknow, 226031, India
| | | | - Mamunur Rashid
- Division of Pharmaceutics, CSIR-CDRI, Lucknow, 226031, India
| | - Chirag Kulkarni
- Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India
| | - Yasir Khan
- Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India
| | | | | | - Naibedya Chattopadhyay
- Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India.
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Dillon S, Staines KA, Millán JL, Farquharson C. How To Build a Bone: PHOSPHO1, Biomineralization, and Beyond. JBMR Plus 2019; 3:e10202. [PMID: 31372594 PMCID: PMC6659447 DOI: 10.1002/jbm4.10202] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/15/2019] [Accepted: 05/05/2019] [Indexed: 12/11/2022] Open
Abstract
Since its characterization two decades ago, the phosphatase PHOSPHO1 has been the subject of an increasing focus of research. This work has elucidated PHOSPHO1's central role in the biomineralization of bone and other hard tissues, but has also implicated the enzyme in other biological processes in health and disease. During mineralization PHOSPHO1 liberates inorganic phosphate (Pi) to be incorporated into the mineral phase through hydrolysis of its substrates phosphocholine (PCho) and phosphoethanolamine (PEA). Localization of PHOSPHO1 within matrix vesicles allows accumulation of Pi within a protected environment where mineral crystals may nucleate and subsequently invade the organic collagenous scaffold. Here, we examine the evidence for this process, first discussing the discovery and characterization of PHOSPHO1, before considering experimental evidence for its canonical role in matrix vesicle–mediated biomineralization. We also contemplate roles for PHOSPHO1 in disorders of dysregulated mineralization such as vascular calcification, along with emerging evidence of its activity in other systems including choline synthesis and homeostasis, and energy metabolism. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Scott Dillon
- The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh, Easter Bush Midlothian UK
| | | | - José Luis Millán
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA USA
| | - Colin Farquharson
- The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh, Easter Bush Midlothian UK
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15
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Komori T. Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2. Int J Mol Sci 2019; 20:ijms20071694. [PMID: 30987410 PMCID: PMC6480215 DOI: 10.3390/ijms20071694] [Citation(s) in RCA: 480] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/03/2019] [Accepted: 04/03/2019] [Indexed: 11/25/2022] Open
Abstract
Runx2 is essential for osteoblast differentiation and chondrocyte maturation. During osteoblast differentiation, Runx2 is weakly expressed in uncommitted mesenchymal cells, and its expression is upregulated in preosteoblasts, reaches the maximal level in immature osteoblasts, and is down-regulated in mature osteoblasts. Runx2 enhances the proliferation of osteoblast progenitors by directly regulating Fgfr2 and Fgfr3. Runx2 enhances the proliferation of suture mesenchymal cells and induces their commitment into osteoblast lineage cells through the direct regulation of hedgehog (Ihh, Gli1, and Ptch1), Fgf (Fgfr2 and Fgfr3), Wnt (Tcf7, Wnt10b, and Wnt1), and Pthlh (Pthr1) signaling pathway genes, and Dlx5. Runx2 heterozygous mutation causes open fontanelle and sutures because more than half of the Runx2 gene dosage is required for the induction of these genes in suture mesenchymal cells. Runx2 regulates the proliferation of osteoblast progenitors and their differentiation into osteoblasts via reciprocal regulation with hedgehog, Fgf, Wnt, and Pthlh signaling molecules, and transcription factors, including Dlx5 and Sp7. Runx2 induces the expression of major bone matrix protein genes, including Col1a1, Spp1, Ibsp, Bglap2, and Fn1, in vitro. However, the functions of Runx2 in differentiated osteoblasts in the expression of these genes in vivo require further investigation.
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Affiliation(s)
- Toshihisa Komori
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
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16
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Zeng Q, Wang Y, Gao J, Yan Z, Li Z, Zou X, Li Y, Wang J, Guo Y. miR-29b-3p regulated osteoblast differentiation via regulating IGF-1 secretion of mechanically stimulated osteocytes. Cell Mol Biol Lett 2019; 24:11. [PMID: 30915127 PMCID: PMC6416934 DOI: 10.1186/s11658-019-0136-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 01/23/2019] [Indexed: 12/31/2022] Open
Abstract
Background Mechanical loading is an essential factor for bone formation. A previous study indicated that mechanical tensile strain of 2500 microstrain (με) at 0.5 Hz for 8 h promoted osteogenesis and corresponding mechanoresponsive microRNAs (miRs) were identified in osteoblasts. However, in osteocytes, it has not been identified which miRs respond to the mechanical strain, and it is not fully understood how the mechanoresponsive miRs regulate osteoblast differentiation. Methods Mouse MLO-Y4 osteocytes were applied to the same mechanical tensile strain in vitro. Using molecular and biochemical methods, IGF-1 (insulin-like growth factor-1), PGE2 (prostaglandin E2), OPG (osteoprotegerin) and NOS (nitric oxide synthase) activities of the cells were assayed. MiR microarray and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were applied to select and validate differentially expressed miRs, and the target genes of these miRs were then predicted. MC3T3-E1 osteoblasts were stimulated by the mechanical tensile strain, and the miR-29b-3p expression was detected with miR microarray and RT-qPCR. Additionally, the effect of miR-29b-3p on IFG-1 secretion of osteocytes and the influence of conditioned medium of osteocytes transfected with miR-29b-3p on osteoblast differentiation were investigated. Results The mechanical strain increased secretions of IGF-1 and PGE2, elevated OPG expression and NOS activities, and resulted in altered expression of the ten miRs, and possible target genes for these differentially expressed miRs were revealed through bioinformatics. Among the ten miRs, miR-29b-3p were down-regulated, and miR-29b-3p overexpression decreased the IGF-1 secretion of osteocytes. The mechanical strain did not change expression of osteoblasts' miR-29b-3p. In addition, the conditioned medium of mechanically strained osteocytes promoted osteoblast differentiation, and the conditioned medium of osteocytes transfected with miR-29b-3p mimic inhibited osteoblast differentiation. Conclusions In osteocytes (but not osteoblasts), miR-29b-3p was responsive to the mechanical tensile strain and regulated osteoblast differentiation via regulating IGF-1 secretion of mechanically strained osteocytes.
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Affiliation(s)
- Qiangcheng Zeng
- 1key laboratory of Functional Bioresource Utilization in University of Shandong, Shandong Key Laboratory of Biophysics, Dezhou University, Dezhou, 253023 China
| | - Yang Wang
- 2Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin City, 541100 Guangxi China.,3Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400044 China
| | - Jie Gao
- 1key laboratory of Functional Bioresource Utilization in University of Shandong, Shandong Key Laboratory of Biophysics, Dezhou University, Dezhou, 253023 China.,Medical Department, Secondary Renmin Hospital of Dezhou, Dezhou, 253023 Shangdong China
| | - Zhixiong Yan
- 2Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin City, 541100 Guangxi China
| | - Zhenghua Li
- 1key laboratory of Functional Bioresource Utilization in University of Shandong, Shandong Key Laboratory of Biophysics, Dezhou University, Dezhou, 253023 China
| | - Xianqiong Zou
- 2Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin City, 541100 Guangxi China
| | - Yanan Li
- 2Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin City, 541100 Guangxi China
| | - Jiahui Wang
- 2Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin City, 541100 Guangxi China
| | - Yong Guo
- 1key laboratory of Functional Bioresource Utilization in University of Shandong, Shandong Key Laboratory of Biophysics, Dezhou University, Dezhou, 253023 China.,2Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin City, 541100 Guangxi China
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Abstract
Parathyroid hormone (PTH) is the major secretory product of the parathyroid glands, and in hypocalcemic conditions, can enhance renal calcium reabsorption, increase active vitamin D production to increase intestinal calcium absorption, and mobilize calcium from bone by increasing turnover, mainly but not exclusively in cortical bone. PTH has therefore found clinical use as replacement therapy in hypoparathyroidism. PTH also may have a physiologic role in augmenting bone formation, particularly in trabecular and to some extent in cortical bone. This action has been applied to the clinic to provide anabolic therapy for osteoporosis.
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Affiliation(s)
- David Goltzman
- Department of Medicine and Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec H4A 3J1, Canada; Departments of Medicine and of Physiology, McGill University, 845 Sherbrooke St West, Montreal, Quebec H3A 0B9, Canada.
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18
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Ding Q, Sun P, Zhou H, Wan B, Yin J, Huang Y, Li Q, Yin G, Fan J. Lack of endogenous parathyroid hormone delays fracture healing by inhibiting vascular endothelial growth factor‑mediated angiogenesis. Int J Mol Med 2018; 42:171-181. [PMID: 29620150 PMCID: PMC5979887 DOI: 10.3892/ijmm.2018.3614] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 12/19/2017] [Indexed: 11/28/2022] Open
Abstract
Intermittent low-dose injections of parathyroid hormone (PTH) have been reported to exert bone anabolic effects and to promote fracture healing. As an important proangiogenic cytokine, vascular endothelial growth factor (VEGF) is secreted by bone marrow mesenchymal stem cells (BMSCs) and osteoblasts, and serves a crucial regulatory role in the process of vascular development and regeneration. To investigate whether lack of endogenous PTH causes reduced angiogenic capacity and thereby delays the process of fracture healing by downregulating the VEGF signaling pathway, a PTH knockout (PTHKO) mouse fracture model was generated. Fracture healing was observed using X-ray and micro-computerized tomography. Bone anabolic and angiogenic markers were analyzed by immunohistochemistry and western blot analysis. The expression levels of VEGF and associated signaling pathways in murine BMSC-derived osteoblasts were measured by quantitative polymerase chain reaction and western blot analysis. The expression levels of protein kinase A (PKA), phosphorylated-serine/threonine protein kinase (pAKT), hypoxia-inducible factor-1α (HIF1α) and VEGF were significantly decreased in BMSC-derived osteoblasts from PTHKO mice. In addition, positive platelet endothelial cell adhesion molecule staining was reduced in PTHKO mice, as determined by immunohistochemistry. The expression levels of HIF1α, VEGF, runt-related transcription factor 2, osteocalcin and alkaline phosphatase were also decreased in PTHKO mice, and fracture healing was delayed. In conclusion, lack of endogenous PTH may reduce VEGF expression in BMSC-derived osteoblasts by downregulating the activity of the PKA/pAKT/HIF1α/VEGF pathway, thus affecting endochondral bone formation by causing a reduction in angiogenesis and osteogenesis, ultimately leading to delayed fracture healing.
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Affiliation(s)
- Qingfeng Ding
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Peng Sun
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hao Zhou
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Bowen Wan
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jian Yin
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yao Huang
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Qingqing Li
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Guoyong Yin
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jin Fan
- Orthopaedic Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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19
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He S, Xue M, Liu C, Xie F, Bai L. Parathyroid Hormone-Like Hormone Induces Epithelial-to-Mesenchymal Transition of Intestinal Epithelial Cells by Activating the Runt-Related Transcription Factor 2. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1374-1388. [PMID: 29577935 DOI: 10.1016/j.ajpath.2018.03.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 03/04/2018] [Accepted: 03/06/2018] [Indexed: 01/18/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) is a key contributor to fibroblast activation in fibrosis of multiple organs, including the intestine. Parathyroid hormone-like hormone (PTHLH) is an important factor in renal fibrosis and regulates several processes, including EMT. Herein, we investigated the role of PTHLH-induced EMT in intestinal fibrosis associated with Crohn disease. The expression levels of the EMT-related proteins, PTHLH, and parathyroid hormone receptor 1 (PTH1R) in intestinal tissues were determined by immunohistochemistry, and our results revealed that PTHLH and PTH1R were significantly elevated and associated with EMT marker expression. Moreover, neutralizing PTH1R and antagonizing PTHLH bioactivity prevented transforming growth factor-β1-induced EMT. PTH1R can propagate the protein kinase A (PKA) signal and activate downstream nuclear transcription factors, including runt-related transcription factor 2 (Runx2). In addition, lentiviral vector-PTHLH-treated mice were highly sensitive to 2,4,6-trinitrobenzene sulfonic acid, and analysis of the PTHLH-PTH1R axis revealed the involvement of PKA-Runx2 in PTHLH-induced EMT. Our results indicate that PTHLH triggered EMT in intestinal epithelial cells through the PKA-Runx2 pathway, which might serve as a therapeutic target for intestinal fibrosis in Crohn disease.
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Affiliation(s)
- Shuying He
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Minmin Xue
- Department of Gastroenterology, Chinese People's Liberation Army 254 Hospital, Tianjin, China
| | - Cuiping Liu
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fang Xie
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lan Bai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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20
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Anastasilakis AD, Makras P, Pikilidou M, Tournis S, Makris K, Bisbinas I, Tsave O, Yovos JG, Yavropoulou MP. Changes of Circulating MicroRNAs in Response to Treatment With Teriparatide or Denosumab in Postmenopausal Osteoporosis. J Clin Endocrinol Metab 2018; 103:1206-1213. [PMID: 29309589 DOI: 10.1210/jc.2017-02406] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 12/19/2017] [Indexed: 02/10/2023]
Abstract
CONTEXT Expression of microRNAs (miRs) related to bone metabolism in the serum may be affected by antiosteoporotic treatment. OBJECTIVE To investigate the effect of two antiosteoporotic agents with opposite effects on bone metabolism on miR expression profile in the serum. DESIGN Observational, open label, nonrandomized clinical trial. SETTING The outpatient clinics for Metabolic Bone Diseases of 424 General Military Hospital, Thessaloniki, Greece. PATIENTS AND INTERVENTIONS Postmenopausal women with low bone mass were treated with either teriparatide (TPTD; n = 30) or denosumab (n = 30) for 12 months. MAIN OUTCOME MEASURES Changes in the serum expression of selected miRs linked to bone metabolism at 3 and 12 months of treatment. Secondary measurements: associations of measured miRs with changes in bone mineral density (BMD) at 12 months and the bone turnover markers (BTMs) C-terminal cross-linking telopeptide of type I collagen and procollagen type I N-terminal propeptide at 3 and 12 months. RESULTS We found significantly decreased relative expression of miR-33-3p at 3 months (P = 0.03) and of miR-133a at 12 months (P = 0.042) of TPTD treatment. BMD values at 12 months of TPTD treatment were significantly and inversely correlated with miR-124-3p expression at 3 months (P = 0.008). Relative expression of miR-24-3p and miR-27a was correlated with changes in BTMs during TPTD treatment and of miR-21-5p, miR-23a-3p, miR-26a-5p, miR-27a, miR-222-5p, and miR-335-5p with changes in BTMs during denosumab treatment. CONCLUSIONS Circulating miRs are differentially affected by treatment with TPTD and denosumab. TPTD affects the relative expression of miRs related to the expression of RUNX-2 (miR-33) and DKK-1 gene (miR-133).
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Affiliation(s)
| | - Polyzois Makras
- Department of Endocrinology and Diabetes, 251 Hellenic Air Force and VA General Hospital, Athens, Greece
| | - Maria Pikilidou
- Laboratory of Clinical and Molecular Endocrinology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Symeon Tournis
- Laboratory of Research of Musculoskeletal System "Th. Garofalidis," Medical School, University of Athens, KAT Hospital, Athens, Greece
| | - Konstantinos Makris
- Laboratory of Research of Musculoskeletal System "Th. Garofalidis," Medical School, University of Athens, KAT Hospital, Athens, Greece
| | - Ilias Bisbinas
- First Department of Orthopedics, 424 General Military Hospital, Thessaloniki, Greece
| | - Olga Tsave
- Laboratory of Clinical and Molecular Endocrinology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - John G Yovos
- Laboratory of Clinical and Molecular Endocrinology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria P Yavropoulou
- Laboratory of Clinical and Molecular Endocrinology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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21
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Corrado A, Sanpaolo ER, Di Bello S, Cantatore FP. Osteoblast as a target of anti-osteoporotic treatment. Postgrad Med 2017; 129:858-865. [PMID: 28770650 DOI: 10.1080/00325481.2017.1362312] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Osteoblasts are mesenchymal cells that play a key role in maintaining bone homeostasis; they are responsible for the production of extracellular matrix proteins, regulation of matrix mineralization, control of bone remodeling and regulate osteoclast differentiation. Osteoblasts have an essential role in the pathogenesis of many bone diseases, particularly osteoporosis. For many decades, the main current available treatments for osteoporosis have been represented by anti-resorptive drugs, such as bisphosphonates, which act mainly by inhibiting osteoclasts maturation, proliferation and activity; nevertheless, in recent years much attention has been paid on anabolic aspects of osteoporosis treatment. Many experimental evidences support the hypothesis of direct effects of the classical anti-resorptive drugs also on osteoblasts, and recent progress in understanding bone physiology have led to the development of new pharmacological agents such as anti-sclerostin antibodies and teriparatide which directly target osteoblasts, inducing anabolic effects and promoting bone formation.
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Affiliation(s)
- Addolorata Corrado
- a Rheumatology Clinic Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Eliana Rita Sanpaolo
- a Rheumatology Clinic Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Silvana Di Bello
- a Rheumatology Clinic Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Francesco Paolo Cantatore
- a Rheumatology Clinic Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
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22
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Lu X, Ding Y, Niu Q, Xuan S, Yang Y, Jin Y, Wang H. ClC-3 chloride channel mediates the role of parathyroid hormone [1-34] on osteogenic differentiation of osteoblasts. PLoS One 2017; 12:e0176196. [PMID: 28437476 PMCID: PMC5402952 DOI: 10.1371/journal.pone.0176196] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 04/06/2017] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION Different concentrations of parathyroid hormone [1-34] (PTH [1-34]) can have totally opposite effects on osteoblasts. Intermittent stimulation with PTH can significantly increase bone mineral density in vitro, mainly through the protein kinase A (PKA) signaling pathway, which phosphorylates runt-related transcription factor 2 (Runx2). The ClC-3 chloride channel, an important anion channel, can also promote osteogenesis via the Runx2 pathway based on recent studies. The purpose of our study, therefore, is to research whether the ClC-3 chloride channel has an effect on PTH osteodifferentiation in MC3T3-E1 cells. METHODS AND RESULTS A cell counting kit (CCK-8) and real-time PCR were used to investigate the impact of different PTH stimulation modes on MC3T3-E1 cell proliferation and osteogenesis-related gene expression, respectively. We found that the minimum inhibitory concentration of PTH was 10-9 M, and the expression of alkaline phosphatase (Alpl) and Runx2 were at the highest levels when treated with 10-9 M PTH. Next, we used real-time PCR and immunofluorescence technique to detect changes in ClC-3 in MC3T3-E1 cells under PTH treatment. The results showed higher expression of the ClC-3 chloride channel at 10-9 M intermittent PTH administration than in the other groups. Finally, we used the ClC-3 siRNA technique to examine the role of the ClC-3 chloride channel in the effect of PTH on the osteogenesis of osteoblasts, and we found an obvious decrease in the expression of bone sialoprotein (Ibsp), osteocalcin (Bglap), osterix (Sp7), Alpl and Runx2, the formation of mineralization nodules as well. CONCLUSIONS From the above data, we conclude that the expression of ClC-3 chloride channels in osteoblasts helps them respond to PTH stimulation, which mediates osteogenic differentiation.
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Affiliation(s)
- Xiaolin Lu
- State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yin Ding
- State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Qiannan Niu
- State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Shijie Xuan
- State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yan Yang
- State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yulong Jin
- Department of Hematology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Huan Wang
- State Key Laboratory of Military Stomatology, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
- * E-mail:
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Osagie-Clouard L, Sanghani A, Coathup M, Briggs T, Bostrom M, Blunn G. Parathyroid hormone 1-34 and skeletal anabolic action: The use of parathyroid hormone in bone formation. Bone Joint Res 2017; 6:14-21. [PMID: 28062525 PMCID: PMC5227055 DOI: 10.1302/2046-3758.61.bjr-2016-0085.r1] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Accepted: 10/24/2016] [Indexed: 12/19/2022] Open
Abstract
Intermittently administered parathyroid hormone (PTH 1-34) has been shown to promote bone formation in both human and animal studies. The hormone and its analogues stimulate both bone formation and resorption, and as such at low doses are now in clinical use for the treatment of severe osteoporosis. By varying the duration of exposure, parathyroid hormone can modulate genes leading to increased bone formation within a so-called 'anabolic window'. The osteogenic mechanisms involved are multiple, affecting the stimulation of osteoprogenitor cells, osteoblasts, osteocytes and the stem cell niche, and ultimately leading to increased osteoblast activation, reduced osteoblast apoptosis, upregulation of Wnt/β-catenin signalling, increased stem cell mobilisation, and mediation of the RANKL/OPG pathway. Ongoing investigation into their effect on bone formation through 'coupled' and 'uncoupled' mechanisms further underlines the impact of intermittent PTH on both cortical and cancellous bone. Given the principally catabolic actions of continuous PTH, this article reviews the skeletal actions of intermittent PTH 1-34 and the mechanisms underlying its effect. CITE THIS ARTICLE L. Osagie-Clouard, A. Sanghani, M. Coathup, T. Briggs, M. Bostrom, G. Blunn. Parathyroid hormone 1-34 and skeletal anabolic action: The use of parathyroid hormone in bone formation. Bone Joint Res 2017;6:14-21. DOI: 10.1302/2046-3758.61.BJR-2016-0085.R1.
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Affiliation(s)
- L Osagie-Clouard
- Institute of Orthopaedics and Musculoskeletal Sciences, University College London, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, London, UK
| | - A Sanghani
- Institute of Orthopaedics and Musculoskeletal Sciences, University College London, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, London, UK
| | - M Coathup
- Institute of Orthopaedics and Musculoskeletal Sciences, University College London, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, London, UK
| | - T Briggs
- Institute of Orthopaedics and Musculoskeletal Sciences, University College London, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, London, UK
| | - M Bostrom
- Hospital for Special Surgery, New York, New York, USA
| | - G Blunn
- Institute of Orthopaedics and Musculoskeletal Sciences, University College London, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, London, UK
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Houston DA, Myers K, MacRae VE, Staines KA, Farquharson C. The Expression of PHOSPHO1, nSMase2 and TNAP is Coordinately Regulated by Continuous PTH Exposure in Mineralising Osteoblast Cultures. Calcif Tissue Int 2016; 99:510-524. [PMID: 27444010 PMCID: PMC5055575 DOI: 10.1007/s00223-016-0176-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 07/12/2016] [Indexed: 11/25/2022]
Abstract
Sustained exposure to high levels of parathyroid hormone (PTH), as observed in hyperparathyroidism, is catabolic to bone. The increase in the RANKL/OPG ratio in response to continuous PTH, resulting in increased osteoclastogenesis, is well established. However, the effects of prolonged PTH exposure on key regulators of skeletal mineralisation have yet to be investigated. This study sought to examine the temporal expression of PHOSPHO1, TNAP and nSMase2 in mineralising osteoblast-like cell cultures and to investigate the effects of continuous PTH exposure on the expression of these enzymes in vitro. PHOSPHO1, nSMase2 and TNAP expression in cultured MC3T3-C14 cells significantly increased from day 0 to day 10. PTH induced a rapid downregulation of Phospho1 and Smpd3 gene expression in MC3T3-C14 cells and cultured hemi-calvariae. Alpl was differentially regulated by PTH, displaying upregulation in cultured MC3T3-C14 cells and downregulation in hemi-calvariae. PTH was also able to abolish the stimulatory effects of bone morphogenic protein 2 (BMP-2) on Smpd3 and Phospho1 expression. The effects of PTH on Phospho1 expression were mimicked with the cAMP agonist forskolin and blocked by the PKA inhibitor PKI (5-24), highlighting a role for the cAMP/PKA pathway in this regulation. The potent down-regulation of Phospho1 and Smpd3 in osteoblasts in response to continuous PTH may provide a novel explanation for the catabolic effects on the skeleton of such an exposure. Furthermore, our findings support the hypothesis that PHOSPHO1, nSMase2 and TNAP function cooperatively in the initiation of skeletal mineralisation.
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Affiliation(s)
- D A Houston
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland, UK.
| | - K Myers
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland, UK
| | - V E MacRae
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland, UK
| | - K A Staines
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland, UK
| | - C Farquharson
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland, UK
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25
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Chen AB, Minami K, Raposo JF, Matsuura N, Koizumi M, Yokota H, Ferreira HG. Transient modulation of calcium and parathyroid hormone stimulates bone formation. Endocrine 2016; 54:232-240. [PMID: 27503319 DOI: 10.1007/s12020-016-1066-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 07/14/2016] [Indexed: 10/21/2022]
Abstract
Intermittent administration of parathyroid hormone can stimulate bone formation. Parathyroid hormone is a natural hormone that responds to serum calcium levels. In this study, we examined whether a transient increase and/or decrease in the serum calcium can stimulate bone formation. Using a mathematical model previously developed, we first predicted the effects of administration of parathyroid hormone, neutralizing parathyroid hormone antibody, calcium, and EGTA (calcium chelator) on the serum concentration of parathyroid hormone and calcium. The model predicted that intermittent injection of parathyroid hormone and ethylene glycol tetraacetic acid transiently elevated the serum parathyroid hormone, while that of parathyroid hormone antibody and calcium transiently reduced parathyroid hormone in the serum. In vitro analysis revealed that parathyroid hormone's transient changes (both up and down) elevated activating transcription factor 4-mediated osteocalcin expression. In the mouse model of osteoporosis, both intermittent administration of calcium and ethylene glycol tetraacetic acid showed tendency to increase bone mineral density of the upper limb (ulna and humerus) and spine, but the effects varied in a region-specific manner. Collectively, the study herein supports a common bone response to administration of calcium and its chelator through their effects on parathyroid hormone.
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Affiliation(s)
- Andy B Chen
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Kazumasa Minami
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
- Department of Medical Physics & Engineering Osaka University Graduate School of Medicine Suita, Osaka, Japan
| | - João F Raposo
- Department of Public Health, Medical School, New University of Lisbon, Lisbon, Portugal
| | - Nariaki Matsuura
- Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Masahiko Koizumi
- Department of Medical Physics & Engineering Osaka University Graduate School of Medicine Suita, Osaka, Japan
| | - Hiroki Yokota
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
| | - Hugo G Ferreira
- REQIMTE, Department of Chemistry, New University of Lisbon, Lisbon, Portugal
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Chen B, Lin T, Yang X, Li Y, Xie D, Cui H. Intermittent parathyroid hormone (1-34) application regulates cAMP-response element binding protein activity to promote the proliferation and osteogenic differentiation of bone mesenchymal stromal cells, via the cAMP/PKA signaling pathway. Exp Ther Med 2016; 11:2399-2406. [PMID: 27284327 DOI: 10.3892/etm.2016.3177] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 03/01/2016] [Indexed: 12/14/2022] Open
Abstract
The potential effects of intermittent parathyroid hormone (1-34) [PTH (1-34)] administration on bone formation have previously been investigated. A number of studies have suggested that the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway is associated with PTH-induced osteogenic differentiation. However, the precise signaling pathways and molecular mechanism by which PTH (1-34) induces the osteogenic differentiation of bone mesenchymal stromal cells (BMSCs) remain elusive. The purpose of the present study was to investigate the mechanism underlying the effect of intermittent PTH (1-34) application on the proliferation and osteogenic differentiation of BMSCs. BMSCs were randomly divided into four groups, as follows: Osteogenic medium (control group); osteogenic medium and intermittent PTH (1-34); osteogenic medium and intermittent PTH (1-34) plus the adenylyl cyclase activator forskolin; and osteogenic medium and intermittent PTH (1-34) plus the PKA inhibitor H-89. A cell proliferation assay revealed that PTH (1-34) stimulates BMSC proliferation via the cAMP/PKA pathway. Furthermore, reverse transcription-quantitative polymerase chain reaction, alkaline phosphatase activity testing and cell examination using Alizarin Red S staining demonstrated that PTH (1-34) administration promotes osteogenic differentiation and mineralization, mediated by the cAMP/PKA pathway. Crucially, the results of western blot analyses suggested that PTH (1-34) treatment and, to a greater degree, PTH (1-34) plus forskolin treatment caused an increase in phosphorylated cAMP response element binding protein (p-CREB) expression, but the effect of PTH on p-CREB expression was blocked by H-89. In conclusion, the current study demonstrated that intermittent PTH (1-34) administration regulates downstream proteins, particularly p-CREB, in the cAMP/PKA signaling pathway, to enhance the proliferation, osteogenic differentiation and mineralization of BMSCs.
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Affiliation(s)
- Bailing Chen
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Tao Lin
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiaoxi Yang
- Department of Spine Surgery, Chinese PLA General Hospital (301 Hospital), Beijing 100853, P.R. China
| | - Yiqiang Li
- Department of Orthopedics, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Denghui Xie
- Department of Spine Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China
| | - Haowen Cui
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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Effects of Intermittent Administration of Parathyroid Hormone (1-34) on Bone Differentiation in Stromal Precursor Antigen-1 Positive Human Periodontal Ligament Stem Cells. Stem Cells Int 2016; 2016:4027542. [PMID: 27069479 PMCID: PMC4812479 DOI: 10.1155/2016/4027542] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 02/17/2016] [Indexed: 12/13/2022] Open
Abstract
Periodontitis is the most common cause of tooth loss and bone destruction in adults worldwide. Human periodontal ligament stem cells (hPDLSCs) may represent promising new therapeutic biomaterials for tissue engineering applications. Stromal precursor antigen-1 (STRO-1) has been shown to have roles in adherence, proliferation, and multipotency. Parathyroid hormone (PTH) has been shown to enhance proliferation in osteoblasts. Therefore, in this study, we aimed to compare the functions of STRO-1(+) and STRO-1(-) hPDLSCs and to investigate the effects of PTH on the osteogenic capacity of STRO-1(+) hPDLSCs in order to evaluate their potential applications in the treatment of periodontitis. Our data showed that STRO-1(+) hPDLSCs expressed higher levels of the PTH-1 receptor (PTH1R) than STRO-1(-) hPDLSCs. In addition, intermittent PTH treatment enhanced the expression of PTH1R and osteogenesis-related genes in STRO-1(+) hPDLSCs. PTH-treated cells also exhibited increased alkaline phosphatase activity and mineralization ability. Therefore, STRO-1(+) hPDLSCs represented a more promising cell resource for biomaterials and tissue engineering applications. Intermittent PTH treatment improved the capacity for STRO-1(+) hPDLSCs to repair damaged tissue and ameliorate the symptoms of periodontitis.
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Shimizu M, Noda H, Joyashiki E, Nakagawa C, Asanuma K, Hayasaka A, Kato M, Nanami M, Inada M, Miyaura C, Tamura T. The Optimal Duration of PTH(1-34) Infusion Is One Hour per Day to Increase Bone Mass in Rats. Biol Pharm Bull 2016; 39:625-30. [PMID: 26822531 DOI: 10.1248/bpb.b15-00756] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Parathyroid hormone (PTH) is a potential medicine for osteoporosis, and subcutaneous (s.c.) PTH treatment enhances bone mass; however, continuous infusion of PTH elicits bone resorption and induces bone loss. To clarify this contradictory phenomenon, we examined bone markers and bone mass in rats to assess the optimal duration of PTH(1-34) infusion. Continuous infusion of PTH at 1 µg/kg/h (Css, steady-state concentration ca. 300 pg/mL) for 1-4 h clearly stimulated the expression both of bone formation-related genes (c-fos, Wnt4, EphrinB2) and of bone resorption-related genes (tnfsf11, tnfsf11b, encoding receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG)), but s.c. treatment stimulated these genes only 1-h after the injection. Rats were treated with 1-, 2-, or 4-h infusions of PTH daily using a totally implanted catheter system, and the femoral bone mineral density (BMD) was measured at 4 weeks. The 1-h infusion of PTH significantly stimulated serum bone formation markers (procollagen I N-terminal propeptide (PINP) and osteocalcin) on day 14 and femoral BMD at 2 and 4 weeks, but the 4-h infusion of PTH did not enhance BMD. Since the 4-h infusion increased the levels of both the bone formation markers and a bone resorption marker (urinary C-terminal telopeptide of type 1 collagen (CTx)), the increased bone resorption may predominate over bone formation. The intermittent elevation of plasma PTH to 300 pg/mL for 1-h each day is optimal for increasing bone mass in rats. In osteoporosis therapy in human, using the optimal duration for the clinical dose of PTH may selectively stimulate bone formation.
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29
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Sheikh Z, Sima C, Glogauer M. Bone Replacement Materials and Techniques Used for Achieving Vertical Alveolar Bone Augmentation. MATERIALS 2015. [PMCID: PMC5455762 DOI: 10.3390/ma8062953] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Alveolar bone augmentation in vertical dimension remains the holy grail of periodontal tissue engineering. Successful dental implant placement for restoration of edentulous sites depends on the quality and quantity of alveolar bone available in all spatial dimensions. There are several surgical techniques used alone or in combination with natural or synthetic graft materials to achieve vertical alveolar bone augmentation. While continuously improving surgical techniques combined with the use of auto- or allografts provide the most predictable clinical outcomes, their success often depends on the status of recipient tissues. The morbidity associated with donor sites for auto-grafts makes these techniques less appealing to both patients and clinicians. New developments in material sciences offer a range of synthetic replacements for natural grafts to address the shortcoming of a second surgical site and relatively high resorption rates. This narrative review focuses on existing techniques, natural tissues and synthetic biomaterials commonly used to achieve vertical bone height gain in order to successfully restore edentulous ridges with implant-supported prostheses.
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Affiliation(s)
- Zeeshan Sheikh
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Room 221, Fitzgerald Building, 150 College Street, Toronto, ON M5S 3E2, Canada; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-514-224-7490
| | - Corneliu Sima
- Department of Applied Oral Sciences, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; E-Mail:
| | - Michael Glogauer
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Room 221, Fitzgerald Building, 150 College Street, Toronto, ON M5S 3E2, Canada; E-Mail:
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30
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Silva BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol 2015; 22:41-50. [PMID: 25854704 DOI: 10.1016/j.coph.2015.03.005] [Citation(s) in RCA: 340] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 03/24/2015] [Indexed: 12/16/2022]
Abstract
Parathyroid hormone (PTH) is essential for the maintenance of calcium homeostasis through, in part, its actions to regulate bone remodeling. While PTH stimulates both bone formation and bone resorption, the duration and periodicity of exposure to PTH governs the net effect on bone mass, that is whether it is catabolic or anabolic. PTH receptor signaling in osteoblasts and osteocytes can increase the RANKL/OPG ratio, increasing both osteoclast recruitment and osteoclast activity, and thereby stimulating bone resorption. In contrast, PTH-induced bone formation is explained, at least in part, by its ability to downregulate SOST/sclerostin expression in osteocytes, permitting the anabolic Wnt signaling pathway to proceed. The two modes of administration of PTH, that is, continuous vs. intermittent, can regulate, in bone cells, different sets of genes; alternatively, the same sets of genes exposed to PTH in sustained vs. transient way, will favor bone resorption or bone formation, respectively. This article reviews the effects of PTH on bone cells that lead to these dual catabolic and anabolic actions on the skeleton.
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Affiliation(s)
- Barbara C Silva
- Santa Casa de Belo Horizonte and Felicio Rocho Hospital, Division of Endocrinology, Brazil
| | - John P Bilezikian
- Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, United States.
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31
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Adhami MD, Rashid H, Chen H, Clarke JC, Yang Y, Javed A. Loss of Runx2 in committed osteoblasts impairs postnatal skeletogenesis. J Bone Miner Res 2015; 30:71-82. [PMID: 25079226 PMCID: PMC4280286 DOI: 10.1002/jbmr.2321] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 06/19/2014] [Accepted: 07/04/2014] [Indexed: 01/09/2023]
Abstract
The Runx2 transcription factor is critical for commitment to the osteoblast lineage. However, its role in committed osteoblasts and its functions during postnatal skeletogenesis remain unclear. We established a Runx2-floxed line with insertion of loxP sites around exon 8 of the Runx2 gene. The Runx2 protein lacking the region encoded by exon 8 is imported into the nucleus and binds target DNA but exhibits diminished transcriptional activity. We specifically deleted the Runx2 gene in committed osteoblasts using 2.3-kb col1a-Cre transgenic mice. Surprisingly, the homozygous Runx2 mutant mice were born alive. The Runx2 heterozygous and homozygous null were grossly indistinguishable from wild-type littermates at birth. Runx2 deficiency did not alter proliferative capacity of osteoblasts during embryonic development (E18). Chondrocyte differentiation and cartilage growth in mutants was similar to wild-type mice from birth to 3 months of age. Analysis of the embryonic skeleton revealed poor calcification in homozygous mutants, which was more evident in bones formed by intramembranous ossification. Runx2 mutants showed progressive retardation in postnatal growth and exhibited significantly low bone mass by 1 month of age. Decreased bone formation was associated with decreased gene expression of osteoblast markers and impaired collagen assembly in the extracellular matrix. Consequently, Runx2 mutant bones exhibited decreased stiffness and structural integrity. By 3 months of age, bone acquisition in mutant mice was roughly half that of wild-type littermates. In addition to impaired osteoblast function, mutant mice showed markedly decreased osteoclast number and postnatal bone resorption. Taken together, functional deficiency of Runx2 in osteoblasts does not result in failed embryonic skeletogenesis but disrupts postnatal bone formation.
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Affiliation(s)
- Mitra D Adhami
- Department of Oral and Maxillofacial Surgery, Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA
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Toscani D, Bolzoni M, Accardi F, Aversa F, Giuliani N. The osteoblastic niche in the context of multiple myeloma. Ann N Y Acad Sci 2014; 1335:45-62. [DOI: 10.1111/nyas.12578] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Denise Toscani
- Myeloma Unit, Department of Clinical and Experimental Medicine; University of Parma; Parma Italy
| | - Marina Bolzoni
- Myeloma Unit, Department of Clinical and Experimental Medicine; University of Parma; Parma Italy
| | - Fabrizio Accardi
- Myeloma Unit, Department of Clinical and Experimental Medicine; University of Parma; Parma Italy
| | - Franco Aversa
- Myeloma Unit, Department of Clinical and Experimental Medicine; University of Parma; Parma Italy
| | - Nicola Giuliani
- Myeloma Unit, Department of Clinical and Experimental Medicine; University of Parma; Parma Italy
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33
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Effects of high phosphorus diet on bone metabolism-related gene expression in young and aged mice. J Nutr Metab 2014; 2014:575932. [PMID: 25505982 PMCID: PMC4253706 DOI: 10.1155/2014/575932] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 11/09/2014] [Indexed: 01/01/2023] Open
Abstract
In this study, the effects of high phosphorus (P) diet on bone metabolism-related gene expression were investigated in young and aged mice. Twelve- and 80-week-old ddY male mice were divided into two groups, respectively, and fed a control diet containing 0.3% P or a high P diet containing 1.2% P. After 4 weeks of treatment, serum parathyroid hormone (PTH) concentration was significantly higher in the high P groups than in the control groups in both young and aged mice and was significantly higher in aged mice than in young mice fed the high P diet. High P diet significantly increased receptor activator of NF-κB ligand (RANKL) mRNA in the femur of both young and aged mice and significantly increased the RANKL/osteoprotegerin (OPG) mRNA ratio only in aged mice. High P diet significantly increased mRNA expression of transient receptor potential vanilloid type 6, calbindin-D9k, and plasma membrane Ca(2+)-ATPase 1b in the duodenum of both young and aged mice. These results suggest that high P diet increased RANKL mRNA expression in the femur and calcium absorption-related gene expression in the duodenum regardless of age. Furthermore, the high P diet-induced increase in PTH secretion might increase the RANKL/OPG mRNA ratio in aged mice.
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Schmitz B, Brand SM, Brand E. Aldosterone signaling and soluble adenylyl cyclase-a nexus for the kidney and vascular endothelium. Biochim Biophys Acta Mol Basis Dis 2014; 1842:2601-9. [PMID: 24907563 DOI: 10.1016/j.bbadis.2014.05.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 05/23/2014] [Accepted: 05/28/2014] [Indexed: 12/14/2022]
Abstract
The steroid hormone aldosterone regulates the reabsorption of water and ions in the kidney and plays a central role in blood pressure regulation and homeostasis. In recent years, the vascular endothelium has been established as an important aldosterone target organ with major implications in renal and cardiovascular health and disease. Different lines of evidence suggest that the calcium- and bicarbonate-activated soluble adenylyl cyclase (sAC) is a novel mediator of aldosterone signaling in both the kidney and vascular endothelium. This review summarizes our current understanding of the molecular mechanisms of sAC gene expression regulation in the kidney and vascular endothelium and outlines the potential clinical implications of sAC in chronic kidney disease and cardiovascular disease. This review is part of a special issue entitled: The role of soluble adenylyl cyclase in health and disease. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.
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Affiliation(s)
- Boris Schmitz
- Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Horstmarer Landweg 39, 48149 Muenster, Germany; Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany
| | - Stefan-Martin Brand
- Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Horstmarer Landweg 39, 48149 Muenster, Germany
| | - Eva Brand
- Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.
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Deregulation of bone forming cells in bone diseases and anabolic effects of strontium-containing agents and biomaterials. BIOMED RESEARCH INTERNATIONAL 2014; 2014:814057. [PMID: 24800251 PMCID: PMC3988913 DOI: 10.1155/2014/814057] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/20/2014] [Accepted: 03/03/2014] [Indexed: 11/30/2022]
Abstract
Age-related bone loss and osteoporosis are associated with bone remodeling changes that are featured with decreased trabecular and periosteal bone formation relative to bone resorption. Current anticatabolic therapies focusing on the inhibition of bone resorption may not be sufficient in the prevention or reversal of age-related bone deterioration and there is a big need in promoting osteoblastogenesis and bone formation. Enhanced understanding of the network formed by key signaling pathways and molecules regulating bone forming cells in health and diseases has therefore become highly significant. The successful development of agonist/antagonist of the PTH and Wnt signaling pathways are profits of the understanding of these key pathways. As the core component of an approved antiosteoporosis agent, strontium takes its effect on osteoblasts at multilevel through multiple pathways, representing a good example in revealing and exploring anabolic mechanisms. The recognition of strontium effects on bone has led to its expected application in a variety of biomaterial scaffolds used in tissue engineering strategies aiming at bone repairing and regeneration. While summarizing the recent progress in these respects, this review also proposes the new approaches such as systems biology in order to reveal new insights in the pathology of osteoporosis as well as possible discovery of new therapies.
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36
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Masuyama R. Role of local vitamin D signaling and cellular calcium transport system in bone homeostasis. J Bone Miner Metab 2014; 32:1-9. [PMID: 24213217 DOI: 10.1007/s00774-013-0508-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 08/07/2013] [Indexed: 12/14/2022]
Abstract
Mouse genetic studies have demonstrated that the 1,25-dihydroxyvitamin D [1,25(OH)2D] endocrine system is required for calcium (Ca(2+)) and bone homeostasis. These studies reported severe hypocalcemia and impaired bone mineralization associated with rickets in mutant mice. Specific phenotypes of these mice with an engineered deletion of 1,25(OH)2D cell signaling resemble the features observed in humans with the same congenital disease or severe 1,25(OH)2D deficiency. Decreased active intestinal Ca(2+) absorption because of reduced expression of epithelial Ca(2+) channels is a crucial mechanism that contributes to the major phenotypes observed in the mutant mice. The importance of intestinal Ca(2+) absorption supported by 1,25(OH)2D-mediated transport was further emphasized by the observation that Ca(2+) supplementation rescues hypocalcemia and restores bone mineralization in both patients and mice lacking 1,25(OH)2D signaling. This observation questions the direct role of 1,25(OH)2D signaling in bone tissue. Studies regarding tissue-specific manipulation of 1,25(OH)2D function have provided a consensus on this issue by demonstrating a direct action of 1,25(OH)2D on cells in bone tissue through bone metabolism and mineral homeostasis. In addition, movement of Ca(2+) from the bone as a result of osteoclastic bone resorption also provides a large Ca(2+) supply in Ca(2+) homeostasis; however, the system controlling Ca(2+) homeostasis in osteoclasts has not been fully identified. Transient receptor potential vanilloid (TRPV) 4 mediates Ca(2+) influx during the late stage of osteoclast differentiation, thereby regulating the Ca(2+) signaling essential for cellular events during osteoclast differentiation; however, the system-modifying effect of TRPV4 activity should be determined. Furthermore, it remains unknown how local Ca(2+) metabolism participates in systemic Ca(2+) homeostasis through bone remodeling. New insights are therefore required to understand this issue.
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Affiliation(s)
- Ritsuko Masuyama
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan,
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Tanaka H, Iwasaki Y, Yamato H, Mori Y, Komaba H, Watanabe H, Maruyama T, Fukagawa M. p-Cresyl sulfate induces osteoblast dysfunction through activating JNK and p38 MAPK pathways. Bone 2013; 56:347-54. [PMID: 23851293 DOI: 10.1016/j.bone.2013.07.002] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 05/14/2013] [Accepted: 07/02/2013] [Indexed: 01/03/2023]
Abstract
Recent data suggest that several uremic toxins may contribute to the development of bone abnormalities in chronic kidney disease. p-Cresyl sulfate (PCS), the sulfate conjugate of p-cresol, is a protein-bound uremic toxin associated with the progression of chronic kidney disease, cardiovascular risk, and mortality. However, the effects of PCS on bone metabolism remain unclear. In the present study, we evaluated the toxic effects of PCS on primary mouse osteoblasts, compared with an extensively studied uremic toxin indoxyl sulfate (IS). Pre-treatment of osteoblasts with PCS at 0.125 mM and above significantly decreased parathyroid hormone (PTH)-induced cAMP production in a dose-dependent manner. PCS also induced a significant increase in intracellular production of reactive oxygen species (ROS) at 0.25 mM and above, but not at lower concentrations. PCS at 0.125 mM (a concentration that did not induce significant ROS increase) decreased cell viability by augmenting DNA fragmentation and reducing cell proliferation. Inhibition of JNK and p38 mitogen-activated protein kinase (MAPK) abolished the PCS-induced increase in DNA fragmentation and decrease in cAMP production in osteoblastic cells. Compared with PCS, IS induced ROS production at 0.05 mM but did not reduce cAMP production from 0.05 to 0.5 mM. IS induced decrease in cell viability and increase in DNA fragmentation at 0.5mM only. These results suggest that PCS damages osteoblastic cells through not only increasing ROS production but also activating JNK/p38 MAPKs, which is different from the mechanism of injury by IS. These damages of osteoblasts induced by PCS may play a critical role in impairing bone metabolism in patients with chronic kidney disease in whom PCS accumulates.
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Affiliation(s)
- Hisae Tanaka
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
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Tsuchie H, Miyakoshi N, Kasukawa Y, Aonuma H, Shimada Y. Intermittent administration of human parathyroid hormone before osteosynthesis stimulates cancellous bone union in ovariectomized rats. TOHOKU J EXP MED 2013; 229:19-28. [PMID: 23221107 DOI: 10.1620/tjem.229.19] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
It has been reported that intermittent administration of human parathyroid hormone (h-PTH) promotes bone healing after surgery for osteoporotic fractures. If bone healing is promoted by the administration of h-PTH during pre-operative waiting period, we can prevent prolonged bed rest. Therefore, we evaluated the effects of pre-operative h-PTH treatment on cancellous bone union and its mechanism for fracture healing in ovariectomized rats as a model for osteoporosis. Ovariectomized 7-month-old female Sprague-Dawley rats underwent an osteotomy of the proximal tibia as a fracture model, and h-PTH (30 μg/kg body weight) or vehicle was administered as a pre-operative treatment for one week. After the one-week treatment, tibiae were fixed with wire for osteosynthesis, and h-PTH or vehicle was administered for 1 or 3 weeks following wire fixation. In addition to bone histomorphometry, we used alcian blue/hematoxylin stained sections for evaluating cartilage volume and immunostained sections for analyzing the expression of proliferating cell nuclear antigen (PCNA) for cell proliferation and that of Sox9 and Runx2, differentiation markers for cartilage cells and osteoblasts, respectively. Pre-operative treatment with PTH significantly increased bone volume. Pre-operative and pre- to post-operative treatment with PTH for 2 weeks significantly promoted bone union. Pre-operative treatment with PTH significantly increased cartilage volume, and pre- to post-operative treatment with PTH for 2 weeks significantly increased the percentage of cells positive for Runx2 (p < 0.01), but not PCNA or Sox9. Pre-operative administration of h-PTH enhances bone union by promoting cartilage formation and cell differentiation to osteoblasts, but not by promoting cell proliferation.
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Affiliation(s)
- Hiroyuki Tsuchie
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita City, Japan.
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Esbrit P, Alcaraz MJ. Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies. Biochem Pharmacol 2013; 85:1417-23. [PMID: 23500550 DOI: 10.1016/j.bcp.2013.03.002] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 03/01/2013] [Accepted: 03/01/2013] [Indexed: 12/19/2022]
Abstract
Osteoporosis is characterized by low bone mineral density and/or poor bone microarchitecture leading to an increased risk of fractures. The skeletal alterations in osteoporosis are a consequence of a relative deficit of bone formation compared to bone resorption. Osteoporosis therapies have mostly relied on antiresorptive drugs. An alternative therapeutic approach for osteoporosis is currently available, based on the intermittent administration of parathyroid hormone (PTH). Bone anabolism caused by PTH therapy is mainly accounted for by the ability of PTH to increase osteoblastogenesis and osteoblast survival. PTH and PTH-related protein (PTHrP)-an abundant local factor in bone- interact with the common PTH type 1 receptor with similar affinities in osteoblasts. Studies mainly in osteoporosis rodent models and limited data in postmenopausal women suggest that N-terminal PTHrP peptides might be considered a promising bone anabolic therapy. In addition, putative osteogenic actions of PTHrP might be ascribed not only to its N-terminal domain but also to its PTH-unrelated C-terminal region. In this review, we discuss the underlying cellular and molecular mechanisms of the anabolic actions of PTH and the similar potential of PTH-related protein (PTHrP) to increase bone mass and improve bone regeneration.
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Affiliation(s)
- Pedro Esbrit
- Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria-IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain.
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Differentiation of mesenchymal stem cells to osteoblasts and chondrocytes: a focus on adenosine receptors. Expert Rev Mol Med 2013; 15:e1. [PMID: 23406574 DOI: 10.1017/erm.2013.2] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Skeletogenesis, either during development, post-injury or for maintenance, is a carefully coordinated process reliant on the appropriate differentiation of mesenchymal stem cells. Some well described, as well as a new regulator of this process (adenosine receptors), are alike in that they signal via cyclic-AMP (cAMP). This review highlights the known contribution of cAMP signalling to mesenchymal stem cell differentiation to osteoblasts and to chondrocytes. Focus has been given to how these regulators influence the commitment of the osteochondroprogenitor to these separate lineages.
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Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, Jurutka PW. Molecular mechanisms of vitamin D action. Calcif Tissue Int 2013; 92:77-98. [PMID: 22782502 DOI: 10.1007/s00223-012-9619-0] [Citation(s) in RCA: 495] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 05/15/2012] [Indexed: 12/14/2022]
Abstract
The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP(9k), and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling. Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer.
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Affiliation(s)
- Mark R Haussler
- Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, 425 North 5th Street, Phoenix, AZ 85004-2157, USA.
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Parathyroid hormone-related protein protects renal tubuloepithelial cells from apoptosis by activating transcription factor Runx2. Kidney Int 2013; 83:825-34. [PMID: 23364519 DOI: 10.1038/ki.2012.476] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Runx2 is a key transcription factor in bone development regulating several processes, including osteoblast apoptosis. The antiapoptotic effects of parathyroid hormone (PTH) in osteoblasts depend on Runx2-mediated transcription of prosurvival genes. In the kidney, PTH-related protein (PTHrP) promotes tubulointerstitial cell survival by activating the PTH/PTHrP type 1 receptor. We found that Runx2 is expressed in renal tubuloepithelial MCT and HK2 cell lines in vitro and in the mouse kidney tubuloepithelium in vivo. The 1-36 amino-acid fragment of PTHrP was found to increase the expression and nuclear translocation of Runx2 in both cell lines in a dose- and time-dependent manner. PTHrP(1-36) protected renal tubuloepithelial cells from folic acid toxicity and serum deprivation, an effect inhibited by a dominant-negative Runx2 construct or a Runx2 siRNA. Furthermore, PTHrP(1-36) upregulated the antiapoptotic proteins Bcl-2 and osteopontin, and these effects were abolished by Runx2 siRNA. Runx2, osteopontin, and Bcl-2 were increased in tubuloepithelial cells from transgenic mice with PTHrP overexpression and in wild-type mice with acute or chronic renal failure. Thus, PTHrP regulates renal tubuloepithelial cell survival via Runx2 in the mammalian kidney.
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Mukherjee A, Larson EA, Carlos AS, Belknap JK, Rotwein P, Klein RF. Congenic mice provide in vivo evidence for a genetic locus that modulates intrinsic transforming growth factor β1-mediated signaling and bone acquisition. J Bone Miner Res 2012; 27:1345-56. [PMID: 22407846 PMCID: PMC4729561 DOI: 10.1002/jbmr.1590] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Osteoporosis, the most common skeletal disorder, is characterized by low bone mineral density (BMD) and an increased risk of fragility fractures. BMD is the best clinical predictor of future osteoporotic fracture risk, but is a complex trait controlled by multiple environmental and genetic determinants with individually modest effects. Quantitative trait locus (QTL) mapping is a powerful method for identifying chromosomal regions encompassing genes involved in shaping complex phenotypes, such as BMD. Here we have applied QTL analysis to male and female genetically-heterogeneous F(2) mice derived from a cross between C57BL/6 and DBA/2 strains, and have identified 11 loci contributing to femoral BMD. Further analysis of a QTL on mouse chromosome 7 following the generation of reciprocal congenic strains has allowed us to determine that the high BMD trait, which tracks with the DBA/2 chromosome and exerts equivalent effects on male and female mice, is manifested by enhanced osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and by increased growth of metatarsal bones in short-term primary culture. An insertion/deletion DNA polymorphism in Ltbp4 exon 12 that causes the in-frame removal of 12 codons in the DBA/2-derived gene maps within 0.6 Mb of the marker most tightly linked to the QTL. LTBP4, one of four paralogous mouse proteins that modify the bioavailability of the transforming growth factor β (TGF-β) family of growth factors, is expressed in differentiating MSC-derived osteoblasts and in long bones, and reduced responsiveness to TGF-β1 is observed in MSCs of mice homozygous for the DBA/2 chromosome 7. Taken together, our results identify a potential genetic and biochemical relationship between decreased TGF-β1-mediated signaling and enhanced femoral BMD that may be regulated by a variant LTBP4 molecule.
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Affiliation(s)
- Aditi Mukherjee
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, United States
| | - Emily A. Larson
- Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Amy S. Carlos
- Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - John K. Belknap
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United States
- Portland Veterans Affairs Medical Center, Portland, OR, United States
| | - Peter Rotwein
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, United States
| | - Robert F. Klein
- Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
- Portland Veterans Affairs Medical Center, Portland, OR, United States
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Zhu W, Yang ML, Yang GY, Boden G, Li L. Changes in serum runt-related transcription factor 2 levels after a 6-month treatment with recombinant human parathyroid hormone in patients with osteoporosis. J Endocrinol Invest 2012; 35:602-6. [PMID: 22104703 DOI: 10.3275/8110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The mechanisms regulating the anabolic response of the skeleton for recombinant human PTH (1- 34) [rhPTH (1-34)] administration has not been fully elucidated. AIM The aim of this study was to evaluate the effect of rhPTH (1-34) on serum levels of runt-related transcription factor 2 (Runx2) in women with osteoporosis. METHODS Sixty post-menopausal women with osteoporosis (EO group) and 45 control subjects (NC group) were enrolled in this study. The EO group received daily injection of 20 μg rhPTH (1-34) plus oral 500 mg elemental calcium and 400 IU vitamin D3 for 6 months. Runx2 and Matrix metalloproteinase 13 (MMP-13) were measured with commercially available enzyme-linked immunosorbent assay kits. Bone mineral density (BMD) was also measured before and 6 months after rhPTH (1-34) treatment. RESULTS Serum total Ca2+, phosphate, and bone-specific alkaline phosphatase were significantly increased (p<0.05 or p<0.01), and the lumbar spine BMD (LS-BMD) was also increased by 4% in patients with osteoporosis after treatment with rhPTH (1-34) (p<0.05). On the contrary, serum Runx2 and MMP-13 were significantly decreased at post treatment (13.1% and 36.6%, respectively, p<0.05 and p<0.01). At baseline, serum Runx2 positively correlated with MMP-13 (r=0.74, p<0.01), the correction remained after adjusting for age and body mass index. CONCLUSION The daily injection of rhPTH (1-34) was able to stimulate bone formation. The therapy of 20 μg rhPTH (1- 34) for 6 months resulted in decrease of serum Runx2 and MMP-13. These changes might reflect the increase of active osteoblasts and the better bone homeostasis.
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Affiliation(s)
- W Zhu
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education and Department of Clinical Biochemistry, Chongqing Medical University College of Laboratory Medicine, Chongqing, China
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Motyl KJ, McCauley LK, McCabe LR. Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. J Cell Physiol 2012; 227:1326-34. [PMID: 21604269 PMCID: PMC4100799 DOI: 10.1002/jcp.22844] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Type 1 diabetic osteoporosis results from impaired osteoblast activity and death. Therefore, anti-resorptive treatments may not effectively treat bone loss in this patient population. Intermittent parathyroid hormone (PTH) treatment stimulates bone remodeling and increases bone density in healthy subjects. However, PTH effects may be limited in patients with diseases that interfere with its signaling. Here, we examined the ability of 8 and 40 µg/kg intermittent PTH to counteract diabetic bone loss. PTH treatment reduced fat pad mass and blood glucose levels in non-diabetic PTH-treated mice, consistent with PTH-affecting glucose homeostasis. However, PTH treatment did not significantly affect general body parameters, including the blood glucose levels, of type 1 diabetic mice. We found that the high dose of PTH significantly increased tibial trabecular bone density parameters in control and diabetic mice, and the lower dose elevated trabecular bone parameters in diabetic mice. The increased bone density was due to increased mineral apposition and osteoblast surface, all of which are defective in type 1 diabetes. PTH treatment suppressed osteoblast apoptosis in diabetic bone, which could further contribute to the bone-enhancing effects. In addition, PTH treatment (40 µg/kg) reversed preexisting bone loss from diabetes. We conclude that intermittent PTH may increase type 1 diabetic trabecular bone volume through its anabolic effects on osteoblasts.
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Affiliation(s)
- Katherine J Motyl
- Department of Physiology, Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan 48824, USA
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Danciu TE, Li Y, Koh A, Xiao G, McCauley LK, Franceschi RT. The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts. J Cell Biochem 2012; 113:70-9. [PMID: 21866569 PMCID: PMC3414260 DOI: 10.1002/jcb.23329] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Parathyroid hormone (PTH) is an essential regulator of endochondral bone formation and an important anabolic agent for the reversal of bone loss. PTH mediates its functions in part by regulating binding of the bone-related activating transcription factor 4 (ATF4) to the osteoblast-specific gene, osteocalcin. The basic helix-loop-helix (bHLH) factors Twist1 and Twist2 also regulate osteocalcin transcription in part through the interaction of the C-terminal "box" domain in these factors and Runx2. In this study, we discovered a novel function of PTH: its ability to dramatically decrease Twist1 transcription. Since ATF4 is a major regulator of the PTH response in osteoblasts, we assessed the mutual regulation between these factors and determined that Twist proteins and ATF4 physically interact in a manner that affects ATF4 DNA binding function. We mapped the interaction domain of Twist proteins to the C-terminal "box" domain and of ATF4, to the N-terminus. Furthermore, we demonstrate that Twist1 overexpression in osteoblasts attenuates ATF4 binding to the osteocalcin promoter in response to PTH. This study thus identifies Twist proteins as novel inhibitory binding partners of ATF4 and explores the functional significance of this interaction.
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Affiliation(s)
- Theodora E Danciu
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109-1245, USA.
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Aslan D, Andersen MD, Gede LB, de Franca TK, Jørgensen SR, Schwarz P, Jørgensen NR. Mechanisms for the bone anabolic effect of parathyroid hormone treatment in humans. Scandinavian Journal of Clinical and Laboratory Investigation 2011; 72:14-22. [PMID: 22085136 DOI: 10.3109/00365513.2011.624631] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Intermittent low-dose treatment with parathyroid hormone (PTH) analogues has become widely used in the treatment of severe osteoporosis. During normal physiological conditions, PTH stimulates both bone formation and resorption, and in patients with primary hyperparathyroidism, bone loss is frequent. However, development of the biochemical measurement of PTH in the 1980s led us to understand the regulation of PTH secretion and calcium metabolism which subsequently paved the way for the use of PTH as an anabolic treatment of osteoporosis as, when given intermittently, it has strong anabolic effects in bone. This could not have taken place without the basic understanding achieved by the biochemical measurements of PTH. The stimulatory effects of PTH on bone formation have been explained by the so-called 'anabolic window', which means that during PTH treatment, bone formation is in excess over bone resorption during the first 6-18 months. This is due to the following: (1) PTH up-regulates c-fos expression in bone cells, (2) IGF is essential for PTH's anabolic effect, (3) bone lining cells are driven to differentiate into osteoblasts, (4) mesenchymal stem cells adhesion to bone surface is enhanced, (5) PTH has a direct antiapoptotic effect on osteoblasts and (6) when PTH interferes with remodelling, the osteoblasts over-compensate, and (7) PTH also decreases sclerostin levels, thereby removing inhibition of Wnt signalling which is required for PTH's anabolic actions. Thus, the net formative effect of PTH given in intermittent treatment emerges through a complex network of pathways. In summary, the effects of PTH on bone turnover are dependent on the mode and dose of administration and studies investigating the mechanisms underlying this effect are reviewed in this article.
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Silva BC, Costa AG, Cusano NE, Kousteni S, Bilezikian JP. Catabolic and anabolic actions of parathyroid hormone on the skeleton. J Endocrinol Invest 2011; 34:801-10. [PMID: 21946081 PMCID: PMC4315330 DOI: 10.3275/7925] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PTH, an 84-amino acid peptide hormone synthesized by the parathyroid glands, is essential for the maintenance of calcium homeostasis.While in its traditional metabolic role, PTH helps to maintain the serum calcium concentration within narrow, normal limits and participates as a determinant of bone remodeling, more specific actions, described as catabolic and anabolic are also well known. Clinically, the catabolic effect of PTH is best represented by primary hyperparathyroidism (PHPT), while the osteoanabolic effect of PTH is best seen when PTH or its biological amino-terminal fragment [PTH(1-34)] is used as a therapy for osteoporosis. These dual functions of PTH are unmasked under very specific pathological (PHPT) or therapeutic conditions. At the cellular level, PTH favors bone resorption, mostly by affecting the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL)-osteoprotegerin- RANK system, leading to an increase in osteoclast formation and activity. Increased bone formation due to PTH therapy is explained best by its ability to enhance osteoblastogenesis and/or osteoblast survival. The PTH-induced bone formation is mediated, in part, by a decrease in SOST/sclerostin expression in osteocytes. This review focuses on the dual anabolic and catabolic actions of PTH on bone, situations where one is enhanced over the other, and the cellular and molecular mechanisms by which these actions are mediated.
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Affiliation(s)
- B C Silva
- Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, USA
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Datta NS. Osteoporotic fracture and parathyroid hormone. World J Orthop 2011; 2:67-74. [PMID: 22474638 PMCID: PMC3302045 DOI: 10.5312/wjo.v2.i8.67] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 04/19/2011] [Accepted: 06/01/2011] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis and age-related bone loss is associated with changes in bone remodeling characterized by decreased bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. Recombinant parathyroid hormone (PTH), PTH(1-34), is an anabolic agent with proven benefits to bone strength and has been characterized as a potential therapy for skeletal repair. In spite of PTH's clinical use, safety is a major consideration for long-term treatment. Studies have demonstrated that intermittent PTH treatment enhances and accelerates the skeletal repair process via a number of mechanisms. Recent research into the molecular mechanism of PTH action on bone tissue has led to the development of PTH analogs to control osteoporotic fractures. This review summarizes a number of advances made in the field of PTH and bone fracture to combat these injuries in humans and in animal models. The ultimate goal of providing an alternative to PTH, currently the sole anabolic therapy in clinical use, to promote bone formation and improve bone strength in the aging population is yet to be achieved.
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