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Liu H, Liu L, Rosen CJ. PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche. Cells 2024; 13:406. [PMID: 38474370 PMCID: PMC10930661 DOI: 10.3390/cells13050406] [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: 12/05/2023] [Revised: 02/05/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH's role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH-catabolic and anabolic-on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH's multifaceted influence on bone health.
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Affiliation(s)
- Hanghang Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China;
- Maine Medical Center, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA;
| | - Linyi Liu
- Maine Medical Center, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA;
| | - Clifford J. Rosen
- Maine Medical Center, MaineHealth Institute for Research, 81 Research Drive, Scarborough, ME 04074, USA;
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Frieling JS, Lynch CC. Proteolytic Regulation of Parathyroid Hormone-Related Protein: Functional Implications for Skeletal Malignancy. Int J Mol Sci 2019; 20:ijms20112814. [PMID: 31181800 PMCID: PMC6600663 DOI: 10.3390/ijms20112814] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/31/2019] [Accepted: 06/04/2019] [Indexed: 01/17/2023] Open
Abstract
Parathyroid hormone-related protein (PTHrP), with isoforms ranging from 139 to 173 amino acids, has long been implicated in the development and regulation of multiple tissues, including that of the skeleton, via paracrine and autocrine signaling. PTHrP is also known as a potent mediator of cancer-induced bone disease, contributing to a vicious cycle between tumor cells and the bone microenvironment that drives the formation and progression of metastatic lesions. The abundance of roles ascribed to PTHrP have largely been attributed to the N-terminal 1-36 amino acid region, however, activities for mid-region and C-terminal products as well as additional shorter N-terminal species have also been described. Studies of the protein sequence have indicated that PTHrP is susceptible to post-translational proteolytic cleavage by multiple classes of proteases with emerging evidence pointing to novel functional roles for these PTHrP products in regulating cell behavior in homeostatic and pathological contexts. As a consequence, PTHrP products are also being explored as potential biomarkers of disease. Taken together, our enhanced understanding of the post-translational regulation of PTHrP bioactivity could assist in developing new therapeutic approaches that can effectively treat skeletal malignancies.
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Affiliation(s)
- Jeremy S Frieling
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
| | - Conor C Lynch
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model. Sci Rep 2018; 8:3492. [PMID: 29472591 PMCID: PMC5823923 DOI: 10.1038/s41598-018-21886-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 02/13/2018] [Indexed: 12/20/2022] Open
Abstract
Periarticular bone loss in rheumatoid arthritis (RA) is considered to be mainly related to synovial inflammation. However, strong bone loss has also described at the time of arthritis onset. Recently, a paradoxical exacerbation of joint damage was described when blocking sclerostin in various arthritis models. Thus, we aimed to determine kinetics of bone loss and its mechanisms in the adjuvant induced arthritis (AIA) rat model of RA. AIA was induced (n = 35) or not (n = 35) at day 0. In addition to well-known arthritis at day 12, we showed with 3D-imaging and histomorphometry that bone microstructural alterations occurred early from day 8 post-induction, characterized by cortical porosity and trabecular bone loss. Active osteoclastic surfaces were increased from day 8 with RANKL upregulation. More surprisingly SOST and DKK1 were overexpressed from day 6 and followed by a dramatic decrease in bone formation from day 8. At the time of arthritis onset, SOST and DKK1 returned to control values, but frizzled related protein 1 (SFRP1), proinflammatory cytokines, and MMPs started to increase. Bone alterations before arthritis onset reinforce the hypothesis of an early bone involvement in arthritis. Kinetics of osteocyte markers expression should be considered to refine Wnt inhibitor treatment strategies.
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Cerci DX, Portela GS, Cunha EJ, Grossi JRDA, Zielak JC, Araújo MR, Scariot R, Deliberador TM, Giovanini AF. Leukocyte-platelet-rich plasma diminishes bone matrix deposition in rat calvaria treated with autograft due to simultaneous increase in immunohistochemical expression of Indian Hedgehog, transforming growth factor-β, and parathyroid-1 receptor. J Craniomaxillofac Surg 2015. [DOI: 10.1016/j.jcms.2015.06.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Alshbool FZ, Alarcon C, Wergedal J, Mohan S. A high-calcium diet failed to rescue an osteopenia phenotype in claudin-18 knockout mice. Physiol Rep 2014; 2:e00200. [PMID: 24744879 PMCID: PMC3967683 DOI: 10.1002/phy2.200] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 12/03/2013] [Indexed: 12/14/2022] Open
Abstract
We have recently demonstrated that mice with disruption of claudin‐18 (Cldn‐18) gene exhibited osteopenia due to increased bone resorption (BR). In this study, we found that gastric pH was significantly higher in Cldn‐18 knockout (KO) mice compared to heterozygous control mice at 10 weeks of age. To test the possibility that the increased BR in the Cldn‐18 KO mice fed a normal‐Ca diet is a consequence of decreased Ca absorption caused by increased stomach pH, we subjected KO and control mice to a normal‐Ca and high‐Ca diet at birth. Serum Ca levels were significantly lower in Cldn‐18 KO mice compared to control mice at a normal‐Ca diet but not at high‐Ca diet. Dual energy X‐ray absorptiometry revealed that a high‐Ca diet significantly increased lumbar bone mineral density (BMD), but had no effect on femur/tibia BMD in both Cldn‐18 KO and control mice compared to a normal‐Ca diet. While a high‐Ca diet did not affect volumetric BMD, trabecular, and cortical parameters of the lumbar vertebra (LV) as measured by μCT, the size of the LV did increase, in both genotypes due to reduced BR. Comparison of the skeletal phenotype of high‐Ca Cldn‐18 KO and control mice revealed that an osteopenia phenotype seen at a normal‐Ca diet was still maintained at different skeletal sites in the KO mice till 10 weeks of age. In conclusion, our findings suggest that increased BR is likely caused by direct effects of a lack of Cldn‐18 on osteoclasts rather than gastric pH changes. In this study, we examined if calcium deficiency caused by low‐gastric acidity was the cause of osteopenia phenotype observed in claudin‐18 (Cldn‐18) knockout (KO) mice. Our findings that high‐calcium diet did not rescue the osteopenia phenotype in Cldn‐18 KO mice suggest that increased bone resorption is likely caused by direct effects of a lack of Cldn‐18 on osteoclasts rather than gastric pH changes.
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Affiliation(s)
- Fatima Z Alshbool
- Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, 92357, California ; Department of Pharmacology, Loma Linda University, Loma Linda, 92354, California
| | - Catrina Alarcon
- Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, 92357, California
| | - Jon Wergedal
- Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, 92357, California ; Department of Medicine, Loma Linda University, Loma Linda, 92354, California
| | - Subburaman Mohan
- Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, 92357, California ; Department of Medicine, Loma Linda University, Loma Linda, 92354, California ; Department of Biochemistry, Loma Linda University, Loma Linda, 92354, California ; Department of Physiology, Loma Linda University, Loma Linda, 92354, California
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Azevedo-Neto RD, Gonzaga CC, Deliberador TM, Klug LG, Da Costa Oliveira L, Zielak JC, De Andrade Urban C, De Araujo MR, Giovanini AF. Fragmented Adipose Tissue Transplanted to Craniofacial Deformities Induces Bone Repair Associated with Immunoexpression of Adiponectin and Parathyroid Hormone 1-Receptor. Cleft Palate Craniofac J 2013; 50:639-47. [DOI: 10.1597/12-121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objective This study analyzed the influence of autogenous white adipose tissue on bone matrix development in critical-size defects created in rabbit calvaria. Materials and Methods A 15-mm-diameter defect was created in the calvaria of 42 rabbits. Twenty-one rabbits were treated with 86 mm3 of immediate transplant of fragmented white subcutaneous adipose tissue (WSAT); the others constituted the control group (sham). The animals were euthanized at 7, 15, and 40 days postsurgery (n = 7), and the histological data were analyzed by histomorphometry and immunohistochemistry using the anti-adiponectin and parathyroid hormone 1-receptor (PTH1R) antibodies. Results The calvariae treated with fragmented WSAT demonstrated significant bone formation. These results coincided with the significant presence of immunopositivity to adiponectin and PTH1R in loci, which in turn coincided with the increase in bonelike matrix deposited both in fat tissue stroma and adipocytes' cytoplasm. In contrast, the control group revealed a small amount of bone-matrix deposition and presented scarce PTH1R expression and a lack of immunostain for adiponectin. Conclusion These results indicate that transplant of fragmented white subcutaneous adipose tissue may be an alternative to treatment of craniofacial bone deformities because adipose tissue suffers from osseous metaplasia and exhibits immunoexpression of the adiponectin and PTH1R, which are proteins associated with bone metabolism
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Risom L, Christoffersen L, Daugaard-Jensen J, Hove HD, Andersen HS, Andresen BS, Kreiborg S, Duno M. Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. PLoS One 2013; 8:e74601. [PMID: 24058597 PMCID: PMC3776825 DOI: 10.1371/journal.pone.0074601] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 08/05/2013] [Indexed: 11/23/2022] Open
Abstract
Primary Failure of tooth Eruption (PFE) is a non-syndromic disorder which can be caused by mutations in the parathyroid hormone receptor 1 gene (PTH1R). Traditionally, the disorder has been identified clinically based on post-emergent failure of eruption of permanent molars. However, patients with PTH1R mutations will not benefit from surgical and/or orthodontic treatment and it is therefore clinically important to establish whether a given failure of tooth eruption is caused by a PTH1R defect or not. We analyzed the PTH1R gene in six patients clinically diagnosed with PFE, all of which had undergone surgical and/or orthodontic interventions, and identified novel PTH1R mutations in all. Four of the six mutations were predicted to abolish correct mRNA maturation either through introduction of premature stop codons (c.947C>A and c.1082G>A), or by altering correct mRNA splicing (c.544-26_544-23del and c.989G>T). The latter was validated by transfection of minigenes. The six novel mutations expand the mutation spectrum for PFE from eight to 14 pathogenic mutations. Loss-of-function mutations in PTH1R are also associated with recessively inherited Blomstrand chondrodysplasia. We compiled all published PTH1R mutations and identified a mutational overlap between Blomstrand chondrodysplasia and PFE. The results suggest that a genetic approach to preclinical diagnosis will have important implication for surgical and orthodontic treatment of patients with failure of tooth eruption.
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Affiliation(s)
- Lotte Risom
- Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark
- * E-mail:
| | - Line Christoffersen
- Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark
| | | | - Hanne Dahlgaard Hove
- Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark
| | | | | | - Sven Kreiborg
- Department of Paediatric Dentistry and Clinical Genetics, University of Copenhagen, Copenhagen, Denmark
| | - Morten Duno
- Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark
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Abstract
The etiology of skeletal disease is driven by genetic and environmental factors. Genome-wide association studies (GWAS) of osteoporotic phenotypes have identified novel candidate genes, but have only uncovered a small proportion of the trait variance explained. This "missing heritability" is caused by several factors, including the failure to consider gene-by-environmental (G*E) interactions. Some G*E interactions have been investigated, but new approaches to integrate environmental data into genomic studies are needed. Advances in genotyping and meta-analysis techniques now allow combining genotype data from multiple studies, but the measurement of key environmental factors in large human cohorts still lags behind, as do the statistical tools needed to incorporate these measures in genome-wide association meta-studies. This review focuses on discussing ways to enhance G*E interaction studies in humans and how the use of rodent models can inform genetic studies. Understanding G*E interactions will provide opportunities to effectively target intervention strategies for individualized therapy.
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Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH. Proc Natl Acad Sci U S A 2013; 110:5864-9. [PMID: 23533279 DOI: 10.1073/pnas.1301674110] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Agonist-induced phosphorylation of the parathyroid hormone (PTH) receptor 1 (PTHR1) regulates receptor signaling in vitro, but the role of this phosphorylation in vivo is uncertain. We investigated this role by injecting "knock-in" mice expressing a phosphorylation-deficient (PD) PTHR1 with PTH ligands and assessing acute biologic responses. Following injection with PTH (1-34), or with a unique, long-acting PTH analog, PD mice, compared with WT mice, exhibited enhanced increases in cAMP levels in the blood, as well as enhanced cAMP production and gene expression responses in bone and kidney tissue. Surprisingly, however, the hallmark hypercalcemic and hypophosphatemic responses were markedly absent in the PD mice, such that paradoxical hypocalcemic and hyperphosphatemic responses were observed, quite strikingly with the long-acting PTH analog. Spot urine analyses revealed a marked defect in the capacity of the PD mice to excrete phosphate, as well as cAMP, into the urine in response to PTH injection. This defect in renal excretion was associated with a severe, PTH-induced impairment in glomerular filtration, as assessed by the rate of FITC-inulin clearance from the blood, which, in turn, was explainable by an overly exuberant systemic hypotensive response. The overall findings demonstrate the importance in vivo of PTH-induced phosphorylation of the PTHR1 in regulating acute ligand responses, and they serve to focus attention on mechanisms that underlie the acute calcemic response to PTH and factors, such as blood phosphate levels, that influence it.
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Mahalingam CD, Sampathi BR, Sharma S, Datta T, Das V, Abou-Samra AB, Datta NS. MKP1-dependent PTH modulation of bone matrix mineralization in female mice is osteoblast maturation stage specific and involves P-ERK and P-p38 MAPKs. J Endocrinol 2013; 216. [PMID: 23197743 PMCID: PMC3796767 DOI: 10.1530/joe-12-0372] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Limited information is available on the role of MAPK phosphatase 1 (MKP1) signaling in osteoblasts. We have recently reported distinct roles for MKP1 during osteoblast proliferation, differentiation, and skeletal responsiveness to parathyroid hormone (PTH). As MKP1 regulates the phosphorylation status of MAPKs, we investigated the involvement of P-ERK and P-p38 MAPKs in MKP1 knockout (KO) early and mature osteoblasts with respect to mineralization and PTH response. Calvarial osteoblasts from 9-14-week-old WT and MKP1 KO male and female mice were examined. Western blot analysis revealed downregulation and sustained expressions of P-ERK and P-p38 with PTH treatment in differentiated osteoblasts derived from KO males and females respectively. Exposure of early osteoblasts to p38 inhibitor, SB203580 (S), markedly inhibited mineralization in WT and KO osteoblasts from both genders as determined by von Kossa assay. In osteoblasts from males, ERK inhibitor U0126 (U), not p38 inhibitor (S), prevented the inhibitory effects of PTH on mineralization in early or mature osteoblasts. In osteoblasts from KO females, PTH sustained mineralization in early osteoblasts and decreased mineralization in mature cells. This effect of PTH was attenuated by S in early osteoblasts and by U in mature KO cells. Changes in matrix Gla protein expression with PTH in KO osteoblasts did not correlate with mineralization, indicative of MKP1-dependent additional mechanisms essential for PTH action on osteoblast mineralization. We conclude that PTH regulation of osteoblast mineralization in female mice is maturation stage specific and involves MKP1 modulation of P-ERK and P-p38 MAPKs.
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Affiliation(s)
- Chandrika D Mahalingam
- Division of Endocrinology, Department of Internal Medicine, Wayne State University School of Medicine, 1107 Elliman Clinical Research Building, 421 East Canfield Avenue, Detroit, Michigan 48201, USA
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Datta NS, Samra TA, Abou-Samra AB. Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice. Am J Physiol Endocrinol Metab 2012; 302:E1183-8. [PMID: 22338074 PMCID: PMC3361988 DOI: 10.1152/ajpendo.00380.2011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3-6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.
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Affiliation(s)
- Nabanita S Datta
- Wayne State Univ. School of Medicine, Dept. Internal Medicine/Endocrinology, 1107 Elliman Bldg., 421 E. Canfield Ave., Detroit, MI 48201, USA.
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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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Mahalingam CD, Datta T, Patil RV, Kreider J, Bonfil RD, Kirkwood KL, Goldstein SA, Abou-Samra AB, Datta NS. Mitogen-activated protein kinase phosphatase 1 regulates bone mass, osteoblast gene expression, and responsiveness to parathyroid hormone. J Endocrinol 2011; 211:145-56. [PMID: 21852324 PMCID: PMC3783352 DOI: 10.1530/joe-11-0144] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Parathyroid hormone (PTH) signaling via PTH 1 receptor (PTH1R) involves mitogen-activated protein kinase (MAPK) pathways. MAPK phosphatase 1 (MKP1) dephosphorylates and inactivates MAPKs in osteoblasts, the bone-forming cells. We previously showed that PTH1R activation in differentiated osteoblasts upregulates MKP1 and downregulates pERK1/2-MAPK and cyclin D1. In this study, we evaluated the skeletal phenotype of Mkp1 knockout (KO) mice and the effects of PTH in vivo and in vitro. Microcomputed tomography analysis of proximal tibiae and distal femora from 12-week-old Mkp1 KO female mice revealed osteopenic phenotype with significant reduction (8-46%) in bone parameters compared with wild-type (WT) controls. Histomorphometric analysis showed decreased trabecular bone area in KO females. Levels of serum osteocalcin (OCN) were lower and serum tartrate-resistant acid phosphatase 5b (TRAP5b) was higher in KO animals. Treatment of neonatal mice with hPTH (1-34) for 3 weeks showed attenuated anabolic responses in the distal femora of KO mice compared with WT mice. Primary osteoblasts derived from KO mice displayed delayed differentiation determined by alkaline phosphatase activity, and reduced expressions of Ocn and Runx2 genes associated with osteoblast maturation and function. Cells from KO females exhibited attenuated PTH response in mineralized nodule formation in vitro. Remarkably, this observation was correlated with decreased PTH response of matrix Gla protein expression. Expressions of pERK1/2 and cyclin D1 were inhibited dramatically by PTH in differentiated osteoblasts from WT mice but much less in osteoblasts from Mkp1 KO mice. In conclusion, MKP1 is important for bone homeostasis, osteoblast differentiation and skeletal responsiveness to PTH.
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Affiliation(s)
- Chandrika D Mahalingam
- Division of Endocrinology, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, 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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Affiliation(s)
- Joseph P Bidwell
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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