PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling
Open accessAbstract
The periosteal and endocortical surfaces of cortical bone dictate the geometry and overall mechanical properties of bone. Yet the cellular and molecular mechanisms that regulate activity on these surfaces are far from being understood. Parathyroid hormone (PTH) has profound effects in cortical bone, stimulating periosteal expansion and at the same time accelerating intracortical bone remodeling. We report herein that transgenic mice expressing a constitutive active PTH receptor in osteocytes (DMP1-caPTHR1 mice) exhibit increased cortical bone area and an elevated rate of periosteal and endocortical bone formation. In addition, DMP1-caPTHR1 mice display a marked increase in intracortical remodeling and cortical porosity. Crossing DMP1-caPTHR1 mice with mice lacking the Wnt coreceptor, LDL-related receptor 5 (LRP5), or with mice overexpressing the Wnt antagonist Sost in osteocytes (DMP1-Sost mice) reduced or abolished, respectively, the increased cortical bone area, periosteal bone formation rate, and expression of osteoblast markers and Wnt target genes exhibited by the DMP1-caPTHR1 mice. In addition, DMP1-caPTHR1 lacking LRP5 or double transgenic DMP1-caPTHR1;DMP1-Sost mice exhibit exacerbated intracortical remodeling and increased osteoclast numbers, and markedly decreased expression of the RANK decoy receptor osteoprotegerin. Thus, whereas Sost downregulation and the consequent Wnt activation is required for the stimulatory effect of PTH receptor signaling on periosteal bone formation, the Wnt-independent increase in osteoclastogenesis induced by PTH receptor activation in osteocytes overrides the effect on Sost. These findings demonstrate that PTH receptor signaling influences cortical bone through actions on osteocytes and defines the role of Wnt signaling in PTH receptor action. © 2011 American Society for Bone and Mineral Research.
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When PTHR1 on osteocytes is activated by chronically high PTH concentrations or when PTHR1 is constitutively active, osteocytes initiate bone remodeling by expanding the osteoclast pool through the release of RANKL, particularly within the bone cortex.
“When PTHR1 on osteocytes is activated by chronically high PTH concentrations or when PTHR1 is constitutively active, osteocytes initiate bone remodeling by expanding the osteoclast pool through the release of RANKL,79 particularly within the bone cortex.80”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [80]
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References 51 · Cited by 208
- Authors
- Rhee, Y., Allen, M. R., Condon, K., Lezcano, V., Ronda, A. C., Galli, C., Olivos, N., Passeri, G., O'Brien, C. A., Bivi, N., Plotkin, L. I., & Bellido, T.
- Affiliations
- Yonsei University (KR)
- Indiana University Indianapolis (US)
- University of Parma (IT)
- Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Division of Endocrinology, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Corresponding author
- Bellido, Teresita
- ORCID
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-12-07
- Volume
- 26
- Issue
- 5
- Pages
- 1035-1046
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- PMC
- PMC3179307
- OpenAlex
- W1969279069
- Cited by
- 208
- References
- 51
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 10 · 2021: 10 · 2020: 20 · 2019: 12 · 2018: 10 · 2017: 18 · 2016: 12 · 2015: 25 · 2014: 14 · 2013: 22 · 2012: 15
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (1s10rr023710-01, AG13918)
- National Institute on Aging (P01 AG-13918, P01AG013918)
- National Institute of General Medical Sciences (GM067592, R25GM067592)
- Fogarty International Center (R03TW006919, TW06919)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076007)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR049794)
- National Center for Research Resources (S10‐RR023710)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- parathyroid hormone receptor, osteocytes, periosteal bone formation, cortical bone, Wnt signaling, LRP5, sclerostin, osteoclastogenesis, osteoprotegerin, RANK, cortical porosity
- MeSH terms
- Animals, Bone Resorption, Glycoproteins, Mice, Transgenic, Organ Size, Osteoblasts, Osteoclasts, Osteocytes, Osteogenesis, Periosteum, Phenotype, Skull, Signal Transduction, Biomarkers, Cytokines, Extracellular Matrix Proteins, Bone Remodeling, LDL-Receptor Related Proteins, Intercellular Signaling Peptides and Proteins, Receptor, Parathyroid Hormone, Type 1, Adaptor Proteins, Signal Transducing, Wnt Proteins, Mice, Low Density Lipoprotein Receptor-Related Protein-5
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