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Resorption Controls Bone Anabolism Driven by Parathyroid Hormone (PTH) Receptor Signaling in Osteocytes

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Title: Resorption Controls Bone Anabolism Driven by Parathyroid Hormone (PTH) Receptor Signaling in Osteocytes
Authors: Matthew R. Allen, Ana C. Ronda, Yumie Rhee, Lilian I. Plotkin, Keith W. Condon, Teresita Bellido, Virginia Lezcano, Eun Young Lee
Contributors: Yumie Rhee, Eun-Young Lee, Virginia Lezcano, Ana C. Ronda, Keith W. Condon, Matthew R. Allen, Lilian I. Plotkin, Teresita Bellido, Rhee, Yumie, Lee, Eun Young
Source: Journal of Biological Chemistry. 288:29809-29820
Publisher Information: Elsevier BV, 2013.
Publication Year: 2013
Subject Terms: 0301 basic medicine, Bone Resorption/metabolism, Gene Expression, Type 1/metabolism, Inbred C57BL, Transgenic, Mice, Absorptiometry, Photon, Alendronate/pharmacology, Bone Density, Osteogenesis, 0303 health sciences, Bone Resorption/prevention & control, Alendronate, Bone Density Conservation Agents, Reverse Transcriptase Polymerase Chain Reaction, Subcutaneous, Signal Transduction, Osteocyte, Osteocytes/metabolism, Photon, Immunohistochemistry, Osteogenesis/drug effects, Resorption, Parathyroid Hormone, Osteogenesis/genetics, Osteoclast, Intercellular Signaling Peptides and Proteins, Bone Remodeling, Wnt Signaling, Receptor, PTH Receptor, Bone Remodeling/genetics, Bone Resorption/genetics, Bone Modeling/Remodeling, Injections, Subcutaneous, Bone and Bones/metabolism, Mice, Transgenic, Gene Expression/drug effects, Glycoproteins/metabolism, Osteocytes, Bone and Bones, Injections, 03 medical and health sciences, Wnt Signaling Pathway/drug effects, Animals, Bone Density Conservation Agents/administration & dosage, Absorptiometry, Bone Density Conservation Agents/pharmacology, Wnt Signaling Pathway/genetics, Bone Resorption, Bone, Adaptor Proteins, Signal Transducing, Glycoproteins, Receptor, Parathyroid Hormone, Type 1, Bone and Bones/drug effects, Glycoproteins/genetics, Bone Density/drug effects, Mice, Inbred C57BL, Alendronate/administration & dosage, Bone Remodeling/drug effects, Osteocytes/drug effects, Sost/Sclerostin, Type 1/genetics
Description: The contribution of remodeling-based bone formation coupled to osteoclast activity versus modeling-based bone formation that occurs independently of resorption, to the anabolic effect of PTH remains unclear. We addressed this question using transgenic mice with activated PTH receptor signaling in osteocytes that exhibit increased bone mass and remodeling, recognized skeletal effects of PTH elevation. Direct inhibition of bone formation was accomplished genetically by overexpressing the Wnt antagonist Sost/sclerostin; and resorption-dependent bone formation was inhibited pharmacologically with the bisphosphonate alendronate. We found that bone formation induced by osteocytic PTH receptor signaling on the periosteal surface depends on Wnt signaling but not on resorption. In contrast, bone formation on the endocortical surface results from a combination of Wnt-driven increased osteoblast number and resorption-dependent osteoblast activity. Moreover, elevated osteoclasts and intracortical/calvarial porosity is exacerbated by overexpressing Sost and reversed by blocking resorption. Furthermore, increased cancellous bone is abolished by Wnt inhibition but further increased by blocking resorption. Thus, resorption induced by PTH receptor signaling in osteocytes is critical for full anabolism in cortical bone, but tempers bone gain in cancellous bone. Dissecting underlying mechanisms of PTH receptor signaling would allow targeting actions in different bone compartments, enhancing the therapeutic potential of the pathway.
Document Type: Article
Language: English
ISSN: 0021-9258
DOI: 10.1074/jbc.m113.485938
Access URL: http://www.jbc.org/content/288/41/29809.full.pdf
https://pubmed.ncbi.nlm.nih.gov/23963454
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795280
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23963454/
https://europepmc.org/articles/PMC3795280
https://yonsei.pure.elsevier.com/en/publications/resorption-controls-bone-anabolism-driven-by-parathyroid-hormone-
https://pubmed.ncbi.nlm.nih.gov/23963454/
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88642
Rights: CC BY
CC BY NC ND
Accession Number: edsair.doi.dedup.....d4325405140eef3062f44aff56fb5ccc
Database: OpenAIRE
Description
Abstract:The contribution of remodeling-based bone formation coupled to osteoclast activity versus modeling-based bone formation that occurs independently of resorption, to the anabolic effect of PTH remains unclear. We addressed this question using transgenic mice with activated PTH receptor signaling in osteocytes that exhibit increased bone mass and remodeling, recognized skeletal effects of PTH elevation. Direct inhibition of bone formation was accomplished genetically by overexpressing the Wnt antagonist Sost/sclerostin; and resorption-dependent bone formation was inhibited pharmacologically with the bisphosphonate alendronate. We found that bone formation induced by osteocytic PTH receptor signaling on the periosteal surface depends on Wnt signaling but not on resorption. In contrast, bone formation on the endocortical surface results from a combination of Wnt-driven increased osteoblast number and resorption-dependent osteoblast activity. Moreover, elevated osteoclasts and intracortical/calvarial porosity is exacerbated by overexpressing Sost and reversed by blocking resorption. Furthermore, increased cancellous bone is abolished by Wnt inhibition but further increased by blocking resorption. Thus, resorption induced by PTH receptor signaling in osteocytes is critical for full anabolism in cortical bone, but tempers bone gain in cancellous bone. Dissecting underlying mechanisms of PTH receptor signaling would allow targeting actions in different bone compartments, enhancing the therapeutic potential of the pathway.
ISSN:00219258
DOI:10.1074/jbc.m113.485938