Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-κB activation, osteoclastogenesis and bone resorption
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Previously we observed that capsaicin treatment in rats inhibited sensory neuropeptide signaling, with a concurrent reduction in trabecular bone formation and bone volume, and an increase in osteoclast numbers and bone resorption. Calcitonin gene-related peptide (CGRP) is a neuropeptide richly distributed in sensory neurons innervating the skeleton and we postulated that CGRP signaling regulates bone integrity. In this study we examined CGRP effects on stromal and bone cell differentiation and activity in vitro. CGRP receptors were detected by immunocytochemical staining and real time PCR assays in mouse bone marrow stromal cells (BMSCs) and bone marrow macrophages (BMMs). CGRP effects on BMSC proliferation and osteoblastic differentiation were studied using BrdU incorporation, PCR products, alkaline phosphatase (ALP) activity, and mineralization assays. CGRP effects on BMM osteoclastic differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase positive (TRAP+) multinucleated cells, pit erosion area, mRNA levels of TRAP and cathepsin K, and nuclear factor-κB (NF-κB) nuclear localization. BMSCs, osteoblasts, BMMs, and osteoclasts all expressed CGRP receptors. CGRP (10-10-10-8M) stimulated BMSC proliferation, up-regulated the expression of osteoblastic genes, and increased ALP activity and mineralization in the BMSCs. In BMM cultures CGRP (10-8M) inhibited receptor activator of NF-κB ligand (RANKL) activation of NF-κB. CGRP also down-regulated osteoclastic genes like TRAP and cathepsin K, decreased the numbers of TRAP+ cells, and inhibited bone resorption activity in RANKL stimulated BMMs. These results suggest that CGRP signaling maintains bone mass both by directly stimulating stromal cell osteoblastic differentiation and by inhibiting RANKL induced NF-κB activation, osteoclastogenesis, and bone resorption.
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CGRP acts with higher potency to inhibit osteoclast activity than osteoclast differentiation.
“suggesting that CGRP acts with higher potency to inhibit osteoclast activity than osteoclast differentiation (213).”
From The Activity of Peptides of the Calcitonin Family in Bone (2019) · cites this paper as [213]
In mouse bone marrow cells induced by M-CSF and RANKL, CGRP reduced resorption pit area at 0.1 nM or higher, whereas 10 nM was required to inhibit TRAP-positive cell formation.
“In cells cultured from mouse bone marrow and induced to differentiate into osteoclasts by M-CSF and RANKL, the area of resorption pits was reduced by CGRP in a concentration of 0.1 nM or higher, whereas higher concentrations of 10 nM CGRP were required for the inhibition of TRAP-positive cell formation”
From The Activity of Peptides of the Calcitonin Family in Bone (2019) · cites this paper as [213]
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- Authors
- Wang, L., Shi, X., Zhao, R., Halloran, B. P., Clark, D. J., Jacobs, C. R., & Kingery, W. S.
- Affiliations
- VA Palo Alto Health Care System (US)
- San Francisco VA Medical Center (US)
- Corresponding author
- Wang, Liping
- Venue
- Bone
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 46
- Issue
- 5
- Pages
- 1369-1379
- ISSN
- 1873-2763 (ISSN-L)
- 8756-3282
- PMC
- PMC2854244
- OpenAlex
- W2039009902
- Semantic Scholar
- 97501e887b43c9d591e6450a3690e83b185845cc
- Cited by
- 198
- References
- 53
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 16 · 2023: 19 · 2022: 16 · 2021: 8 · 2020: 17 · 2019: 18 · 2018: 18 · 2017: 10 · 2016: 7 · 2015: 14 · 2014: 6 · 2013: 10 · 2012: 3
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bone (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service (A4265R)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK067197)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- calcitonin gene-related peptide, mesenchymal stem cells, osteogenic differentiation, osteoclastogenesis, bone resorption, RANKL, NF-κB activation, bone marrow-derived macrophages, CGRP receptor, sensory neuropeptides, bone mass regulation, capsaicin, cathepsin K, traps
- MeSH terms
- Alkaline Phosphatase, Animals, Bone Resorption, Cell Differentiation, Cells, Cultured, Male, Mice, Inbred C57BL, Microscopy, Fluorescence, Osteoclasts, Osteogenesis, Blotting, Western, Calcitonin Gene-Related Peptide, Polymerase Chain Reaction, NF-kappa B, Stromal Cells, Microscopy, Confocal, Cell Proliferation, Mice, RANK Ligand
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