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Cited by 57Bone Metabolism and DiseasesConnective Tissue Growth Factor ResearchBone and Dental Protein Studies

The Matricellular Protein CYR61 Inhibits Osteoclastogenesis by a Mechanism Independent of αvβ3 and αvβ5

Crockett, Julie C., Schütze, Norbert, Tosh, Denise, Jatzke, Susanne, Duthie, Angela, Jakob, Franz, Rogers, Michael J.·2007·Endocrinology
DOI 10.1210/en.2007-0473
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Abstract

Cysteine-rich protein 61 (CYR61/CCN1) belongs to the family of CCN matricellular proteins. Most of the known effects of CCN proteins appear to be due to binding to extracellular growth factors or integrins, including αvβ3 and αvβ5. Although CYR61 can stimulate osteoblast differentiation, until now the effect of CYR61 on osteoclasts was unknown. We demonstrate that recombinant human CYR61 inhibits the formation of multinucleated, αvβ3-positive, or tartrate-resistant acid phosphatase-positive human, mouse, and rabbit osteoclasts in vitro. CYR61 markedly reduced the expression of the osteoclast phenotypic markers tartrate-resistant acid phosphatase, matrix metalloproteinase-9, calcitonin receptor, and cathepsin K. However, CYR61 did not affect the formation of multinucleated osteoclasts when added to osteoclast precursors prior to fusion or affect the number or resorptive activity of osteoclasts cultured on dentine discs, indicating that CYR61 affects early osteoclast precursors but not mature osteoclasts. CYR61 did not affect receptor activator of nuclear factor-κB (RANK) ligand-induced phosphorylation of p38 or ERK1/2 in human macrophages and did not affect RANK ligand-induced activation of nuclear factor-κB, indicating that CYR61 does not appear to inhibit osteoclastogenesis by affecting RANK signaling. Furthermore, a mutant form of CYR61 defective in binding to αvβ3 also inhibited osteoclastogenesis, and CYR61 inhibited osteoclastogenesis similarly in cultures of mouse wild-type or β5−/− macrophages. Thus, CYR61 does not appear to inhibit osteoclast formation by interacting with αvβ3 or αvβ5. These observations demonstrate that CYR61 is a hitherto unrecognized inhibitor of osteoclast formation, although the exact mechanism of inhibition remains to be determined. Given that CYR61 also stimulates osteoblasts, CYR61 could represent an important bifunctional local regulator of bone remodeling.

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  • CCN1 stimulates osteoblast differentiation through an αvβ3/ILK-dependent pathway but inhibits osteoclastogenesis, suggesting it is a bifunctional regulator of bone remodeling that promotes bone formation and inhibits bone resorption.

    “Moreover, CCN1 stimulates osteoblast differentiation through an αvβ3/ILK-dependent pathway but inhibits osteoclastogenesis, suggesting its role as a bifunctional regulator of bone remodeling that promotes bone formation but inhibits bone resorption [90–92].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [91]

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Authors
Crockett, J. C., Schütze, N., Tosh, D., Jatzke, S., Duthie, A., Jakob, F., & Rogers, M. J.
Affiliations
  • University of Aberdeen (GB)
  • Orthopaedic Institute (N.S., S.J., F.J.), Molecular Orthopaedics, 97074 Wuerzburg, Germany
Corresponding author
Rogers, Michael J.
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2007-12-01
Volume
148
Issue
12
Pages
5761-5768
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2007-0473
OpenAlex
W1913960463
Cited by
57
References
48
Citations by year
2025: 2 · 2024: 3 · 2023: 2 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 2 · 2012: 7
FWCI
0.93
Type
journal article
Language
en
Open access
closed
Locations
  • Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
Keywords
CYR61, osteoclastogenesis, osteoclasts, alpha v beta 3 integrin, alpha v beta 5 integrin, RANK signaling, tartrate-resistant acid phosphatase, MMP-9, cathepsin K, calcitonin receptor, bone remodeling, osteogenic differentiation
MeSH terms
Animals, Bone Resorption, Cell Differentiation, Cell Line, Cells, Cultured, Humans, Mice, Inbred C57BL, Mice, Inbred Strains, Osteoclasts, Phosphorylation, Rabbits, Recombinant Proteins, Signal Transduction, Integrins, Immediate-Early Proteins, Receptors, Vitronectin, Mitogen-Activated Protein Kinase 1, Reverse Transcriptase Polymerase Chain Reaction, Intercellular Signaling Peptides and Proteins, Integrin alphaVbeta3, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Mice, RANK Ligand, Cysteine-Rich Protein 61

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