Osteoclast-derived complement component 3a stimulates osteoblast differentiation.
Bone remodeling is regulated by a coupling of resorption to subsequent formation; however, the "coupling factor" and underlying mechanism are not fully understood. Here, we found that the condition medium (CM) of mature osteoclasts contains a humoral factor that stimulates the differentiation of primary osteoblasts, as determined by alkaline phosphatase (ALP) activity. We purified osteoblastogenesis-stimulating activity from 3 L of osteoclast CM through successive ion exchange chromatographies by monitoring the ALP activity of osteoblasts and identified complement component 3 (C3). Expression of the C3 gene increased during osteoclastogenesis, and the cleavage product C3a was detected by ELISA in the CM of osteoclasts but not in that of bone marrow macrophages. The osteoblastogenesis-stimulating activity present in osteoclast CM was inhibited by a specific antagonist of the C3a receptor (C3aR), SB290157. Conversely, the retroviral expression of C3a as well as treatment with the C3aR agonist, benzeneacetamide, stimulated osteoblast differentiation. C3 gene expression in bone was increased in the high bone turnover states of ovariectomy (OVX) or a receptor activator of NF-κB ligand (RANKL) injection, and blocking the action of C3a with the daily administration of SB290157 resulted in the attenuation of bone formation elevated by OVX and the exacerbation of bone loss. These results suggest that osteoclast-derived C3a functions in the relay from bone resorption to formation and may be a candidate for a coupling factor.
Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Japan.
Kazuhiko
K
Matsuoka
Kyoung-Ae
KA
Park
Masako
M
Ito
Kyoji
K
Ikeda
Sunao
S
Takeshita
D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation; D002845:Chromatography; D015926:Complement C3a / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy
D017077:Culture Media, Conditioned; D015926:Complement C3a
MOLECULAR PATHWAYS - REMODELING < BONE MODELING AND REMODELING; OSTEOBLASTS < CELLS OF BONE; OSTEOCLASTS < CELLS OF BONE