title: Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1.
abstract: Collagen triple helix repeat-containing1 (Cthrc1) has previously been implicated in osteogenic differentiation and positive regulation of bone mass, however, the underlying mechanisms remain unclear. Here we characterized the bone phenotype of a novel Cthrc1 null mouse strain using bone histomorphometry, μCT analysis and functional readouts for bone strength. In male Cthrc1 null mice both trabecular bone as well as cortical bone formation was impaired, whereas in female Cthrc1 null mice only trabecular bone parameters were altered. Novel and highly specific monoclonal antibodies revealed that CTHRC1 is expressed by osteocytes and osteoblasts, but not osteoclasts. Furthermore, Cthrc1 null mice exhibited increased bone resorption with increased number of osteoclast and increased osteoclast activity together with enhanced expression of osteoclastogenic genes such as c-Fos, Rankl, Trap, and Nfatc1. Differentiation of bone marrow-derived monocytes isolated from Cthrc1 null mice differentiated into osteoclasts as effectively as those from wildtype mice. In the presence of CTHRC1 osteoclastogenic differentiation of bone marrow-derived monocytes was dramatically inhibited as was functional bone resorption by osteoclasts. This process was accompanied by downregulation of osteoclastogenic marker genes, indicating that extrinsically derived CTHRC1 is required for such activity. In vitro, CTHRC1 had no effect on osteogenic differentiation of bone marrow stromal cells, however, calvarial osteoblasts from Cthrc1 null mice exhibited reduced osteogenic differentiation compared to osteoblasts from wildtypes. In a collagen antibody-induced arthritis model Cthrc1 null mice suffered significantly more severe inflammation and joint destruction than wildtypes, suggesting that CTHRC1 expressed by the activated synoviocytes has anti-inflammatory effects. Mechanistically, we found that CTHRC1 inhibited NFκB activation by preventing IκBα degradation while also inhibiting ERK1/2 activation. Collectively our studies demonstrate that CTHRC1 secreted from osteocytes and osteoblasts functions as an inhibitor of osteoclast differentiation via inhibition of NFκB-dependent signaling. Furthermore, our data suggest that CTHRC1 has potent anti-inflammatory properties that limit arthritic joint destruction.
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, United States.
authors.forename: Yong-Ri
authors.initials: YR
authors.lastname: Jin
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, United States.
authors.forename: J Patrizia
authors.initials: JP
authors.lastname: Stohn
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, United States.
authors.forename: Qiaozeng
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, United States.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagano
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, United States.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, United States.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, United States.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.affiliation: Department of Biology, Nazarbayev University, Astana, Kazakhstan.
authors.forename: Vyacheslav A
authors.initials: VA
authors.lastname: Adarichev
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, United States. Electronic address: lindnv@mmc.org.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Lindner
mesh_terms: D000818:Animals; D000906:Antibodies; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology*; D001696:Biomechanical Phenomena; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012886:Skull / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D000906:Antibodies; C530500:Cthrc1 protein, mouse; D016326:Extracellular Matrix Proteins; D016328:NF-kappa B; D053245:RANK Ligand
keywords: Arthritis; Bone strength; CTHRC1; NFκB; Osteoclastogenesis