title: The C-terminal domain of chondroadherin: a new regulator of osteoclast motility counteracting bone loss.
abstract: Chondroadherin (CHAD) is a leucine-rich protein promoting cell attachment through binding to integrin α2 β1 and syndecans. We observed that CHAD mRNA and protein were lower in bone biopsies of 50-year-old to 65-year-old osteoporotic women and in bone samples of ovariectomized mice versus gender/age-matched controls, suggesting a role in bone metabolism. By the means of an internal cyclic peptide (cyclicCHAD), we observed that its integrin binding sequence impaired preosteoclast migration through a nitric oxide synthase 2-dependent mechanism, decreasing osteoclastogenesis and bone resorption in a concentration-dependent fashion, whereas it had no effect on osteoblasts. Consistently, cyclicCHAD reduced transcription of two nitric oxide downstream genes, migfilin and vasp, involved in cell motility. Furthermore, the nitric oxide donor, S-nitroso-N-acetyl-D,L-penicillamine, stimulated preosteoclast migration and prevented the inhibitory effect of cyclicCHAD. Conversely, the nitric oxide synthase 2 (NOS2) inhibitor, N5-(1-iminoethyl)-l-ornithine, decreased both preosteoclast migration and differentiation, confirming a role of the nitric oxide pathway in the mechanism of action triggered by cyclicCHAD. In vivo, administration of cyclicCHAD was well tolerated and increased bone volume in healthy mice, with no adverse effect. In ovariectomized mice cyclicCHAD improved bone mass by both a preventive and a curative treatment protocol, with an effect in line with that of the bisphosphonate alendronate, that was mimicked by the NOS2 inhibitor [L-N6-(1-Iminoethyl)-lysine.2 dihydrochloride]. In both mouse models, cyclicCHAD reduced osteoclast and bone resorption without affecting osteoblast parameters and bone formation. In conclusion, CHAD is a novel regulator of bone metabolism that, through its integrin binding domain, inhibits preosteoclast motility and bone resorption, with a potential translational impact for the treatment of osteoporosis.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Capulli
authors.forename: Ole K
authors.initials: OK
authors.lastname: Olstad
authors.forename: Patrik
authors.initials: P
authors.lastname: Onnerfjord
authors.forename: Viveka
authors.initials: V
authors.lastname: Tillgren
authors.forename: Maurizio
authors.initials: M
authors.lastname: Muraca
authors.forename: Kaare M
authors.initials: KM
authors.lastname: Gautvik
authors.forename: Dick
authors.initials: D
authors.lastname: Heinegård
authors.forename: Nadia
authors.initials: N
authors.lastname: Rucci
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008875:Middle Aged; D010010:Osteoclasts; D010052:Ovariectomy; D010455:Peptides / Q000494:pharmacology
chemical_list: D050071:Bone Density Conservation Agents; D016326:Extracellular Matrix Proteins; D010455:Peptides; C088980:chondroadherin
keywords: CHONDROADHERIN; OSTEOCLASTS; OSTEOPOROSIS