title: Novel role of CCN3 that maintains the differentiated phenotype of articular cartilage.
abstract: Knowledge of the microenvironment of articular cartilage in health and disease is the key to accomplishing fundamental disease-modifying treatments for osteoarthritis. The proteins comprising the CCN Family are matricellular proteins with a remarkable relevance within the context of cartilage metabolism. CCN2 displays a great capability for regenerating articular cartilage, and CCN3 has been shown to activate the expression of genes related to articular chondrocytes and to repress genes related to endochondral ossification in epiphyseal chondrocytes. Moreover, mice lacking CCN3 protein have been shown to display ostearthritic changes in their knee articular cartilage. In this study, we employed a monoiodoacetic acid (MIA)-induced osteoarthritic model to investigate whether osteoarthritic changes in the cartilage are reciprocally accompanied by CCN3 down-regulation and an inducible overexpression system to evaluate the effects of CCN3 on articular chondrocytes in vitro. Finally, we also investigated the effects of exogenous CCN3 in vivo during the early stages of MIA-induced osteoarthritis. We discovered that CCN3 is expressed by articular chondrocytes in normal rat knees, whereas it is rapidly down-regulated in osteoarthritic knees. In vitro, we also discovered that CCN3 increases the proteoglycan accumulation, the gene expression of type II collagen, tenascin-C and lubricin, as well as the protein production of tenascin-C and lubricin in articular chondrocytes. In vivo, it was discovered that exogenous CCN3 increased tidemark integrity and produced an increased production of lubricin protein. The potential utility of CCN3 as a future therapeutic agent and possible strategies to improve its therapeutic functions are also discussed.
authors.affiliation: Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan.|Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
authors.forename: Danilo
authors.initials: D
authors.lastname: Janune
authors.affiliation: Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan.
authors.forename: Tarek
authors.initials: T
authors.lastname: Abd El Kader
authors.affiliation: Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Aoyama
authors.affiliation: Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan. kubota1@md.okayama-u.ac.jp.|Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan. kubota1@md.okayama-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, Japan. takigawa@md.okayama-u.ac.jp.|Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan. takigawa@md.okayama-u.ac.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takigawa
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004251:DNA Transposable Elements / Q000235:genetics; D005121:Extremities / Q000473:pathology; D005780:Gelatin / Q000737:chemistry; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D019807:Iodoacetic Acid; D008297:Male; D051379:Mice; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D019063:Tenascin / Q000378:metabolism; D000099158:Proteoglycan 4
chemical_list: D004251:DNA Transposable Elements; D005780:Gelatin; D006023:Glycoproteins; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D019807:Iodoacetic Acid; D055514:Nephroblastoma Overexpressed Protein; D011994:Recombinant Proteins; D019063:Tenascin; D000099158:Proteoglycan 4
keywords: Articular; CCN3/Nov; Cartilage phenotype; Chondrocytes; Osteoarthritis