title: Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products.
abstract: The multiligand receptor for advanced glycation end products (RAGE) mediates certain chronic vascular and neurologic degenerative diseases accompanied by low-grade inflammation. RAGE ligands include S100/calgranulins, a class of low-molecular-mass, calcium-binding polypeptides, several of which are chondrocyte expressed. Here, we tested the hypothesis that S100A11 and RAGE signaling modulate osteoarthritis (OA) pathogenesis by regulating a shift in chondrocyte differentiation to hypertrophy. We analyzed human cartilages and cultured human articular chondrocytes, and used recombinant human S100A11, soluble RAGE, and previously characterized RAGE-specific blocking Abs. Normal human knee cartilages demonstrated constitutive RAGE and S100A11 expression, and RAGE and S100A11 expression were up-regulated in OA cartilages studied by immunohistochemistry. CXCL8 and TNF-alpha induced S100A11 expression and release in cultured chondrocytes. Moreover, S100A11 induced cell size increase and expression of type X collagen consistent with chondrocyte hypertrophy in vitro. CXCL8-induced, IL-8-induced, and TNF-alpha-induced but not retinoic acid-induced chondrocyte hypertrophy were suppressed by treatment with soluble RAGE or RAGE-specific blocking Abs. Last, via transfection of dominant-negative RAGE and dominant-negative MAPK kinase 3, we demonstrated that S100A11-induced chondrocyte type X collagen expression was dependent on RAGE-mediated p38 MAPK pathway activation. We conclude that up-regulated chondrocyte expression of the RAGE ligand S100A11 in OA cartilage, and RAGE signaling through the p38 MAPK pathway, promote inflammation-associated chondrocyte hypertrophy. RAGE signaling thereby has the potential to contribute to the progression of OA.
authors.affiliation: Veterans Affairs Medical Center, Department of Medicine, University of California, San Diego, CA 92161, USA.
authors.forename: Denise L
authors.initials: DL
authors.lastname: Cecil
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: John
authors.initials: J
authors.lastname: Rediske
authors.forename: Martin
authors.initials: M
authors.lastname: Lotz
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
mesh_terms: D000328:Adult; D002358:Cartilage, Articular / Q000166:cytology; D019902:Chondrocytes / Q000473:pathology*; D006801:Humans; D006984:Hypertrophy; D007249:Inflammation / Q000473:pathology*; D008875:Middle Aged; D010003:Osteoarthritis / Q000209:etiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D009418:S100 Proteins / Q000502:physiology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; C072337:S100A11 protein, human; D048051:p38 Mitogen-Activated Protein Kinases