Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products.
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.
Cecil
Denise L
DL
Veterans Affairs Medical Center, Department of Medicine, University of California, San Diego, CA 92161, USA.
Johnson
Kristen
K
Rediske
John
J
Lotz
Martin
M
Schmidt
Ann Marie
AM
Terkeltaub
Robert
R
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
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; C072337:S100A11 protein, human; D048051:p38 Mitogen-Activated Protein Kinases