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.

Stimulation of chondrocyte‐mediated cartilage destruction by S100A8 in experimental murine arthritis

“…RAGE-ligand interaction also activates MAP kinase family members, such as JNK, p38, and ERK. Members of the S100 family, such as S100A4, S100A11, and S100A12, have been shown to stimulate chondrocytes by binding to RAGE and further signaling via the MAP kinase pathway (47,48). In the present study, however, inhibition of RAGE itself using a neutralizing antibody (49) did not impair S100A8-stimulated MMP activation, in contrast to blockade of carboxylated glycans, which partially inhibited MMP activation, suggesting that other as yet unknown carboxylated glycan receptors are important in S100A8 signaling.…”

Transamidation by Transglutaminase 2 Transforms S100A11 Calgranulin into a Procatabolic Cytokine for Chondrocytes

“…IL-1␤ increases RAGE expression in cultured chondrocytes. RAGE expression and S100A11 surrounding chondrocytes are elevated in OA cartilage in situ (19,21). In cultured chondrocytes, IL-1␤, TNF-␣, and CXCL8 induce S100A11 release.…”

“…In cultured chondrocytes, IL-1␤, TNF-␣, and CXCL8 induce S100A11 release. Moreover, hypertrophic chondrocyte differentiation induced by exogenous S100A11, CXCL8, and TNF-␣ is dependent on RAGE signaling transduced in part by the p38 MAPK pathway (19).…”

The Roles of S100 Proteins and RAGE in Melanoma

“…S100A11 binds to p53 and to the DNA repair protein Rad54B as well (FernandezFernandez, Rutherford, and Fersht 2008;Murzik et al 2008). S100A11 has also been found to interact with RAGE and to trigger RAGE dependent intracellular signaling in osteoarthritis (OA) and in human keratinocytes (Cecil et al 2005;Sakaguchi et al 2008). …”