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

Abstract

In osteoarthritis (OA), low-grade joint inflammation promotes altered chondrocyte differentiation and cartilage catabolism. S100/calgranulins share conserved calcium-binding EF-hand domains, associate noncovalently as homodimers and heterodimers, and are secreted and bind receptor for advanced glycation end products (RAGE). Chondrocyte RAGE expression and S100A11 release are stimulated by IL-1β in vitro and increase in OA cartilage in situ. Exogenous S100A11 stimulates chondrocyte hypertrophic differentiation. Moreover, S100A11 is covalently cross-linked by transamidation catalyzed by transglutaminase 2 (TG2), itself an inflammation-regulated and redox stress-inducible mediator of chondrocyte hypertrophic differentiation. In this study, we researched mouse femoral head articular cartilage explants and knee chondrocytes, and a soluble recombinant double point mutant (K3R/Q102N) of S100A11 TG2 transamidation substrate sites. Both TG2 and RAGE knockout cartilage explants retained IL-1β responsiveness. The K3R/Q102N mutant of S100A11 retained the capacity to bind to RAGE and chondrocytes but lost the capacity to signal via the p38 MAPK pathway or induce chondrocyte hypertrophy and glycosaminoglycans release. S100A11 failed to induce hypertrophy, glycosaminoglycan release, and appearance of the aggrecanase neoepitope NITEGE in both RAGE and TG2 knockout cartilages. We conclude that transamidation by TG2 transforms S100A11 into a covalently bonded homodimer that acquires the capacity to signal through the p38 MAPK pathway, accelerate chondrocyte hypertrophy and matrix catabolism, and thereby couple inflammation with chondrocyte activation to potentially promote OA progression.

Sumoylation and Nuclear Translocation of S100A4 Regulate IL-1β-mediated Production of Matrix Metalloproteinase-13

“…S100A11 is covalently modified by transamidation in chondrocytes and promotes chondrocyte hypertrophy and matrix catabolism. A mutant S100A11 protein that was incapable of undergoing transamidation could not induce chondrocyte hypertrophy (45). In one report (46), S100A6 was found to be glutathionylated and cysteinylated in cells exposed to ionizing radiation.…”

Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1

“…For example, (1) increased levels of the S100A family of proteins stimulate chondrocyte hypertrophy and catabolic activity (Cecil and Terkeltaub, 2008;Van Lent et al, 2008;Bian, 2011;Yammani, 2012); (2) Age-related loss of HMGB2 is associated with reduced cellularity and onset of OA. HMGB2 and LEF-1 enhance Wnt signaling and promote superficial zone chondrocyte survival in mice.…”

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

“…8). This accelerates chondrocyte hypertrophy and matrix catabolism via receptor for advanced glycation end products (RAGE) signaling (58). In a surgically induced knee joint instability model of osteoarthritis, mixed strain (SVJ129-C57BL/6) TG2 Ϫ/Ϫ mice had reduced cartilage destruction and increased osteophyte formation relative to wild-type littermates (214).…”