TGF-β inhibits IL-1β-activated PAR-2 expression through multiple pathways in human primary synovial cells

Osteoarthritis (OA) is a degenerative disease characterized by depletion of articular cartilage and formation of osteophytes [1]. OA formed under the condition of imbalance between anabolic and catabolic mediators, when catabolism is greater than anabolism, the risk of OA raises. The catabolic mediators include MMPs, ADAMTS, ADAM, IL-1β, IL-17, IL-18 and TNF-α, which increase degradation of cartilage and inhibit synthesis of metalloproteinase inhibitors such as TIMPs, tenascin and YKL-40. The anabolic mediators include TGF-β, IGF-1, FGFs and BMPs, which stimulate synthesis and repairing of cartilage. The secreted proinflammatory cytokines and metalloproteinases up-regulate expression of chondrocyte PAR-2, stimulating more secretion of proinflammatory cytokines and metalloproteinases to enhance inflammatory response [2,3] and degradation of ECM components of cartilage tissue, causing progressive loss of cartilage. Furthermore, fragments of protein degradation, like fibronectin fragments and collagen type II fragments, seem to play a role in inducing degradation of cartilage [4,5] as well as stimulating chondrocytes to repair the matrix.TGF-β, a prominent member of the TGF-β superfamily of ligands which include TGF-β s and BMPs, is vital for the homeostasis of numerous cellular functions, including cell growth, differentiation, and apoptosis in a broad spectrum of tissues [6]. TGF-β signals are propagated through direct physical interactions with the extracellular domain of essentially two transmembrane serine/threonine kinase receptors (Tβ-RI and Tβ-RII), which transduce a number of secondary signals, most notably Smads 2 and 3 as well as PI3-kinase and various members of the mitogen activated protein kinase (MAPK) family [7-10]. CTGF, a member of CCN family, is a cysteine-rich matricellular protein. Expression of this protein is potently induced by TGF-β via Smad pathway. CTGF promotes chondrocytes proliferation through p38 MAPK and differentiation via p42/p44 MAPK.