The effects of cyclic tensile strain on the metabolism and gene expression of articular chondrocytes

Biomechanical stimuli directly influence the homeostasis of articular cartilage, but the relevance between mechanical strain and the downstream biological responses, as well as the precise molecular mechanisms to the development of osteoarthritis (OA) remain to be elucidated. In order to investigate the effects of cyclic tensile strain (CTS, 0.5 Hz, 10% strain) on the metabolism and gene expression of articular chondrocytes, an in vitro monolayer culture model of porcine articular chondrocytes was established, to which relative high frequency and magnitude (0.5Hz, 10%) cyclic tensile strain (CTS) was applied through the stretching of deformable silicone substrate membrane upon which the cells grew. Inflammatory agents such as nitric oxide (NO), prostaglandin E2 (PGE2) and gelatinase were measured to study the cellular responses to CTS. In addition, the expressions of selected anabolic and catabolic genes were examined using quantitative real-time RT-PCR.; The results show that cyclic tensile strain at this level causes multiple detrimental effects to cartilage, inducing proinflammatory mediators and matrix metalloproteinases (MMPs) that degrade cartilaginous matrix as well as down-regulating mRNA levels for type II collagen and proteoglycan. The production of two inflammatory metabolites (NO and PGE2) and the mRNA level of cyclooxygenase-2 (COX-2) were up-regulated in response to mechanical stimuli. Therefore, the inducible nitric oxide synthase (iNOS) and COX-2 are probably some of the earliest and most important agents in this cascade. In addition, our data showed that iNOS and COX enzymes interact in a coordinated way, suggesting that NO and PGE2 induced by cyclic tensile strain mutually serve as positive regulatory factors between these two pathways. Interestingly, two different isoforms of transforming growth factors: TGFbeta1 and TGFbeta3 differentially responded to CTS. TGFbeta3 was transiently activated within 3 hours of initiation of stretch, whereas TGFbeta1 increased much later in response to cyclic stretching.; This study demonstrates the relevance between mechanical stimulation and biological responses in articular chondrocytes. It also indicates the complicated processes of mechanotransduction and mechanobiology in articular cartilage, as well as the development of osteoarthritis.