s and its ligand are phy siologically involved in chondrocyte apo

s and its ligand are phy siologically involved in chondrocyte apoptosis, in our present study we used an anti Fas antibody to evaluate the role of LRP5 in chondrocyte apoptosis. The decreased chondrocyte apoptosis in Lrp5fl fl.Col2a1 cre mice sub jected to DMM surgery supports our contention that LRP5 plays a catabolic role in OA cartilage destruction. Conclusions Herein we provide evidence suggesting that LRP5 is a catabolic regulator of OA pathogenesis and report that IL 1B treatment increases LRP5 e pression largely via JNK and NF ��B signaling. On the basis of our results, we suggest that LRP5 plays a catabolic role in OA cartilage destruction by decreasing type II collagen syn thesis, increasing MMP3 and or MMP13 e pression and pro moting chondrocyte apoptosis.

These results provide new insight into the mechanisms by which LRP5 upreg ulation contributes to OA cartilage and suggest that LRP5 could be a candidate therapeutic target for new Brefeldin_A strategies to treat or prevent OA. Introduction Osteoarthritis is the most common arthritis, char acterized by progressive loss of articular cartilage, sub chondral bone remodeling, and synovial inflammation, leading to debilitating joint pain and functional limita tion. The underlying pathophysiologic process of cartilage destruction in OA has not been completely elucidated. Inflammation is believed to be implicated in the OA pathogenesis, even in early stages, by shifting the balance from the anabolic toward the catabolic state with gradually progressive cartilage loss.

In OA, chon drocytes, the only cells residing in cartilage, are a target of catabolic cytokines, including interleukin 1B, tumor necrosis factor, and IL 6. IL 1B in par ticular has been considered a key amplifier and perpetu ator of cartilage damage because it suppresses matri protein synthesis and induces matri degrading enzymes and other proinflammatory cytokines, including IL 6. However, postsurgical or spontaneous OA development is parado ically accelerated in IL 1B or IL 6 knockout mice, suggestive of their intricate role in cartilage biology. the proinflammatory cytokines might slow the OA pro gression via yet unknown mechanisms. Suppressors of cytokine signaling belong to a protein family that is composed of eight SH2 containing proteins and forms E3 ubiquitin ligase comple es to de grade target proteins by proteasomes.

As negative feed back, these proteins are induced by a variety of cytokines and inhibit, in turn, intracellular signaling of diverse cyto kines and growth factors. SOCS1 and SOCS3 are the best characterized, and SOCS1 is considered more potent than SOCS3. Although IL 1B is not a main inducer of SOCS family proteins or a potent activator of signal transducer and activator of transcription, IL 1B has been reported to induce SOCS1 or SOCS3 in several types of cells including chondrocytes. Further more, SOCS1 may inhibit IL 1B signaling pathways. SOCS1null T cells were found to be hypersensitive to IL 1B. When HEK293 cells

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