transforming-growth-factor-alpha and Osteoarthritis--Knee

Topics: Aged; Asian People; Case-Control Studies; China; Ethnicity; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Male; Middle Aged; Osteoarthritis, Knee; Polymorphism, Single Nucleotide; Severity of Illness Index; Transforming Growth Factor alpha

Osteoarthritis (OA) is a complex degenerative joint disorder, which has contributions from both environmental and genetic factors. Several recent publications have established the connection between hip OA susceptibility and genetic markers within the TGFA gene, however, the relationship of these markers with knee OA has not been elucidated. Therefore, the present study was designed to investigate the potential linkage between common variants of the TGFA gene with knee OA in a large sample of Han Chinese individuals.. We conducted a case-control study, including 338 knee OA patients and 985 unrelated healthy controls using both single nucleotide polymorphism (SNP) markers and haplotype-based analyses to examine the genotypic and allelic distribution of 19 tagging SNPs.. We identified a significant association between the SNP rs2862851 and disease status of knee OA (p = 0.000314, OR = 1.40). Allelic analyses showed that the T allele of this SNP significantly elevated the risks of OA. This result was replicated in genotypic association analyses. In addition, haplotype-based analyses have also identified a strong association signal between one haplotype block, including rs2862851, and the disease status of knee OA (p < 0.00001).. Our findings suggest that the rs2862851 allele of the TGFA gene may significantly contribute to the susceptibility to knee OA in the Han Chinese population.

Topics: Aged; Alleles; Asian People; Biomarkers; Case-Control Studies; Ethnicity; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Osteoarthritis, Hip; Osteoarthritis, Knee; Polymorphism, Single Nucleotide; Risk Factors; Transforming Growth Factor alpha

To investigate the pathogenesis of late phase osteoarthritic (OA) synovial fluid (SF) on normal articular cartilage in vivo and provide an understanding of degenerative cartilage extending in OA joint.. A random knee, each of 8 beagle dogs, received anterior cruciate ligament transection (ACLT) and was confirmed to have late phase OA degenerative changes at 24 weeks after operation. Thereafter, one random elbow of each canine was injected with autologous late phase OA knee SF. The contralateral elbow was injected with normal saline (NS) of the same volume as SF aspirated from ACLT knee. These two groups of elbows were labeled "SF" and "NS". 8 other beagle dogs were left intact and placed in Group Control. After aseptic arthrocentesis was performed weekly on both elbows for 24 weeks, morphological changes were observed in the cartilage of the elbows, and expressions of 7 biological etiological factors of chondrocytes of the elbows were determined in Group SF, Group NS and Group Control, respectively.. Morphological changes were observed in articular cartilage of the elbows in Group SF. Levels of unit area of collagen type I in the noncalcified, calcified and full zones of articular cartilage of the elbows in Group SF increased significantly. Level of unit area of collagen type III in the calcified zone of articular cartilage of the elbows in Group SF remained unchanged. Meanwhile, expressions of MMP-1 and MMP-3 of chondrocytes of the elbows in Group SF increased significantly. There was almost no difference between articular cartilage in Group NS and Group Control.. Based on these results, we conclude that OA degeneration of normal articular cartilage can be independently induced by late phase OA SF. Endogenous OA biological etiological factor may be one of the reasons causing degenerative cartilage extending in OA joint.

Topics: Animals; Blood Proteins; Cartilage, Articular; Chondrocytes; Dogs; Gene Expression; Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nitric Oxide; Nitric Oxide Synthase Type II; Osteoarthritis, Knee; Synovial Fluid; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor alpha; Transforming Growth Factor beta1

To define the roles of transforming growth factor alpha (TGFalpha) in cartilage degradation.. Primary rat articular chondrocytes and articular osteochondral explants were cultured with TGFalpha to assess the effects of TGFalpha on chondrocyte physiology and phenotype.. TGFalpha altered chondrocyte morphology through reorganization of the actin cytoskeleton and formation of stress fibers. Expression of anabolic genes, including aggrecan, type II collagen, and cartilage link protein, was reduced in response to TGFalpha. Proliferation of chondrocytes and formation of articular chondrocyte clusters was stimulated by TGFalpha. Expression of matrix metalloproteinase 13 and cathepsin C was increased by TGFalpha. We demonstrated the down-regulation of Sox9 messenger RNA and protein levels by TGFalpha. This was associated with reduced levels of phosphorylated and total SOX9 in cartilage explants upon TGFalpha treatment. In contrast, another growth factor identified in our microarrays, Kitl, had no effects on the chondrocyte parameters tested. To examine correlations between the increased levels of TGFalpha in experimental knee osteoarthritis (OA) with the levels of TGFalpha in humans with knee OA, a microarray analysis of mRNA from 13 normal and 12 late-stage OA cartilage samples was performed. Seven OA samples showed TGFA mRNA levels similar to those in the normal controls, but expression was markedly increased in the other 5 OA samples. These data confirm that TGFA transcript levels are increased in a subset of patients with OA.. This study adds TGFalpha to the list of dysregulated cytokines present in degrading cartilage in OA. Since TGFalpha inhibits articular chondrocyte anabolic capacity, increases catabolic factors, and contributes to the development of chondrocyte clusters, TGFalpha may be a potential target for therapeutic strategies in the treatment of OA.

Topics: Aged; Animals; Cartilage, Articular; Cell Division; Cells, Cultured; Chondrocytes; Disease Models, Animal; Gene Expression; High Mobility Group Proteins; Humans; Male; Middle Aged; Osteoarthritis, Knee; Phenotype; Phosphorylation; Rats; Rats, Sprague-Dawley; SOX9 Transcription Factor; Stem Cell Factor; Transcription Factors; Transforming Growth Factor alpha