Transforming growth factor-? stimulates nerve growth factor production in osteoarthritic synovium.

ABSTRACT: BACKGROUND:Nerve growth factor (NGF) contributes to pain in knee osteoarthritis (KOA) patients. Transforming growth factor-beta (TGF-?) stimulates NGF expression in chondrocytes from KOA patients. However, the correlation between synovial TGF-? and NGF levels has not been sufficiently studied in human KOA patients. Further, the mechanism governing NGF regulation by TGF-? in synovial cells is unclear. METHODS:During total knee arthroplasty, we extracted the synovial tissue (SYT) of 107 subjects with unilateral Kellgren/Lawrence grade 3-4 KOA confirmed by radiography. We examined the distribution of TGF-? and NGF using immunohistochemistry, and analyzed the relationship between NGF and TGFB mRNA levels. Cultured synovial cells extracted from SYT were exposed to culture medium (control), human recombinant TGF-? (rhTGF-?), rhTGF-??+?ALK5 inhibitor SB505124, rhTGF-??+?transforming growth factor activating kinase 1 (TAK1) inhibitor (5Z)-7-oxozeaenol, or rhTGF-??+?p38 inhibitor SB203580 for 30?min, 6?h and 24?h. NGF mRNA expressed by the cultured cells and NGF protein levels in the cell supernatant were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Phosphorylation of p38 was evaluated by western blotting. RESULTS:NGF mRNA levels were positively correlated with those of TGFB. Cells expressing TGF-? and NGF protein were observed in the lining layer of SYT. TGF-? stimulated increased NGF mRNA expression and NGF protein production. The ALK5 inhibitor completely suppressed the TGF-?-mediated increase in NGF expression and NGF production in synovial cells. ALK5, TAK1 and p38 inhibitors inhibited the TGF-?-induced phosphorylation of p38, and TAK1 and p38 inhibitors partially inhibited the TGF-?-mediated increase in NGF expression and NGF production in synovial cells. CONCLUSION:TGF-? regulates NGF production via the TGF-?/ALK5 signaling pathway in osteoarthritic synovium. This effect may partially occur through inhibition of the TAK1/p38 pathway in the SYT of KOA patients.

SUBMITTER: Takano S 

PROVIDER: S-EPMC6511148 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature