TAK-242 induces osteoblastogenesis in fibroblast-like synoviocytes derived from rheumatoid arthritis patients

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation, joint destruction, impaired bone homeostasis, and severely affects patients’ quality of life. Bone destruction due to osteoclast activity and inadequate osteoblast activity is a hallmark of RA, necessitating innovative therapeutic strategies to restore bone balance and alleviate disease progression. This study proposed that TAK-242 (resatorvid), an inhibitor targeting Toll-like receptor 4 (TLR4), may alleviate RA-associated bone degradation by reducing inflammation and promoting osteogenic-associated responses in fibroblast-like synoviocytes (FLSs). FLSs isolated from RA patients were cultured and verified. Cells were divided into four groups to receive LPS, an osteogenic environment, TAK-242, and untreated or control. Osteoblastogenesis-related gene expression ( ALPL , RUNX2 , BMP2 , IBSP , SP7 , and PTPRVP ) was assessed using quantitative PCR in FLS cells. Osteonectin expression was evaluated by immunofluorescence (IF) staining, and calcium deposition was assessed through Alizarin Red staining. TAK-242 significantly modulated the expression of osteogenesis-related genes, notably enhancing ALPL , BMP2 , IBSP , PTPRVP , RUNX2 , and SP7 expression in an inflammatory osteogenic environment. Also, TAK-242 enhanced osteogenic-associated marker expression and mineralisation-related activity in FLSs. Enhanced osteonectin expression and calcium deposition were observed in the TAK-242-treated group, indicating increased osteoblast activity. Also, ALP staining revealed that LPS strongly induced early osteogenic activity, while TAK-242 moderated this response, maintaining higher ALP activity than the control. TAK-242 facilitates bone repair mechanisms and mitigates the effects of RA-induced bone destruction by enhancing FLS transformation into osteoblast-like cells, highlighting its potential for clinical application in mitigating bone loss associated with RA.