mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR.

TA both showed significantly loss of proteoglycan compared to saline, while low dose ER TA showed significantly loss of proteoglycan compared to its equipotent dose of TA, as well as saline. ER TA was therefore observed to result in more proteoglycan loss and underlying chondrotoxicity than TA alone. Conclusions: TLC599, a novel extended-release formulation of DSP, showed high level exposure of DSP in synovial fluid after single IA injection but no observation of cartilage toxicity in preclinical dog and rabbit studies of TLC599. In contrast, a moderate proteoglycan loss in cartilage was observed for both TA and ER TA. All animal studies indicated that TLC599 could be an effective and a safer chronic treatment for OA.