TD-198946, a potent chondrogenic agent, is a thienoindazole derivative.

In cell and metatarsal organ cultures, TD-198946 markedly induces chondrogenic differentiation without promoting hypertrophy. In ATDC5 cells, TD-198946 induces stronger?Col2a1?promoter activity than insulin. In C3H10T1/2 cells, ATDC5 cells and primary mouse chondrocytes, TD-198946 dose-dependently stimulates endogenous expression of the chondrocyte markers?Acan?and?Col2a1 (maximum effects: 1-10 μM).

TD-198946 can prevent and repair degeneration of the articular cartilage by administered directly into the joint space. TD-198946 regulates Runx1 expression, which is downregulated in both mouse and human OA cartilage compared with normal tissue. TD-198946 may prevent the progression of osteoarthritis by acting on the remaining chondrocytes rather than repairing damaged cartilage. Cartilaginous cell-sheets are generated by culturing human mesenchymal stem cells and canine and mouse costal chondrocytes with TD-198946 on temperature-responsive dishes.

For intra-articular injection, TD-198946 is dissolved at 100 nM in a solution of 45% 2-hydropropyl-b-cyclodextrin in saline.Mouse: Each of the prevention and repair models had two groups: (1) TD-198946-treated animals and (2) saline-treated animals. In all the mice tested the left knee joints underwent the operation and the right knee joints are sham-operated. Mice are re-anesthetized and given a 10 μL intra-articular injection of TD-198946 or saline immediately after surgery (prevention model) or 4 weeks following surgery (repair model) every 5 days for 8 or 4 weeks, respectively.