Identification of Sik3-targeting compound, pterosin B, for treatment of osteoarthritis

Osteoarthritis is a common joint disorder that causes debilitating conditions among the elderly. Risk factors of osteoarthritis include age, which is often associated with the thinning of articular cartilage. We generated conditional knockout mice that lack salt-inducible kinase 3 (Sik3) specifically in chondrocytes after birth by tamoxifen administration. Deletion of Sik3 at 2 or 8 weeks after birth increased the thickness of articular cartilage by increasing the chondrocyte population. Additionally, Sik3 deletion protected cartilage against osteoarthritis development. We identified the edible Pteridium aquilinum ingredient, pterosin B, as a compound that inhibits the Sik3 pathway. Intraarticular injection of pterosin B protected cartilage against osteoarthritis development. Sik3 deletion or pterosin B treatment inhibited activation of the hypertrophic program through the histone deacetylase 4 (Hdac4) pathway, increased Prg4 expression in chondrocytes, and protected cartilage against osteoarthritic attack. Collectively, our results suggest Sik3 is a regulator that regulates homeostasis of articular cartilage thickness and a target for treatment of osteoarthritis, and that pterosin B can be the lead compound for relevant drugs. Overall design: RNA-seq analysis for pellet culture of mouse primary chondrocytes in the presence or absence of 300 micromolar pterosin B (n = 3 each) and 13 mouse tissues (n = 1 each).