Abstract
Osteoarthritis is a common debilitating joint disorder. Risk factors for osteoarthritis include age, which is associated with thinning of articular cartilage. Here we generate chondrocyte-specific salt-inducible kinase 3 (Sik3) conditional knockout mice that are resistant to osteoarthritis with thickened articular cartilage owing to a larger chondrocyte population. We also identify an edible Pteridium aquilinum compound, pterosin B, as a Sik3 pathway inhibitor. We show that either Sik3 deletion or intraarticular injection of mice with pterosin B inhibits chondrocyte hypertrophy and protects cartilage from osteoarthritis. Collectively, our results suggest Sik3 regulates the homeostasis of articular cartilage and is a target for the treatment of osteoarthritis, with pterosin B as a candidate therapeutic.
Highlights
We investigated the expression of total SIK3 and phosphorylated SIK3 at T163, which is the active form of SIK3, in articular cartilage
Immunohistochemical analysis revealed that total SIK3 was uniformly detected from the surface to deep layer, whereas pSik[3] was detected only in the deep layer of normal articular cartilage (Supplementary Fig. 1a)
PSIK3 was expressed in the superficial layer of severely affected osteoarthritic articular cartilage (Supplementary Fig. 1b)
Summary
A 100 mg per gram of body weight tamoxifen (Sigma) was intraperitoneally injected into the peritoneal spaces of 7-week-old Col11a2-CreER; Sik3flox/flox and Sik3flox/flox male mice daily for 5 consecutive days. The right knee joints of the mice were subjected to DMM surgery[33] or sham surgery (skin and joint capsule incision) at 8 weeks of age. The mice were killed 8 weeks after the operation, and the knee joints were subjected to histological analysis. The mice were put on a Rota-Rod (UGO BASILE)
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