Intermittent Hydrostatic Pressure Promotes Cartilage Repair in an Inflammatory Environment through Hippo-YAP Signaling In Vitro and In Vivo

Abstract

The study of chondrogenic progenitor cells (CPCs) as seed cells has become a new focus of cartilage regeneration. The inflammatory environment of osteoarthritis (OA) inhibits the repair ability of CPCs. But the OA patients' CPCs showed an excellent regeneration ability with intermittent hydrostatic pressure (IHP). However, the mechanism is unclear. We compared the expression of the Hippo signaling effect factor YAP between OA and normal cartilages. Then, the relationship between the Kellgren-Lawrence (K-L) score of OA and the rate of YAP-positive cells was analyzed. The changes of CPCs after IHP and IL-1β applications were observed. The OA model was established by cutting the anterior cruciate ligament of rats. The knee joint of the OA rats was distracted by hinged external fixator to create suitable IHP, named as the IHP group. The IHP group plus intra-articular injection of Verteporfin (VP) was named as the IHP+VP group, and the untreated rat group was named as the CON group. Four and 8 weeks after the operation, the reparative effect was evaluated by MASSON staining and immunohistochemical staining. Lower levels of YAP1 and higher expressions of p-YAP1 were found in the OA group as compared to the normal group. IHP inhibited the Hippo signaling in an inflammatory environment and promoted the proliferation of CPCs. The cartilage deterioration in the CON group progressed more significantly than that in the IHP+VP group. The best reparative effect was observed in the IHP group with increased expression of YAP1 and decreased p-YAP1. These results hint that mechanical stress can activate CPCs and promote cartilage repair in an inflammatory environment through inhibiting Hippo signaling.