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.

Mechanisms of vascular invasion after cartilage injury and potential engineering cartilage treatment strategies

“…Hydrostatic pressure (HP) is an important mechanical stimulus to which chondrocytes are exposed. Intermittent HP can boost the differentiation of CPCs to promote OA cartilage repair 167,168 . Ogura et al.…”

“…Intermittent HP can boost the differentiation of CPCs to promote OA cartilage repair. 167,168 Ogura et al intermittently applied HP to collagen gel/sponge scaffolds containing human articular chondrocytes, resulting in increased ECM synthesis and accumulation. 169 In addition, Montagne et al used continuous high HP stimulation and observed that this condition was not conducive to maintaining the cell phenotype and matrix synthesis.…”

The role of YAP/TAZ on joint and arthritis

“…Yao et al found a lower expression of YAP1 and higher expression of phosphorylated YAP1 in OA patients after balancing the age factors, and the inhibition degree of the YAP1 is positively correlated with the severity of OA. 144 Furthermore, appropriate mechanical stress could inhibit the Hippo signaling to up-regulate the expression of YAP1, which promotes chondrocyte proliferation and cartilage repair in OA. 144 According to a newly published study, both pharmacological inhibition and gene knockdown of YAP in OA chondrocytes reduce chondrocyte anabolic activity and cause further cartilage defect, while IGF-induced YAP nuclear translocation in turn promotes anabolic activity.…”

“…144 Furthermore, appropriate mechanical stress could inhibit the Hippo signaling to up-regulate the expression of YAP1, which promotes chondrocyte proliferation and cartilage repair in OA. 144 According to a newly published study, both pharmacological inhibition and gene knockdown of YAP in OA chondrocytes reduce chondrocyte anabolic activity and cause further cartilage defect, while IGF-induced YAP nuclear translocation in turn promotes anabolic activity. 145 Consistent with that, several murine models of experimental OA revealed that YAP can facilitate chondrogenesis and cartilage reconstruction by the alternative Wnt…”

“…Yao et al. found a lower expression of YAP1 and higher expression of phosphorylated YAP1 in OA patients after balancing the age factors, and the inhibition degree of the YAP1 is positively correlated with the severity of OA 144 . Furthermore, appropriate mechanical stress could inhibit the Hippo signaling to up‐regulate the expression of YAP1, which promotes chondrocyte proliferation and cartilage repair in OA 144 .…”