A new study in Nature Communications identifies the transcriptional co-activator YAP as a mediator of crosstalk between Hippo and NF-κB signalling that is central to cartilage homeostasis and the degeneration that occurs in osteoarthritis (OA).

“This study is an extension of our previous work on the role of YAP in chondrocyte differentiation during skeletal development and bone repair,” says corresponding author Kingston King-Lun Mak.

Credit: CSA Images/Getty

In the Hippo signalling pathway, LATS1 and LATS2 phosphorylate YAP and thereby sequester it in the cytoplasm, preventing it from translocation into the nucleus where it can affect gene expression.

In the new study, the researchers show that the NF-κB signalling pathway protein TAK1 can regulate YAP in the same way and tag it for proteasomal degradation.

The importance of these signalling interactions in cartilage degeneration and OA is supported by in vivo data. The researchers show that expression of YAP by chondrocytes declines with age in mice, and there is a similar reduction in patients with OA. To show that YAP is more than just a marker of age or cartilage degeneration, the researchers also used two surgically induced models of OA (anterior cruciate ligament transection and destabilization of the medial meniscus). After surgery, mice with Hippo signalling mediator MST1/2-deficient chondrocytes maintained higher expression of chondrocyte YAP and had less cartilage degeneration than mice with normal Hippo signalling. The same cartilage-protective effect of YAP was clear in transgenic mice in which YAP was overexpressed specifically in chondrocytes, and the reverse was true in mice in which YAP was deleted specifically from chondrocytes.

As proof of principle, the researchers also implanted inhibitor-soaked alginate beads into the joints of mice immediately after joint destabilization. Implantation of the indirect YAP activator lysophosphatidic acid and the direct YAP inhibitor verteporfin had the same effects on cartilage as overexpression and knockout of YAP, respectively.

targeting Hippo signalling or otherwise promoting expression of YAP might be a viable therapeutic strategy

Although this strategy of direct implantation of inhibitors is not validated in humans and these inhibitors do not naturally target the joints, it does hint that targeting Hippo signalling or otherwise promoting expression of YAP might be a viable therapeutic strategy to reduce cartilage destruction in patients with OA.