Abstract
Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. This warrants investigation of signaling mechanisms that could protect cartilage from degeneration and degradation. Here we show in a murine model of experimental osteoarthritis that YAP activation by transgenic overexpression or by deletion of its upstream inhibitory kinases Mst1/2 preserves articular cartilage integrity, whereas deletion of YAP in chondrocytes promotes cartilage disruption. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis. Mechanistically, inflammatory cytokines, such as TNFα or IL-1β, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Furthermore, YAP directly interacts with TAK1 and attenuates NF-κB signaling by inhibiting substrate accessibility of TAK1. Our study establishes a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling in regulating the induction of matrix-degrading enzyme expression and cartilage degradation during osteoarthritis pathogenesis.
Highlights
Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage
We found that the integrity of articular cartilage of the Mst1f/f;Mst2f/f; Col2a1-Cre mutant mice was maintained significantly better than that of the control group under both anterior cruciate ligament transection (ACLT) (Anterior Cruciate Ligament Transection) and DMM (Destabilization of the Medial Meniscus) surgical conditions (Fig. 2a, b and Supplementary Figure 1c)
We found that TAK1 purified from HEK293T cells phosphorylated YAP purified from a separate set of HEK293T cells or GST-YAP recombinant proteins isolated from Escherichia coli (Fig. 5h, i)
Summary
Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis Inflammatory cytokines, such as TNFα or IL-1β, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Pro-inflammatory mediators such as tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), and IL-6 are implicated in OA pathophysiology[8] These catabolic factors activate a series of pathways including NF-κB signaling, which plays a major role in OA pathogenesis[9]. Inactivation of the Hippo pathway increases YAP/TAZ nuclear translocation They interact with TEADs or other transcription factors to regulate downstream signaling cascades in order to control cell proliferation, apoptosis, differentiation, and maturation[15]. Our findings suggest that targeting YAP is a viable strategy for treating OA
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