ROCK inhibition with Y-27632 reduces joint inflammation and damage in serum-induced arthritis model and decreases in vitro osteoclastogenesis in patients with early arthritis

Abstract

Rheumatoid arthritis (RA) is a common chronic inflammatory disease affecting primarily peripheral joints, which is only partially controlled with current treatments. RA leads to pain, disability, deformities, and life expectancy shortening. Its pathogenesis is complex involving multiple cell types and signaling pathways that we incompletely understand. One of the pathways we have elucidated starts with WNT5A signaling and contributes to the aggressive phenotype of the RA synoviocytes through RYK-RhoA/ROCK signaling. Now, we have explored the contribution of ROCK to arthritis in vivo, using the K/BxN serum-transfer arthritis model; and to osteoclastogenesis, using the arthritis model and cells from patients with inflammatory arthritis. The mice and cells were treated with the ROCK inhibitor Y-27632 that caused a significant improvement of arthritis and reduction of osteoclastogenesis. The improvement in mouse arthritis was observed in the clinical evaluation and, histologically, in synovial inflammation, cartilage damage, bone erosion, and the abundance of multinucleated TRAP+ cells. Expression of inflammatory mediators in the arthritic joints, as assessed by real-time PCR, was also significantly reduced. The effect on bone was confirmed with in vitro assays using bone marrow precursors of arthritic mice and peripheral blood monocytes of patients with inflammatory arthritis. These assays showed dramatically reduced osteoclastogenesis and bone resorption. Overall, our findings suggest that ROCK inhibition could be part of a therapeutic strategy for RA by its dual action on inflammation and bone erosion.

Phillygenin prevents osteoclast differentiation and bone loss by targeting RhoA

“…remains unclear. Previous studies have indicated that ROCK inhibitors restrained osteoclast differentiation(Rodríguez-Trillo et al, 2022), and our current work supported this finding, as we observed that Y-27632 reduced osteoclast formation (Figure6k). Furthermore, we found that Y-27632 decreased the expression of NFATc1 and disrupted actin formation, which further supported the notion that ROCK inhibition played a role in osteoclastogenesis (Figures6l and 8b).To better illustrate the effect of Phi on the RhoA/ROCK1 pathway, we examined the protein levels of ROCK1 and downstream signaling.…”

Direct Mapping of Cytomechanical Homeostasis Destruction in Osteoarthritis Based on Silicon Nanopillar Array

“…[ 40 ] Inhibiting RhoA/ROCK can alleviate OA in vitro and in vivo. [ 41 ] Therefore, we assessed the role of RhoA/ROCK in CTF degradation in patients with OA. We inhibited RhoA/ROCK using Y‐27632 and found that F‐actin and FA expression decreased, F‐actin was distributed (Figure 4a), and the CTF significantly recovered (Figure 4e).…”

Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease

“… 406 As Wnt5a promotes RA via ROCK signaling, ROCK inhibitor Y-27632 inhibits Wnt5a-induced RA FLS migration and reduced inflammatory cytokines IL-1β, IL-6, MMP3, MMP9 and MMP13 levels. 408 Moreover, traditional Chinese medicine, such as Ginkgolide B and Resveratrol, show anti-RA effect for reducing articular cartilage and bone destruction and decreasing inflammatory cytokine levels through suppressing Wnt5a level. 409 , 410 All these results suggest Wnt5a a critical drug target for treating RA (for review, see Huang et al 381 ).…”