Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis

Abstract

Osteoarthritis (OA) is an aging-related degenerative joint disease, which has no cure partly due to limited understanding of its pathological mechanism(s). Here we report that the focal adhesion protein Kindlin-2, but not Kindlin-1 or -3, is highly expressed in articular chondrocytes of the hyaline cartilage, which is dramatically decreased in the degenerated articular cartilage of aged mice and patients with OA. Inducible deletion of Kindlin-2 in chondrocytes at adult stage leads to spontaneous OA and much severe OA lesions in the mice receiving the surgery of destabilization of the medial meniscus. Mechanistically, Kindlin-2 deficiency promotes mitochondrial oxidative stress and activates Stat3 in articular chondrocytes, leading to Runx2-mediated chondrocyte hypertrophic differentiation and catabolism. In vivo, systemic pharmacological blockade of Stat3 activation or genetic ablation of Stat3 in chondrocytes reverses aberrant accumulation of Runx2 and ECM-degrading enzymes and limits OA deteriorations caused by Kindlin-2 deficiency. Furthermore, genetic inactivation of Runx2 in chondrocytes reverses structural changes and OA lesions caused by Kindlin-2 deletion without down-regulating p-Stat3 in articular chondrocytes. Of translational significance, intraarticular injection of Kindlin-2-expressing adeno-associated virus decelerates progression of aging-and instability-induced knee joint OA in mice. Collectively, we identify a novel pathway comprising of Kindlin-2, Stat3 and Runx2 in articular chondrocytes responsible for maintaining integrity of the articular cartilage and define a potential therapeutic target for OA.

Brief research report: Effects of Pinch deficiency on cartilage homeostasis in adult mice

“…Our previous studies have shown that both Kindlin-2 and Pinch proteins are required for chondrogenesis and skeletal development in mice ( Wu et al, 2015 ; Lei et al, 2020 ). Most recently, we have demonstrated that the expression of Kindlin-2 is also critical for the maintenance of cartilage homeostasis during adulthood ( Wu et al, 2022a ; Lai et al, 2022 ). It is interesting to compare the phenotypes of mice lacking Kindlin-2 in adult cartilage (Aggrecan CreERT2 ; Kindlin-2 flox/flox ) in our previous study with mice lacking Pinch1/2 in adult cartilage (Aggrecan CreERT2 ; Pinch1 flox/flox ; Pinch2 −/− ) in this study.…”

“…It should be noted that the Pinch2 gene is globally inactivated in the Aggrecan CreERT2 ; Pinch1 flox/flox ; Pinch2 −/− mice. For inducible deletion of the Pinch1 gene in aggrecan-expressing chondrocytes, 2-month-old male Aggrecan CreERT2 ; Pinch1 flox/flox ; Pinch2 −/− mice were administrated with tamoxifen (Sigma T5648, 100 mg/kg per body weight/day) via intraperitoneal injections as previously described ( Wu et al, 2022a ; Wu et al, 2022b ; Chen et al, 2022 ). Age-matched male Aggrecan CreERT2 ; Pinch1 flox/flox ; Pinch2 −/− mice were administrated with corn oil and used as the control group.…”

“…The histological analyses of mouse knee joints were performed according to our previously established protocols ( Liu et al, 2021 ; Wu et al, 2022a ; Wu et al, 2022b ; Lai et al, 2022 ). The 5-μm thick knee joint sections were stained with safranin O and fast green using a commercial kit (Solarbio, Cat#G1371).…”

“…The 5-μm thick knee joint sections were stained with safranin O and fast green using a commercial kit (Solarbio, Cat#G1371). The OA-related parameters, including the OARSI score, synovitis score, and osteophyte score were quantified using the histological scoring systems as previously described ( Wu et al, 2022a ). The areas of safranin O-stained articular cartilage were measured by ImageJ (version 1.53k) as previously described ( Wu et al, 2022a ).…”

“…The OA-related parameters, including the OARSI score, synovitis score, and osteophyte score were quantified using the histological scoring systems as previously described ( Wu et al, 2022a ). The areas of safranin O-stained articular cartilage were measured by ImageJ (version 1.53k) as previously described ( Wu et al, 2022a ). Representative images of safranin O and fast green staining were selected based on the mean values of histological scores.…”