A small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development

Abstract

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis.

Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior

“…To obtain mouse primary chondrocytes, we harvested the knee joints from the femoral condyles and tibial plateaus of postnatal day 3-4 C57BL/6 mice, and digested with 0.1% collagenase (Biosharp) overnight, as described previously [27]. A 2-mm biopsy punch was used to harvest macroscopically intact human cartilage explants from femoral condyles of total knee arthroplasty patients as described elsewhere [28]. Written informed consent was obtained from all participants.…”

Chondroprotective Effect of Cynaroside in IL-1β-Induced Primary Rat Chondrocytes and Organ Explants via NF-κB and MAPK Signaling Inhibition

“…OA is a common degenerative joint disease, with a considerable social and economic burden disease owing to the absence of therapeutic drugs [26]. The exact pathogenic mechanism of OA has not yet been elucidated, but it is widely accepted that OA is triggered by degradation of the cartilaginous matrix due to inflammation-induced upregulation of catabolism in chondrocytes [16,20]. Therefore, a commonly used approach utilizes the inhibition of ECM degradation by protecting the chondrocytes from external stimuli as a key target for OA mitigation [16][17][18][19][20].…”

“…The exact pathogenic mechanism of OA has not yet been elucidated, but it is widely accepted that OA is triggered by degradation of the cartilaginous matrix due to inflammation-induced upregulation of catabolism in chondrocytes [16,20]. Therefore, a commonly used approach utilizes the inhibition of ECM degradation by protecting the chondrocytes from external stimuli as a key target for OA mitigation [16][17][18][19][20]. In this study, we demonstrate that cynaroside shows beneficial chondroprotective effects by inhibiting the expression of various pathological factors affecting OA, including nitrosative and oxidative stress, degradation of articular ECM, and expression of proinflammatory cytokines and mediators via NF-κB and MAPK signaling pathways.…”

“…The main hallmark of OA is progressive and excessive degradation of cartilage extracellular matrix (ECM), which accounts for 95% of total cartilage tissue mass [16][17][18]. The ECM is mainly composed of collagen type II (COL2A1) and proteoglycans, such as aggrecan, that provide a high degree of structural integrity to the cartilage and absorb compressive force and impact [19,20]. They are synthesized and maintained in equilibrium between the anabolism and catabolism of chondrocytes, which are the only cell types present in the cartilage [21].…”

Insights into superoxide dismutase 3 in regulating biological and functional properties of mesenchymal stem cells

“…In addition, overexpression of SOD3 found to suppress the release of inflammatory mediators and adhesion molecules, thereby restricting the inflammation during tissue damage [10]. Similarly, activating a small molecule N-(2-Bromo-4-(phenylsulfonyl)thiophen-3-yl)-2-chlorobenzamide) (BNTA) with SOD3 found to facilitate cartilage ECM synthesis in osteoarthritis model [11]. Various studies also confer the possible role of SOD3 in modulating the ECM dynamics in cancer.…”