Sulfated carboxymethylcellulose mediated enhancement of Timp3 efficacy synergistically attenuates osteoarthritis through inhibition of NFκB and JNK

Osteoarthritis (OA) is a prevalent degenerative joint condition with no effective disease modifying treatments. In this study, we aimed to address multiple OA hallmarks using a combination of pro-chondrogenic sulfated carboxymethylcellulose (sCMC) and anti-catabolic tissue inhibitor of metalloproteases 3 (Timp3) in relevant disease systems. Firstly, we chemically sulfated carboxymethylcellulose to impart a negative charge and improve the stability of cationic Timp3. The modified sCMC exhibited a molecular weight of 10 kDa and a degree of sulfation of ∼10 %. We further demonstrated that sulfation of CMC confers pro-chondrogenic characteristics. Subsequently, we demonstrated that the combination of sCMC and Timp3 effectively reduced key OA hallmarks, such as matrix degradation, inflammation, and protease expression, in a goat ex vivo OA model compared to individual treatments. We further demonstrated that the anti-OA effect of sCMC and Timp3 is mediated through the suppression of NFκB and JNK activation. To validate the clinical potential and mechanism of action, we conducted experiments on human OA explants. The combination treatment synergistically reduced the expression of MMP13 and NFκB in human OA explants. Overall, sCMC-mediated enhancement of Timp3 efficacy synergistically reduced OA-like traits and demonstrates the potential for OA amelioration.