Inducible knockout of CHUK/IKKα in adult chondrocytes reduces progression of cartilage degradation in a surgical model of osteoarthritis

• Published in: Scientific reports Vol. 9; no. 1; pp. 8905 - 10
• Main Authors: Culley, Kirsty L., Lessard, Samantha G., Green, Jordan D., Quinn, Justin, Chang, Jun, Khilnani, Tyler, Wondimu, Elisabeth B., Dragomir, Cecilia L., Marcu, Kenneth B., Goldring, Mary B., Otero, Miguel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.06.2019; Nature Publishing Group
• Subjects: 13/2; 38/77; 38/90; 631/80/304; 64/60; 692/4023/1670/407; 82/51; Animals; Apoptosis; Arthritis; Cartilage (articular); Cartilage diseases; Cartilage, Articular - metabolism; Cell Survival; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - pathology; Chondrogenesis; Collagen; Collagenase; Disease Models, Animal; Extracellular matrix; Homeostasis; Humanities and Social Sciences; Humans; Hypertrophy; I-kappa B Kinase - genetics; Meniscus; Mice, Knockout; multidisciplinary; Osteoarthritis; Osteoarthritis - surgery; Phenotypes; Science; Science (multidisciplinary); Tamoxifen
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-45334-5

CHUK/IKKα contributes to collagenase-driven extracellular matrix remodeling and chondrocyte hypertrophic differentiation in vitro , in a kinase-independent manner. These processes contribute to osteoarthritis (OA), where chondrocytes experience a phenotypic shift towards hypertrophy concomitant with abnormal matrix remodeling. Here we investigated the contribution of IKKα to OA in vivo . To this end, we induced specific IKKα knockout in adult chondrocytes in AcanCreER T2/+ ; IKKα f/f mice treated with tamoxifen (cKO). Vehicle-treated littermates were used as wild type controls (WT). At 12 weeks of age, WT and cKO mice were subjected to the destabilization of medial meniscus (DMM) model of post-traumatic OA. The cKO mice showed reduced cartilage degradation and collagenase activity and fewer hypertrophy-like features at 12 weeks after DMM. Interestingly, in spite of the protection from structural articular cartilage damage, the postnatal growth plates of IKKα cKO mice after DMM displayed abnormal architecture and composition associated with increased chondrocyte apoptosis, which were not as evident in the articular chondrocytes of the same animals. Together, our results provide evidence of a novel in vivo functional role for IKKα in cartilage degradation in post-traumatic OA, and also suggest intrinsic, cell-autonomous effects of IKKα in chondrocytes that control chondrocyte phenotype and impact on cell survival, matrix homeostasis, and remodeling.