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

ABSTRACT: CHUK/IKK? 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 IKK? to OA in vivo. To this end, we induced specific IKK? knockout in adult chondrocytes in AcanCreER^T2/+; IKK?^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 IKK? 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 IKK? in cartilage degradation in post-traumatic OA, and also suggest intrinsic, cell-autonomous effects of IKK? in chondrocytes that control chondrocyte phenotype and impact on cell survival, matrix homeostasis, and remodeling.

SUBMITTER: Culley KL

PROVIDER: S-EPMC6586628 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Culley Kirsty L KL Lessard Samantha G SG Green Jordan D JD Quinn Justin J Chang Jun J Khilnani Tyler T Wondimu Elisabeth B EB Dragomir Cecilia L CL Marcu Kenneth B KB Goldring Mary B MB Otero Miguel M

Scientific reports 20190620 1

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<sup>T2/+</sup>; IKKα<sup>f/f< ...[more]

PMID: 31222033

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Project description:BackgroundCartilage degradation is a typical characteristic of arthritis. This study examined whether there was a subset of phagocytic chondrocytes that expressed the specific macrophage marker, CD163, and investigated their role in cartilage degradation.MethodsCartilage from the knee and temporomandibular joints of Sprague-Dawley rats was harvested. Cartilage degradation was experimentally-induced in rat temporomandibular joints, using published biomechanical dental methods. The expression levels of CD163 and inflammatory factors within cartilage, and the ability of CD163(+) chondrocytes to conduct phagocytosis were investigated. Cartilage from the knees of patients with osteoarthritis and normal cartilage from knee amputations was also investigated.ResultsIn the experimentally-induced degrading cartilage from temporomandibular joints, phagocytes were capable of engulfing neighboring apoptotic and necrotic cells, and the levels of CD163, TNF-? and MMPs were all increased (P<0.05). However, the levels of ACP-1, NO and ROS, which relate to cellular digestion capability were unchanged (P>0.05). CD163(+) chondrocytes were found in the cartilage mid-zone of temporomandibular joints and knee from healthy, three-week old rats. Furthermore, an increased number of CD163(+) chondrocytes with enhanced phagocytic activity were present in Col-II(+) chondrocytes isolated from the degraded cartilage of temporomandibular joints in the eight-week experimental group compared with their age-matched controls. Increased number with enhanced phagocytic activity of CD163(+) chondrocytes were also found in isolated Col-II(+) chondrocytes stimulated with TNF-? (P<0.05). Mid-zone distribution of CD163(+) cells accompanied with increased expression of CD163 and TNF-? were further confirmed in the isolated Col-II(+) chondrocytes from the knee cartilage of human patients with osteoarthritis, in contrast to the controls (both P<0.05).ConclusionsAn increased number of CD163(+) chondrocytes with enhanced phagocytic activity were discovered within degraded joint cartilage, indicating a role in eliminating degraded tissues. Targeting these cells provides a new strategy for the treatment of arthritis.

Dataset Information

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

Publications

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

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