Secreted α-Klotho maintains tissue homeostasis by repressing NOS2-ZIP8-MMP13 catabolic axis

Progressive loss of tissue homeostasis hallmarks numerous age-related pathologies. By using parabiosic approaches in animal models, recent evidences demonstrate that age-regulated geronic factors such as GDF11 or CCL11 could widely control positively or negatively tissue homeostasis. Here we evaluated the impact of the first identified anti-geronic hormone a-Klotho on tissue homeostasis taken articular cartilage and osteoarthritis (OA) as studying models. We show that a-Klotho is secreted during an in vitro induced chondrogenesis of osteo-chondral stem cells. Expression of a-Klotho is reduced in both cartilage of OA patients compared to healthy donors and in cartilage of OA murine models. Gain and loss of function experiments followed by a genome-wide gene array analysis identified Nos2-Zip8-MMP13 catabolic axis as repressed in OA chondrocytes upon a-Klotho treatment. Accordingly, intra-articular delivery of secreted a-klotho delays cartilage loss of functions in experimental OA mouse models thus revealing a novel chondroprotective function for this anti-geronic hormone. Gain and loss of function experiments on human primary OA chondrocytes to identify opposite gene expression profiles obtained from chondrocytes treated with 40ng/ml of recombinant a-Klotho normalized to untreated versus SiRNA against Klotho transfected chondrocytes normalized to siRNA control.