Abstract
Progressive loss of tissue homeostasis is a hallmark of numerous age-related pathologies, including osteoarthritis (OA). Accumulation of senescent chondrocytes in joints contributes to the age-dependent cartilage loss of functions through the production of hypertrophy-associated catabolic matrix-remodeling enzymes and pro-inflammatory cytokines. Here, we evaluated the effects of the secreted variant of the anti-aging hormone α-Klotho on cartilage homeostasis during both cartilage formation and OA development. First, we found that α-Klotho expression was detected during mouse limb development, and transiently expressed during in vitro chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. Genome-wide gene array analysis of chondrocytes from OA patients revealed that incubation with recombinant secreted α-Klotho repressed expression of the NOS2 and ZIP8/MMP13 catabolic remodeling axis. Accordingly, α-Klotho expression was reduced in chronically IL1β-treated chondrocytes and in cartilage of an OA mouse model. Finally, in vivo intra-articular secreted α-Kotho gene transfer delays cartilage degradation in the OA mouse model. Altogether, our results reveal a new tissue homeostatic function for this anti-aging hormone in protecting against OA onset and progression.
Highlights
Tissue homeostasis is ensured through self-repair of specialized cells and their replacements via differentiation of tissue-specific adult stem cells [1, 2]
Www.aging‐us.com damage accumulation through nitric oxide synthase 2 (NOS2)-dependent nitric oxide production [7], (2) the expression of senescence marker p16INK4A [6] (3) the onset of the hypoxia-inducible factor 2 (HIF2)-dependent terminal phase of endochondral ossification [8, 9], and (4) the activation of the catabolic axis formed by the zinc importer ZIP8, metal-regulatory transcription factor-1 (MTF1) and the matrix metalloproteinase-13 (MMP13) [10]
We found that the secreted form of the anti-aging factor α-Klotho is a new homeostatic regulator of cartilage integrity
Summary
Tissue homeostasis is ensured through self-repair of specialized cells and their replacements via differentiation of tissue-specific adult stem cells [1, 2] During aging, this equilibrium is gradually lost [2] through the expression of cellular senescence markers in tissues and the establishment of a senescence-associated secretory phenotype (SASP), that includes inflammatory and catabolic factors [2]. The full-length transmembrane form contains two KL domains (KL1 and KL2) and acts as co-receptor of growth factors (such as FGF23 and VEGF) [12, 15] This membranebound form can be cleaved by a disintegrin and metalloprotease (ADAM) cell surface proteases to form the two soluble KL1-KL2 and KL1 forms [16] that control the Ca2+/K+ reabsorption activity of transient receptor potential cation channel subfamily V member 5 (TRPV5) in kidney epithelial cells (for review, [12]). Using in vitro and in vivo OA models, we determined the expression level of secreted α-Klotho during OA and tested whether intraarticular α-KL gene transfer has chondroprotective effects
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