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

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.

SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

“…The Klotho enzyme is encoded by the human KL (mouse Kl ) gene; the gene product is a type-I membrane protein, related to β-glucuronidases; clinically, Klotho appears to improve cognition, kidney disease, and catabolic diseases of aging (reviewed in [81]). Because OA is correlated with increased hypertrophy-associated catabolic matrix-remodeling enzymes and pro-inflammatory cytokines, effects of Klotho were assessed in mouse cartilage homeostasis during both normal cartilage formation and development of OA; Kl expression was detected during embryonic limb development, and transiently during chondrogenic differentiation of bone marrow-derived mesenchymal stem cells in culture [82]. Genome-wide transcriptomics of chondrocytes from OA patients revealed that incubation with recombinant-delivered Klotho repressed the expression of nitric-oxide synthase-2 ( NOS2 ) and the SLC39A8 / MMP13 catabolic-remodeling axis.…”

Systemic Transplantation of Adult Multipotent Stem Cells Prevents Articular Cartilage Degeneration in a Mouse Model of Accelerated Ageing

“…In the AC of progeroid mice, we observed a statistically significant increase in Il1a, Il6, and Tnf-pro-inflammatory factors associated with the senescence-associated secretory phenotype (SASP)-compared to WT littermates ( Fig.1a). Gene expression of Mmp3, Mmp13, and Adamts5catabolic factors involved with cleaving ECM components such as collagen type II and aggrecans, [31,32] [33] were also significantly increased in Zmpste24 −/− progeroid mice (Fig. 1b).…”

Recent advances in understanding the regulation of metalloproteinases

“…α-Klotho acts as a co-receptor for FGF23 but was not required in this context; however, Chuchana et al . determined that treatment of human chondrocytes with recombinant α-Klotho or α-Klotho–targeting small interfering RNA (siRNA) suppressed or induced MMP13 expression, respectively 44 . The mechanism was not examined, but elsewhere α-Klotho is reported to disrupt signalling pathways, including Wnt, transforming growth factor-beta (TGF-β) and insulin-like growth factor (IGF) 44, 45 .…”

“…determined that treatment of human chondrocytes with recombinant α-Klotho or α-Klotho–targeting small interfering RNA (siRNA) suppressed or induced MMP13 expression, respectively 44 . The mechanism was not examined, but elsewhere α-Klotho is reported to disrupt signalling pathways, including Wnt, transforming growth factor-beta (TGF-β) and insulin-like growth factor (IGF) 44, 45 . The authors suggest a chondroprotective role for α-Klotho in OA, although more detailed in vivo experiments are needed 44 .…”

“…The mechanism was not examined, but elsewhere α-Klotho is reported to disrupt signalling pathways, including Wnt, transforming growth factor-beta (TGF-β) and insulin-like growth factor (IGF) 44, 45 . The authors suggest a chondroprotective role for α-Klotho in OA, although more detailed in vivo experiments are needed 44 . Notch signalling plays a key role in skeletal development where it can regulate chondrocyte differentiation 46 .…”