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

Paul Chuchana, Anne Laure Mausset-Bonnefont, Marc Mathieu, Francisco Espinoza, Marisa Teigell, Karine Toupet, Chantal Ripoll, Farida Djouad, Danièle Noel, Christian Jorgensen, Jean Marc Brondello*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 antiaging 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 IL1ß-treated chondrocytes and in cartilage of an OA mouse model. Finally, in vivo intra-articular secreted a-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.

Original languageEnglish
Pages (from-to)1442-1453
Number of pages12
JournalAging
Volume10
Issue number6
DOIs
StatePublished - 1 Jun 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018, Impact Journals LLC.

Keywords

  • Aging
  • Cartilage
  • Homeostasis
  • Hormone
  • α-Klotho

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