Role of the anti-aging factor alpha-klotho in osteoarthritis – KLOTHOA

Osteoarthritis (OA) is the most prevalent joint degenerative disease with a huge unmet medical need. So far, only painkillers are used in clinic and alternative long-term innovative therapies are required. Various clinical OA phenotypes have been described including post-traumatic and age-associated OA. However irrespective of the phenotype, OA is characterized by cartilage erosion, osteophyte formation, subchondral bone sclerosis and synovial inflammation. OA is also commonly described as a consequence of disturbed cartilage tissue homeostasis where catabolic products accumulate within the cartilage and strengthen joint inflammation. To maintain cartilage homeostasis notably during aging, chondrocytes mainly depends on their autophagic activity for the removal of damaged and dysfunctional organelles and macromolecules. With age, this autophagic activity gradually decreases in chondrocytes pushing cells toward a senescent phenotype. Of clinical relevance, it has been recently suggested that restoring autophagy process and deleting senescent cells using senolytic compounds in cartilage may be protective against OA progression.
Given that aging is one of the main risk factor for OA, antiaging factors have been contemplated with interest for the treatment of OA. Among the anti-geronic factors, alpha-klotho (a-KL) appears to be one of the most relevant since several polymorphisms of the a-KL gene are associated to increased risks of OA and differential levels of a-KL mRNA have been reported between OA and healthy articular cartilage. The expression of a-KL has also been evidenced in porcine articular and growth plate cartilage. Likewise, recent publications have interestingly established a relationship between a-KL, the senescence-associated inflammatory secretome, the autophagy processes and several other age-related diseases.
However and despite this large body of converging data suggesting a pathophysiological link between autophagy, a-KL and OA, the role of Klotho in articular cartilage physiopathology remains unknown. In this context, the overall objective of the KLOTHOA project is to in depth exploring the role of the anti-geronic protein a-KL in aging process of articular cartilage and in the OA pathophysiology. The ultimate goal of KLOTHOA is to determine whether a-KL could be a relevant therapeutic target for the treatment of OA. To address this clinically relevant issue, we propose a 3-year project divided in 3 experimental Work Packages (WP1 to WP3) with specific aims as described below:
• WP1: to compare the expression pattern of a-KL with autophagy/senescence markers during the onset and progression of OA in murine models available in the laboratory and in human OA joints.
• WP2: to assess the in vitro impact of a-KL on the inflammatory and catabolic phenotypes of human and murine chondrocytes with particular interest in autophagy and senescence processes.
• WP3: to determine the impact of a-KL modulation on articular cartilage aging and OA using (i) murine preclinical models of OA with tissue-specific and conditional genetic ablation of the different forms of a-KL and (ii) AAV-mediated up- or down-regulation of a-KL expression in murine knee OA joints.
The KLOTHOA project will provide a better understanding of the mechanisms involved in aging of articular cartilage and in the process of age-dependent OA. Through the in depth exploration of the role of a-KL in articular cartilage aging and OA onset/progression as well as the pathways regulated by a-KL, our project may identify a-KL as a new therapeutic target in OA treatment.