Purpose: Aging represents a major risk factor for knee osteoarthritis (OA). However, systematic review of the literature reveals that the underlying mechanisms of the age-related knee OA are poorly understood. While the α-Klotho has been shown to regulate senescence and autophagy in a variety of cell types in an age-dependent manner, to our best of knowledge, there have been no studies addressing the role of α-Klotho in the pathogenesis of age-related knee OA. This study aims to elucidate the role of α-Klotho in the pathogenesis of age-related knee OA. We hypothesize that α-Klotho plays a protective role for knee joint, and the reduction of α-Klotho level, caused by aging or gene knock-down, will result in the increased development of knee OA.
Methods: The knee joints of young (3-6 months old), aged (21-24 months old), and young α-Klotho+/- mice (3-6 months, which displayed a reduced expression level of α-Klotho) were harvested (n = 5 in each group). Normal human articular cartilage tissue from young (15 years old; n = 1) and older (69 years old; n = 1) donors were collected with the approval from the Committee for Oversight of Research and Clinical Training Involving Decedents (CORID). Knee joints were decalcified and embedded in paraffin. Safranin O/Fast green staining and immunofluorescence were performed to evaluate: (i) the cartilage degeneration , (ii) α-Klotho expression level in chondrocytes. ImageJ and Matlab were used to perform quantification of irregularity of the knee cartilage surface, and NIS Elements software was used to quantify α-Klotho expression per cell.
Results: Histology results indicated that aged mice displayed more severe cartilage degeneration with increased cartilage surface irregularity compared to young mice. Similar results were found in the cartilage from humans. Klotho-signal intensity per cell in aged mice and older donor was significantly lower than that in young mice and young donor, respectively. In addition, the aged-relevant OA phenotype was recapitulated in Klotho+/- mice, as evidenced by an accelerated articular cartilage degeneration, increased cartilage surface irregularity and reduced cellularity when compared to age-matched wild type mice.
Conclusions: Age-related cartilage degeneration in knee joint was associated with decreased α-Klotho expression in both murine and human models. Genetically engineered mice that express decreased α-Klotho displayed an aged phenotype with the accelerated development of OA, suggesting that age-related decline in α-Klotho may contribute to the onset of OA. These studies also suggest that the development of α-Klotho therapeutics as a means to counteract the effect of age on cartilage degeneration may be an interesting direction for future research.
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