Abstract
To investigate the effects and mechanisms of irisin, a newly discovered myokine, in cartilage development, osteoarthritis (OA) pathophysiology and its therapeutic potential for treating OA we applied the following five strategical analyses using (1) murine joint tissues at different developmental stages; (2) human normal and OA pathological tissue samples; (3) experimental OA mouse model; (4) irisin gene knockout (KO) and knock in (KI) mouse lines and their cartilage cells; (5) in vitro mechanistic experiments. We found that Irisin was involved in all stages of cartilage development. Both human and mouse OA tissues showed a decreased expression of irisin. Intra-articular injection of irisin attenuated ACLT-induced OA progression. Irisin knockout mice developed severe OA while irisin overexpression in both irisin KI mice and intraarticular injection of irisin protein attenuated OA progression. Irisin inhibited inflammation and promoted anabolism in chondrogenic ADTC5 cells. Proliferative potential of primary chondrocytes from KI mice was found to be enhanced, while KO mice showed an inhibition under normal or inflammatory conditions. The primary chondrocytes from irisin KI mice showed reduced expression of inflammatory factors and the chondrocytes isolated from KO mice showed an opposite pattern. In conclusion, it is the first time to show that irisin is involved in cartilage development and OA pathogenesis. Irisin has the potential to ameliorate OA progression by decreasing cartilage degradation and inhibiting inflammation, which could lead to the development of a novel therapeutic target for treating bone and cartilage disorders including osteoarthritis.
Highlights
Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration of cartilage and subchondral bone within the joint
We found for the first time that irisin is prominently expressed in the prehypertrophic and hypertrophic zones of growth plate cartilage as early as E14.5 and E16.5 (Figure 1A), while expression was absent in the proliferating and resting zones at those stages
The expression of irisin was present in the articular cartilage of postnatal mice (Figure 1A)
Summary
Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration of cartilage and subchondral bone within the joint. It afflicts about 10% of the population (Lawrence et al, 2008) and is currently a major cause of pain and disability worldwide. Conservative treatments, including weight loss, physical therapy/exercise, and activity modification, may not always elicit desired outcomes due to three major therapeutic limitations of conservative treatments: unsatisfactory clinical efficacy for pain relief, the potential for side effects with certain drug options, and the inability to delay disease progression (Zhang et al, 2011a). In joint replacement surgery (arthroplasty), surgical risks include infections and blood clots. Investigating the pathogenesis of OA and searching for an effective and robust therapy to prevent and treat OA is important and significant
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