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Roles and Mechanisms of Irisin in Attenuating Pathological Features of Osteoarthritis.

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.

SUBMITTER: Li X

PROVIDER: S-EPMC8509718 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOsteoarthritis (OA) is a progressive joint disease and a major cause of chronic pain in adults. The prevalence of OA is higher in female patients, who tend to have worse OA outcomes, partially due to pain. The association between joint pain and OA pathology is often inconclusive. Preclinical research studies have largely overlooked sex as a potential determinant in joint pain during OA. This study aimed to investigate the role of sex in joint pain in the collagenase-induced OA (CiOA) model and its link with joint pathology.MethodsMultiple aspects of pain were evaluated during identically executed experiments of CiOA in male and female C57BL/6J mice. Cartilage damage, osteophyte formation, synovial thickness, and cellularity were assessed by histology on day 56. The association between pain and pathology was investigated, disaggregated by sex.ResultsDifferences in pain behavior between sexes were found in the majority of the evaluated pain methods. Females displayed lower weight bearing ability in the affected leg compared to males during the early phase of the disease, however, the pathology at the end stage was comparable between sexes. In the second cohort, males displayed increased mechanical sensitivity in the affected joint compared to females but also showed more cartilage damage at the end stage of the model. Within this cohort, gait analysis showed varied results. Males used the affected paw less often and displayed dynamic weight-bearing compensation in the early phase of the model. These differences were not observed in females. Other evaluated parameters displayed comparable gait behavior between males and females. A detailed analysis of individual mice revealed that seven out of 10 pain measurements highly correlated with OA histopathology in females (Pearson r range: 0.642-0.934), whereas in males this measurement was only two (Pearson r range: 0.645-0.748).ConclusionOur data show that sex is a determinant in the link between pain-related behavior with OA features. Therefore, to accurately interpret pain data it is crucial to segregate data analysis by sex to draw the correct mechanistic conclusion.

Project description:IntroductionChanges to bone physiology play a central role in the development of osteoarthritis with the mechanosensing osteocyte releasing factors that drive disease progression. This study developed a humanised in vitro model to detect osteocyte responses to either interleukin-6, a driver of degeneration and bone remodelling in animal and human joint injury, or mechanical loading, to mimic osteoarthritis stimuli in joints.MethodsHuman MSC cells (Y201) were differentiated in 3-dimensional type I collagen gels in osteogenic media and osteocyte phenotype assessed by RTqPCR and immunostaining. Gels were subjected to a single pathophysiological load or stimulated with interleukin-6 with unloaded or unstimulated cells as controls. RNA was extracted 1-hour post-load and assessed by RNAseq. Markers of pain, bone remodelling, and inflammation were quantified by RT-qPCR and ELISA.ResultsY201 cells embedded within 3D collagen gels assumed dendritic morphology and expressed mature osteocytes markers. Mechanical loading of the osteocyte model regulated 7564 genes (Padj p<0.05, 3026 down, 4538 up). 93% of the osteocyte transcriptome signature was expressed in the model with 38% of these genes mechanically regulated. Mechanically loaded osteocytes regulated 26% of gene ontology pathways linked to OA pain, 40% reflecting bone remodelling and 27% representing inflammation. Load regulated genes associated with osteopetrosis, osteoporosis and osteoarthritis. 42% of effector genes in a genome-wide association study meta-analysis were mechanically regulated by osteocytes with 10 genes representing potential druggable targets. Interleukin-6 stimulation of osteocytes at concentrations reported in human synovial fluids from patients with OA or following knee injury, regulated similar readouts to mechanical loading including markers of pain, bone remodelling, and inflammation.DiscussionWe have developed a reproducible model of human osteocyte like cells that express >90% of the genes in the osteocyte transcriptome signature. Mechanical loading and inflammatory stimulation regulated genes and proteins implicated in osteoarthritis symptoms of pain as well as inflammation and degeneration underlying disease progression. Nearly half of the genes classified as 'effectors' in GWAS were mechanically regulated in this model. This model will be useful in identifying new mechanisms underlying bone and joint pathologies and testing drugs targeting those mechanisms.

Project description:Knee instability resulting from anterior cruciate ligament (ACL) rupture is a high-risk factor for posttraumatic osteoarthritis (PTOA) in the patellofemoral joint (PFJ). However, whether non-weight-bearing and weight-bearing treatments have chondroprotective effects remains unclear. Twenty-four adult New Zealand White male rabbits were employed in this study. All animals received ACL transection in the right knee and sham surgery in the left knee. The rabbits were randomly assigned to the following groups: (I) In the sedentary (SED) group, the rabbits (n = 6) were simply kept in their cage; (II) In the continuous passive motion (CPM) group, the rabbits (n = 6) performed CPM exercise for 7 days, starting from the first postoperative day; (III) In the active treadmill exercise (TRE) group, the rabbits (n = 6) performed TRE for 2 weeks; (IV) In the CPM + TRE group, the rabbits (n = 6) executed CPM exercise, followed by TRE. Two joint surfaces (the retropatella and femoral trochlear groove) were assessed at 4 weeks after operation. Although the gross appearance in each group was comparable, histological examination revealed significant differences in the articular cartilage status. The CPM group exhibited a greater thickness of articular cartilage, maintenance of tidemark continuity, abundant glycosaminoglycan (GAG), and significantly lower inflammatory cytokine 9, e.g., tumor necrosis factor-alpha (TNF-α) 0 levels, with modest cell apoptosis (i.e., caspase-3). By contrast, the TRE group displayed the worst pathological features: an irregular cartilage surface and chondrocyte disorganization, reduced cartilage thickness, breakdown of the tidemark, depletion of collagen fibers, loss of GAG, and the highest levels of TNF-α and caspase-3 expression. Furthermore, the CPM + TRE group had more favorable outcomes than the SED group, indicating that suitable exercise is needed. The sham treatment displayed no variance in the changes in the two joint surfaces among groups. These data indicate that the application of early CPM rehabilitation is suggested for subjects in order to decrease the risk of PTOA without ACL reconstruction in the PFJ compartment in rabbits. The early TRE program, however, had harmful outcomes. Additionally, inactivity was discovered to initiate the development of PTOA.

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Roles and Mechanisms of Irisin in Attenuating Pathological Features of Osteoarthritis.

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