Assessment of functional roles and therapeutic potential of integrin receptors in osteoarthritis: A systematic review and meta-analysis of preclinical studies

Abstract

Background: Integrins are heterodimeric transmembrane receptors that mediate a variety of biological function and plays a critical role in osteoarthritis (OA) pathogenesis, which may provide new targets for the development of OA therapies. However, the roles of integrins in different stages of OA remain elusive.

Objectives: This study aimed to synthesize all published preclinical evidence on the roles of integrin receptors in different stages of OA to identify the potential target for drug development in alleviating OA pathogenesis.

Methods: Major electronic databases were used to identify related original articles. The methodological quality of all included studies was appraised using the SYRCLE risk of bias tool. We used the generic inverse variance with random effects model to calculate standardized mean differences (SMDs) and 95% confidence interval (CI).

Results: Seventeen studies were included in this systematic review. Integrin α5β1 activation increases the histopathological score both in early [SMD, 6.39; 95%CI (2.90, 9.87); p = 0.0003] and late [SMD, 3.41; 95%CI (2.44, 4.38); p < 0.00001] stage of OA. Integrin α5β1 also increased the core catabolic factors like MMP-3, IL-1β, and TNF-α. Interestingly, the inactivation of α5β1 integrin did not change the histopathological score (p = 0.84). Similarly, β1 integrin notably increased histopathological score at both stages of OA [early; SMD, 7.13; 95%CI (2.01, 12.24); p = 0.006]; [late; SMD, 10.25; 95%CI (5.11, 15.39); p < 0.0001], and increased the MMP-13 levels. However, integrin β1 was upregulated at the early stage and downregulated at the late stage of OA. Furthermore, α2β1 integrin significantly increased histopathological score [SMD, 3.14; 95%CI (2.18, 4.10); p < 0.00001] and MMP-13 [SMD, 2.24; 95%CI (0.07, 4.41); p = 0.04]. Deactivating integrin α1β1 increased histopathological score in late [SMD, 1.53; 95%CI (0.80, 2.26); p < 0.0001], but not in early [SMD, 0.90; 95%CI (-1.65, 3.45); p = 0.49] stage of OA.

Conclusion: This study provides evidence that α5β1, α2β1, and α1β1 integrin might be the potential target for future drug development in alleviating OA pathogenesis. Further work is required to establish our findings through activating/deactivating these receptors in different stages of OA.

Keywords: Integrins; Meta-analysis; Osteoarthritis, Cartilage; Systematic review.