Regulation of osteoarthritis and associated anxiety-related behaviours by retinoic acid binding protein 2 and its interaction with the insular cortex.

Abstract

BACKGROUND AND PURPOSE: Osteoarthritis (OA) is the most common form of arthritis worldwide. Here, we have sought to clarify the regulatory mechanisms by which the cellular retinoic acid-binding protein 2 (Crabp2) modulated OA occurrence and to elucidate the role of the insular cortex in regulating OA and anxiety. EXPERIMENTAL APPROACH: A model of OA was established following intra-articular injection of monosodium iodoacetate in mice, and a series of assessments and behavioural experiments were conducted to investigate the pathological features of OA and anxiety-related behaviours. KEY RESULTS: RNA-sequencing analysis revealed an increased Crabp2 expression in the articular cartilage of OA mice. Using the adeno-associated virus (AAV) strategy, Crabp2 overexpression in articular cartilage was shown to exacerbate progression of OA and anxiety-related behaviours. Neural linkages from the insular cortex to the knee joints were identified using a retrograde transneuronal viral tracing technique. Hyperexcitability of glutamatergic neurons in the insular cortex of OA mice was assessed by monitoring expression of FosB and Ca-sensitive fibre photometry recordings. Activation of glutamatergic neurons in the insular cortex promoted the development of OA and anxiety-related behaviours, whereas inhibiting these neurons attenuated the pathological features of OA and anxiety phenotypes. CONCLUSION AND IMPLICATIONS: Our results emphasized the role of Crabp2 in the regulation of OA and related anxiety disorders by interacting with the insular cortex. This brain area may function as a pathogenetic gene and serve as a therapeutic target in the treatment of OA and its related anxiety disorders.