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

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 2+ ‐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.