The cereblon-AMPK (AMP-activated protein kinase) axis in chondrocytes regulates the pathogenesis of osteoarthritis

Objective: AMP-activated protein kinase (AMPK) dysregulation is implicated in osteoarthritis (OA), but the mechanisms underlying this dysregulation remain unclear. We investigated the role of Cereblon, a substrate-recognition protein within the E3-ligase ubiquitin complex, in AMPK dysregulation and OA pathogenesis.

Methods: Cereblon expression was examined in human (n = 5) and mouse (n = 10) OA cartilage. The role of Cereblon was investigated through its adenoviral overexpression (n = 10) or knockout (KO, n = 15) in the destabilization of the medial meniscus (DMM)-operated mice. The therapeutic potentials of the chemical Cereblon Degrader, TD-165, and the AMPK Activator, metformin, were assessed through intra-articular (IA) injection to mice (n = 15).

Results: Immunostaining revealed that Cereblon is upregulated in human and mouse OA cartilage. In DMM model mice, cartilage destruction was exacerbated by overexpression of Cereblon in mouse joint tissues (OARSI grade; 1.11 [95% CI: 0.50 to 2.75]), but inhibited in global (-2.50 [95% CI: -3.00 to -1.17]) and chondrocyte-specific (-2.17 [95% CI: -3.14 to -1.06]) Cereblon KO mice. The inhibitory effects were more pronounced in mice fed a high-fat diet compared to a regular diet. The degradation of Cereblon through IA injection of TD-165 inhibited OA cartilage destruction (-2.47 [95% CI: -3.22 to -1.56]). Mechanistically, Cereblon exerts its catabolic effects by negatively modulating AMPK activity within chondrocytes. Consistently, activation of AMPK by IA injection of metformin inhibited posttraumatic OA cartilage destruction (-1.20 ([95% CI: -1.89 to -0.45]).

Conclusions: The cereblon-AMPK axis acts as a catabolic regulator of OA pathogenesis and seems to be a promising therapeutic target in animal models of OA.

AMP-activated protein kinase; Cartilage; Cereblon; Chondrocytes; Osteoarthritis; Therapeutic targets.