PPP2CA Drives Chondrocyte Metabolic Disorders and Underpins Osteoarthritis Pathogenesis through Targeting AMPK Dephosphorylation

Osteoarthritis (OA) is a debilitating degenerative joint disease with limited therapeutic options. Emerging evidence implicates that metabolic disorder is the major risk factor in OA pathogenesis, with dysfunction in AMP-activated protein kinase (AMPK) signaling. AMPK is a central metabolic sensor and is activated by phosphorylation and inactivated by dephosphorylation. Dysruption of the steady-state protein levels of AMPK affects energy balance and promotes inflammation, mitochondrial dysfunction, and catabolic activation in chondrocytes. While metformin, an AMPK activator, has shown clinical promising in alleviating OA symptoms, its limited efficacy highlights the need for alternative strategies targeting AMPK regulatory mechanisms. Protein phosphatase 2A (PP2A), particularly its catalytic subunit alpha (PPP2CA), is a major serine/threonine phosphatase responsible for AMPK dephosphorylation. Here, we identified PPP2CA as a central regulator of metabolic homeostasis in OA pathogenesis. Chondrocyte-specific deletion of Ppp2ca restored AMPK signaling, preserved mitochondrial integrity, as evidenced by reduced ROS, enhanced ATP production and suppressed catabolic gene expression, resulting in attenuation of OA progression in mice. We further assessed the therapeutic potential of targeting AMPK dephosphorylation using a PPP2CA inhibitor LB-100 for OA treatment. We engineered yeast-microcapsule microrobots encapsulating LB-100 (YC-LB-100), enabling oral delivery and macrophage-mediated targeting to inflamed joints. YC-LB-100 reversed pain behaviors and reduced cartilage erosion in a DMM-induced OA mouse model. Our findings reveal that PPP2CA is a critical enzyme mediating AMPK dephosphorylation and regulating AMPK activity in chondrocytes, positioning PPP2CA as a novel therapeutic target for OA management.