Hypothalamus Regulates Anabolic Metabolism of Articular Cartilage Superficial Chondrocytes through PGE2 Skeletal Interoception

Degeneration of articular cartilage is the key underlying cause of most joint-related diseases and yet little is known about its regeneration. Here, we report that skeletal interoception induces anabolic synthesis of superficial membrane by tuning down sympathetic norepinephrine (NE). Specifically, the superficial membrane is consumed during animal activity and anabolically renewed by the underneath chondrocytes in the superficial zone (SFZ). Notably, by stereotactic knockdown of sympathetic NE synthesis in the paraventricular nucleus, articular cartilage thickness increases. Moreover, deletion of the gene encoding the prostaglandin E2 (PGE2) receptor, EP4, in sensory nerves for ascending interoceptive pathway induces damage of superficial membrane and articular cartilage degeneration. In contrast, increase of interoceptive signaling by elevation of local PGE2 reduces sympathetic outflow to promote the anabolic renewal of superficial membrane. Importantly, inducible knockout of the beta-2-adrenergic-receptor (Adrb2) in the SFZ chondrocytes damages superficial membrane and treadmill running aggravates the damage. Mechanistically, NE-mediated activation of Adrb2 induces internalization of Adrb2 and TGF-beta type II receptor as a complex, thereby regulating TGF-beta activity for articular cartilage homeostasis regeneration. Together, physical activity induces an anabolic renewal of the superficial membrane by downregulation hypothalamic NE for optimized thickness and integrity of articular cartilage.