A brain-driven neural circuit contributes to tissue regeneration in joint cartilage

Objectives: Most mammalian tissues have limited regenerative capacity. It has been speculated that the brain might regulate tissue regeneration, while this concept has yet to be experimentally addressed. Using cartilage, a tissue with limited regenerative capacity as an example, we investigated this hypothesis. Methods: We employed magnetic resonance imaging, polysynaptic retrograde tracing, chemogenetic/optogenetic manipulations, and single-cell RNA sequencing to characterise a functional brain-cartilage neural circuit regulating cartilage regeneration in human and mouse models. Results: We found that fractional anisotropy and amplitude of low-frequency fluctuations values of the paraventricular nucleus (PVN) are elevated, and correlate with Western Ontario and McMaster Universities Arthritis Index scores and synovial fluid norepinephrine (NE) concentrations in patients with osteoarthritis. We further demonstrate the existence of a functional trans-neuronal circuit to regulate cartilage regeneration, which originates from PVNCRH neurons to sympathetic nerves in the synovium of joint. Inhibition of the circuit is sufficient to strongly promote the production of stable mature articular cartilage instead of fibrocartilage. This process fosters the regeneration of articular cartilage by inhibiting the pathways mediated by NE/articular cartilage via the β2-adrenergic receptor (ADRB2) in Proteoglycan 4+ cells. Furthermore, treatment with an ADRB2 inverse agonist prevented cartilage degradation in human articular cartilage explants. Conclusions: Our findings unveil a brain-cartilage circuit that regulates cartilage regeneration, providing valuable insights into the inherent limitations of tissue regeneration and suggesting a promising treatment strategy for enhancing cartilage regeneration.