Work

Ablation of hypothalamic Cnr1 leads to reduced meniscal mineral volume and articular cartilage damage in aging male mice

Year: 2025

Type: article

Abstract: Objective Aging is associated with reduced central nervous system endocannabinoid ‎tone. Here we ‎sought to decipher the involvement of hypothalamic cannabinoid receptor type-1 (Cnr1) in ‎driving peripheral tissue aging, with a particular focus on bone and joint structural changes. ‎Methods To this end, we generated mice with hypothalamus-specific ablation of Cnr1 (i.e. CB1 hypoKO ), or with hypothalamus-specific rescue of the receptor (CB1 STOPhypoRS ) using stereotaxic viral injections into the mediobasal hypothalamus at 2-3-‎months of Cnr1 fl/fl or CB1 STOP mice. Animals were aged to 18 or 19 months and assessed for body weight, ‎temperature and frailty. After sacrifice, we examined structural and histological features of hypothalamic tissue, skin, ‎testis, joint, and bone as well as circulating hormone levels. ‎Results CB1 hypoKO exhibited reduced frailty index vs WT at 17 months of age, with unchanged body weight, temperature and survival vs WT mice. Interestingly, CB1 hypoKO mice displayed a reduction in the lateral meniscal ‎mineral volume of the tibiofemoral joint, associated with less blood vessels and articular cartilage damage. Imunohistochemical analysis revealed that CB1 hypoKO mice displayed enriched tyrosine hydroxylase (TH) intensity surround blood vessels, yet meniscal tissue displayed reduced TH positive cells and ATF4 nuclear coappearence for CB1 hypoKO mice vs WT. Conclusions These results suggest that a lack of hypothalamic CB1 tone increases meniscal sympathetic tone, impairs ATF4 nuclear localisation and is associated with an increase in meniscal mineralisation. This subsequently hinders OA development with age.

Source: Osteoarthritis and Cartilage

DOI: 10.1016/j.joca.2025.08.006