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

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 age in Cnr1^fl/fl or CB1^STOP mice. Animals were aged to 18 or 19 months and assessed for body weight, ‎temperature, frailty and circulating hormones. 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. Interestingly, CB1^hypoKO mice displayed a reduction in the lateral meniscal ‎mineral volume of the tibiofemoral joint, which was associated with less blood vessels and articular cartilage damage. Immunofluorescence analysis revealed that CB1^hypoKO mice displayed enriched tyrosine hydroxylase (TH) intensity surrounding blood vessels, yet meniscal tissue showed reduced TH positive cells and ATF4 nuclear co-appearence in CB1^hypoKO mice vs WT. Finally, CB1^hypoKO mice displayed signficantly lower circulating levels of corticosterone. Conclusions: These results suggest that a lack of hypothalamic CB1 tone reduced circulating levesl of corticosterone, while increasing local meniscal sympathetic tone, which is associated with impaired ATF4 nuclear localization and meniscal mineralization. These events subsequently hinder OA development with age.