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However, the literature presents conflicting evidence regarding the role of adiponectin signaling in bone homeostasis and fracture repair across different health states, ages, and disease conditions. These inconsistencies may arise from the complex endocrine and paracrine feedback mechanisms regulating adiponectin, as well as the variability in adiponectin isoforms and receptor expressions. In this study, we observed differential expression of adiponectin receptors in the bone marrow (BM) of aged mice, characterized by elevated levels of adiponectin receptor 2 and reduced levels of receptor 1, as corroborated by both single\u2010cell sequencing and in\u00a0vivo staining. Additionally, circulating levels of adiponectin and its local expression were significantly higher in aged mice compared to younger counterparts. Treatment with adiponectin receptor agonist, AdipoRon, enhanced bone regeneration and repair in young mice by promoting osteogenesis and reducing osteoclastogenesis. Conversely, in aged mice, AdipoRon treatment led to cellular senescence, delayed bone repair, and inhibited osteogenic activity. Notably, the adiponectin receptor 1\u2010Wnt and adiponectin receptor 2\u2010MAPK and mTOR signaling pathways were differentially activated in AdipoRon\u2010treated BM mesenchymal stem cells from young and aged mice. Additionally, the NF\u2010\u03baB, and AKT pathways were consistently downregulated in BM macrophages of both age groups following AdipoRon administration. In conclusion, aging significantly modulates the impact of adiponectin receptor signaling on BM mesenchymal stem cells. This modulation is potentially attributable to changes in receptor transcription and distribution, as well as differential activation of downstream signaling pathways.<\/jats:p>","DOI":"10.1111\/acel.14390","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T04:44:57Z","timestamp":1730090697000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Aging alters the effect of adiponectin receptor signaling on bone marrow\u2010derived mesenchymal stem cells"],"prefix":"10.1111","volume":"24","author":[{"given":"Hanghang","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan University  Chengdu Sichuan China"},{"name":"MaineHealth Institute for Research  Scarborough Maine 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