Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells (BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2 (Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling. RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.

Inhibitors that target diabetes pathology-related signaling pathways have great therapeutic potential for diabetic wound healing. Metal–organic frameworks (MOFs) are increasingly popular drug delivery systems that have high loading capacity and can release their intrinsic metal ions to act as bioactive agents. In light of this, a receptor for advanced glycation end products (RAGE) inhibitor, 4-chloro-N-cyclohexyl-N-(phenylmethyl)-benzamide (FPS-ZM1), was loaded into a cobalt (Co)-based MOF (zeolitic imidazolate framework-67, ZIF-67) to fabricate FPS-ZM1 encapsulated ZIF-67 (FZ@ZIF-67) nanoparticles (NPs). As a result, FZ@ZIF-67 NPs could dually deliver Co ions and FPS-ZM1 in a controlled manner for over 14 days. Our in vitro study showed that FZ@ZIF-67 NPs not only enhanced angiogenesis by delivering Co ions but also released FPS-ZM1 to promote M2 macrophage polarization and attenuated high glucose (HG)- and/or inflammation-induced impairment of angiogenesis through RAGE inhibition. Moreover, in an in vivo study, FZ@ZIF-67 NPs markedly improved re-epithelialization, collagen deposition, neovascularization, and relieved inflammation in diabetic wounds in rats. This study not only provides a low-cost, effective, and synergistic proangiogenic bioactive agent but also demonstrates that targeting diabetes-related pathological signaling pathways is necessary to ameliorate vascularization impairment during diabetic wound healing.