RESUMEN
The metabolicosteopathy known as postmenopausal osteoporosisiscaused by disruption of the balance between bone resorption and osteogenesis, processes that are mediated by osteoclasts and osteoblasts, respectively. The current therapeutic approaches to treating osteoporosis have several limitations. In this study, we demonstrated that the natural chemical compound isoalantolactone (IAL) could inhibit osteoclastogenesis, without affecting osteogenesis. This is the first study reporting a role of IAL in suppressing the receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation in a dose-dependent manner, and downregulating the expression of osteoclast-related marker genes. Furthermore, IAL abrogated the phosphorylation of c-Jun N-terminal kinase (JNK)/p38, NF-κB, and phosphatidylinositol 3-kinase (PI3K)-AKT, and also diminished the expression of osteoclastogenesis-related proteins. In conclusion, our results indicated that IAL has promise for the treatment of osteoporosis and other metabolicbone diseases.
Asunto(s)
Resorción Ósea/tratamiento farmacológico , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Sesquiterpenos/uso terapéutico , Actinas/metabolismo , Animales , Catepsina K/genética , Catepsina K/metabolismo , Células Cultivadas , Femenino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Ovariectomía , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK , Sesquiterpenos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Interleukin (IL)-37, a pivotal anti-inflammatory cytokine and a fundamental inhibitor of innate immunity, has recently been shown to be abnormally expressed in several autoimmune-related orthopedic diseases, including rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. However, the role of IL-37 during osteogenic differentiation of mesenchymal stem cells (MSCs) remains largely unknown. In this study, extracellular IL-37 significantly increased osteoblast-specific gene expression, the number of mineral deposits, and alkaline phosphatase activity of MSCs. Moreover, a signaling pathway was activated in the presence of IL-37. The enhanced osteogenic differentiation of MSCs due to supplementation of IL-37 was partially rescued by the presence of a PI3K/AKT signaling inhibitor. Using a rat calvarial bone defect model, IL-37 significantly improved bone healing. Collectively, these findings indicate that extracellular IL-37 enhanced osteogenesis of MSCs, at least in part by activation of the PI3K/AKT signaling pathway.