Osthole improves therapy for osteoporosis through increasing autophagy of mesenchymal stem cells

Abstract

Osteoporosis is a common skeletal disorder resulting in elevated fracture risk. Improvement of osteogenic differentiation is thought to be the top priority in osteoporosis treatment projects. Significant characteristics of bone marrow mesenchymal stem cells (BMMSCs), especially attractive ability to differentiate into osteoblasts, have made them alternatives for osteoporosis treatment. However, therapeutic effect with BMMSCs remains to be improved. Here, osthole, a bioactive simple coumarin derivative extracted from many medicinal plants, was introduced to pre-stimulate BMMSCs and then applied in osteoporosis therapy. The results showed that osthole-treated-BMMSCs (OBMMSCs) brought a better outcome than BMMSCs alone in estrogen deficiency-induced osteoporosis model. And elevated autophagy level was suggested to be the underlying mechanism of the ability of osthole to promote osteoblast differentiation, which is indicated by the upregulation of protein and mRNA expression level of autophagy-associated genes, Beclin1 and LC3. We concluded from these experiments that OBMMSCs are more effective than BMMSCs in osteoporosis treatment maybe through upregulation level of autophagy level induced by osthole.

Osthole: an overview of its sources, biological activities, and modification development

“…In addition, Zheng et al reported that osthole-treated bone marrow mesenchymal stem cells (BMMSCs) were more effective than BMMSCs in osteoporosis treatments. One hypothesis suggestes that the upregulation of protein and mRNA expression level of autophagy-associated genes, Beclin1, and LC3 may be the cause [107]. Yang et al found osthole could restore the immunosuppressive ability of osteoporotic BMMSCs and enhance the immunosuppressive effects by promoting the Fas/FasL system [108].…”

High-Throughput Metabolomics Discovers Metabolic Biomarkers and Pathways to Evaluating the Efficacy and Exploring Potential Mechanisms of Osthole Against Osteoporosis Based on UPLC/Q-TOF-MS Coupled With Multivariate Data Analysis

“…At the molecular level, osthole can regulate the JNK pathway by inhibiting the expression of related proteins level to stimulate osteoclast apoptosis and restrain bone resorption. Other reports have found that osthole possess ability to prohibit osteoclast conformation and partly deteriorate bone loss in nephrectomized mice by significantly increasing the expression of osteogenic differentiation-related factors and promoting Osteoprotegerin (OPG) secretion and calcium salt deposition ( Li et al, 2002 ; Ming et al, 2011 ; Wang et al, 2018 ; Zheng et al, 2019 ). It suggested that osthole has medicinal value in promoting osteoblast bone formation.…”

Osthole enhances the immunosuppressive effects of bone marrow‐derived mesenchymal stem cells by promoting the Fas/FasL system

“…A growing number of studies have confirmed that inflammation plays an important role in osteoporosis and colitis 1,2,14 . Pro‐inflammatory cytokines are important risk factors in the pathogenesis of osteoporosis 14 . In experimental colitis, activated T cells facilitate the infiltration and activation of macrophages, leading to the production of numerous inflammatory cytokines and chemokines 15 .…”

“…In experimental colitis, activated T cells facilitate the infiltration and activation of macrophages, leading to the production of numerous inflammatory cytokines and chemokines 15 . Therefore, one of the most common treatments for both osteoporosis and colitis involves reducing pro‐inflammatory cytokine production through immunosuppression, 14,15 which makes these two diseases a promising model for BMSC‐mediated cytotherapy. Inflammatory diseases caused by cell dysfunction include inflammatory colitis, osteoporosis and graft versus host disease (GVHD) 1,15 .…”