Abstract
Non-traumatic osteonecrosis of the femoral head (ONFH) is clinically a devastating and progressive disease without an effective treatment. Mesenchymal stem cells (MSCs) transplantation has been used to treat ONFH in early stage, but the failure rate of this therapy is high due to the reduced osteogenic differentiation and migration of the transplanted MSCs related with pathological bone tissues. However, the mechanism responsible for this decrease is still unclear. Therefore, we assume that the implanted MSCs might be influenced by signals delivered from pathological bone tissue, where the exosomes might play a critical role in this delivery. This study showed that exosomes from ONFH bone tissues (ONFH-exos) were able to induce GC-induced ONFH-like damage, in vivo and impair osteogenic differentiation and migration of MSCs, in vitro. Then, we analyzed the differentially expressed proteins (DEPs) in ONFH-exos using proteomic technology and identified 842 differentially expressed proteins (DEPs). On the basis of gene ontology (GO) enrichment analysis of DEPs, fold-changes and previous report, cell adhesion-related CD41 (integrin α2b) was selected for further investigation. Our study showed that the CD41 (integrin α2b) was distinctly decreased in ONFH-exos, compared to NOR-exos, and downregulation of CD41 could impair osteogenic differentiation and migration of the MSCs, where CD41-integrin β3-FAK-Akt-Runx2 pathway was involved. Finally, our study further suggested that CD41-affluent NOR-exos could restore the glucocorticoid-induced decline of osteogenic differentiation and migration in MSCs, and prevent GC-induced ONFH-like damage in rat models. Taken together, our study results revealed that in the progress of ONFH, exosomes from the pathological bone brought about the failure of MSCs repairing the necrotic bone for lack of some critical proteins, like integrin CD41, and prompted the progression of experimentally induced ONFH-like status in the rat. CD41 could be considered as the target of early diagnosis and therapy in ONFH.
Highlights
Non-traumatic osteonecrosis of the femoral head (ONFH) is a common disease characterized by rapid procession, high disability rate and severe influence on life quality[1,2]
As the nuclei and mitochondria are the common contaminants in the exosomes isolated by ultracentrifugation, we measured the lamin A and mitofilin and found that these two proteins were lower expressed in the NOR-exos and ONFH-exos (Fig. S1)
To test whether the exosomes can be internalized by the host cells, we conducted an uptake assay, and the results showed the exosomes were internalized by C3H10T1/2 cells for 12 h and internalized by human primary bone marrow MSCs (HMSCs) for 6 h (Fig. 2f)
Summary
Non-traumatic osteonecrosis of the femoral head (ONFH) is a common disease characterized by rapid procession, high disability rate and severe influence on life quality[1,2]. In the US, 10,000–20,000 patients are newly found to be affected with the disease per year[3] and in China, 100,000–200,000 new cases were reported per year[4]. Various medical treatments have been introduced, Official journal of the Cell Death Differentiation Association. Zhu et al Cell Death and Disease (2020)11:293 but no pharmacological prevention or treatment of osteonecrosis is recommendable[5]. Mesenchymal stem cells (MSCs) transplantation has been used to treat the ONFH in early stage, but the failure rate is about 30%. ONFH affects the patients physically and psychologically and brings a huge financial burden on family and society. The difficulties in diagnosis and treatment for this disease mainly result from the unclear underlying mechanism
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