Background: Osteogenesis is tightly coupled with angiogenesis during bone repair and regeneration. However, the underlying mechanisms linking these processes remain largely undefined. The present study aimed to test the hypothesis that epidermal growth factor-like domain-containing protein 6 (EGFL6), an angiogenic factor, also functions in bone marrow mesenchymal stem cells (BMSCs), playing a key role in the interaction between osteogenesis and angiogenesis. Methods: We evaluated how EGFL6 affects angiogenic activity of human umbilical cord vein endothelial cells (HUVECs) via proliferation, transwell migration, wound healing, and tube-formation assays. Alkaline phosphatase (ALP) and Alizarin Red S (AR-S) were used to assay the osteogenic potential of BMSCs. qRT-PCR, western blotting, and immunocytochemistry were used to evaluate angio- and osteo-specific markers and pathway-related genes and proteins. In order to determine how EGFL6 affects angiogenesis and osteogenesis in vivo, EGFL6 was injected into fracture gaps in a rat tibia distraction osteogenesis (DO) model. Radiography, histology, and histomorphometry were used to quantitatively evaluate angiogenesis and osteogenesis. Results: EGFL6 stimulated both angiogenesis and osteogenic differentiation through Wnt/β-catenin signaling in vitro. Administration of EGFL6 in the rat DO model promoted CD31^hiEMCN^hi type H-positive capillary formation associated with enhanced bone formation. Type H vessels were the referred subtype involved during DO stimulated by EGFL6. Conclusion: EGFL6 enhanced the osteogenic differentiation potential of BMSCs and accelerated bone regeneration by stimulating angiogenesis. Thus, increasing EGFL6 secretion appeared to underpin the therapeutic benefit by promoting angiogenesis-coupled bone formation. These results imply that boosting local concentrations of EGFL6 may represent a new strategy for the treatment of compromised fracture healing and bone defect restoration.

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.

Background: The functional outcomes and therapeutic costs between digit replantation and revision amputation have remained controversial. Methods: A total of 1023 patients with single-digit traumatic amputation or devascularization who underwent successful digit replantation (failure excluded) or revision amputation from January 1, 2013, to January 1, 2016, were included in this study. All cases were subgrouped based on Tamai level of amputation and the injured digit. The clinical outcomes were assessed using the Michigan Hand Outcomes Questionnaire 1 year after the initial operation. The authors also compared the cost of treatment, the duration of hospitalization, and the duration of sick leave between the two treatments. Results: Replantation of small (level I to V), ring (level I to III), and long (level I) fingers showed no functional benefit compared with initial revision amputation. In contrast, replantation of thumb (level I to V), index (level I to V), long (level II to V), and ring (level IV to V) fingers had better outcomes. The cost of replantation was higher and the durations of hospitalization and sick leave of replantation were also longer compared with the revision amputation group. Conclusions: Single amputated injuries of small (level I to V), ring (level I to III), and long (level I) fingers are a relative contradiction for replantation. Replantation of thumb (level I to V), index (level I to V), long (level II to V), and ring (level IV to V) fingers showed extra benefit compared with revision amputation.