Objectives: Endothelial cells (ECs) are an integral component of the bone microenvironment, lining blood vessels that deliver oxygen and nutrients to developing bone tissue. Furthermore, ECs themselves may directly participate in the growth and differentiation of osteo-progenitor cells. The aim of these studies was to determine if ECs modulate the osteogenic differentiation of bone marrow stromal cells (BMSCs). Methods: BMSCs were co-cultured with ECs and osteogenic differentiation of BMSCs was measured through analysis of alkaline phosphatase activity. RNA was isolated from ECs and analyzed by RT-PCR for expression of bone morphogenetic proteins (BMPs). Protein was also extracted from ECs and analyzed for production of BMP-2. In our in vivo studies, BMSCs and ECs were co-transplanted into SCID mice on biodegradable polymer matrices. Following retrieval of implants, qualitative histological and quantitative histomorphometric analyses were performed to determine extent of new bone and blood vessel formation. Results: In co-cultures of BMSCs and ECs, BMSCs exhibited as much as a two-fold increase in osteogenic differentiation compared to cultures of BMSCs alone. Osteogenic differentiation was also enhanced as a function of increased EC number. ECs expressed mRNA for BMP-2, but neither BMP-4 nor BMP-7 was detected. Western blotting also confirmed the production of BMP-2 by ECs. Finally, BMSCs co-transplanted with ECs into murine model systems resulted in an increase in bone and blood vessel formation compared to BMSCs transplanted alone. Conclusions: The results indicate that ECs enhance the osteogenic potential of BMSCs in vitro and in vivo. The observed BMP-2 production by ECs could play a key role in this interaction. Taken together, this data suggests that ECs not only function to form the microvasculature that delivers nutrients to developing and engineered bone, but also function to modulate the differentiation of osteoprogenitor cells. DK was supported by an NIDCR grant (F30-DE05747).

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