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We have found that the previously uncharacterized bone morphogeneticprotein-9 (BMP9) is one of the most osteogenic factors.However, it is unclear if BMP9 cross-talks with TGFβ1 during osteogenicdifferentiation. Using the recombinant BMP9 adenovirus,we find that low concentration of rhTGFβ1 synergistically inducesalkaline phosphatase activity in BMP9-transduced C3H10T1/2cells and produces more pronounced matrix mineralization.However, higher concentrations of TGFβ1 inhibit BMP9-inducedosteogenic activity. Real-time PCR and Western blotting indicatethat BMP9 in combination with low dose of TGFβ1 potentiates theexpression of later osteogenic markers osteopontin, osteocalcinand collagen type 1 (COL1a2), while higher concentrations ofTGFβ1 decrease the expression of osteopontin and osteocalcin butnot COL1a2. Cell cycle analysis reveals that TGFβ1 inhibitsC3H10T1/2 proliferation in BMP9-induced osteogenesis and restrictsthe cells in G0/G1 phase. Our findings strongly suggest thatTGFβ1 may exert a biphasic effect on BMP9-induced osteogenicdifferentiation of mesenchymal stem cells.