Abstract
BackgroundAs one of the least studied bone morphogenetic proteins (BMPs), BMP9 is one of the most osteogenic BMPs. Retinoic acid (RA) signaling is known to play an important role in development, differentiation and bone metabolism. In this study, we investigate the effect of RA signaling on BMP9-induced osteogenic differentiation of mesenchymal progenitor cells (MPCs).Methodology/Principal FindingsBoth primary MPCs and MPC line are used for BMP9 and RA stimulation. Recombinant adenoviruses are used to deliver BMP9, RARα and RXRα into MPCs. The in vitro osteogenic differentiation is monitored by determining the early and late osteogenic markers and matrix mineralization. Mouse perinatal limb explants and in vivo MPC implantation experiments are carried out to assess bone formation. We find that both 9CRA and ATRA effectively induce early osteogenic marker, such as alkaline phosphatase (ALP), and late osteogenic markers, such as osteopontin (OPN) and osteocalcin (OC). BMP9-induced osteogenic differentiation and mineralization is synergistically enhanced by 9CRA and ATRA in vitro. 9CRA and ATRA are shown to induce BMP9 expression and activate BMPR Smad-mediated transcription activity. Using mouse perinatal limb explants, we find that BMP9 and RAs act together to promote the expansion of hypertrophic chondrocyte zone at growth plate. Progenitor cell implantation studies reveal that co-expression of BMP9 and RXRα or RARα significantly increases trabecular bone and osteoid matrix formation.Conclusion/SignificanceOur results strongly suggest that retinoid signaling may synergize with BMP9 activity in promoting osteogenic differentiation of MPCs. This knowledge should expand our understanding about how BMP9 cross-talks with other signaling pathways. Furthermore, a combination of BMP9 and retinoic acid (or its agonists) may be explored as effective bone regeneration therapeutics to treat large segmental bony defects, non-union fracture, and/or osteoporotic fracture.
Highlights
Mesenchymal progenitor cells (MPCs) are adherent marrow stromal cells that can self-renew [1] and differentiate into osteogenic, chondrogenic, and adipogenic lineages [2,3,4,5], mesenchymal progenitor cells (MPCs) have been isolated from many tissues, such as adipose, skeletal muscle, periosteum, brain, liver, bone marrow, amniotic fluid and hair follicle [6,7,8,9,10,11,12,13,14,15]
Stem cell implantation studies reveal that co-expression of BMP9 and RXRa or RARa significantly increases trabecular bone and osteoid matrix formation
These results strongly suggest that Retinoic acid (RA) signaling can effectively augment BMP9-induced osteogenic differentiation of MPCs
Summary
Mesenchymal progenitor cells (MPCs) are adherent marrow stromal cells that can self-renew [1] and differentiate into osteogenic, chondrogenic, and adipogenic lineages [2,3,4,5], MPCs have been isolated from many tissues, such as adipose, skeletal muscle, periosteum, brain, liver, bone marrow, amniotic fluid and hair follicle [6,7,8,9,10,11,12,13,14,15]. Upon analyzing the 14 types of BMPs, we found that BMP9 is one of the most potent BMPs in inducing osteogenic differentiation of MPCs [19,24,25,26,27,28,29,30,31]. The functional role of BMP9 in skeletal system remains to be fully understood, its potent osteogenic activity suggests that it may be used as an efficacious bone regeneration agent. As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is one of the most osteogenic BMPs. Retinoic acid (RA) signaling is known to play an important role in development, differentiation and bone metabolism. We investigate the effect of RA signaling on BMP9-induced osteogenic differentiation of mesenchymal progenitor cells (MPCs)
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