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Abstract
BackgroundOsteoblasts are considered to primarily arise from osseous progenitors within the periosteum or bone marrow. We have speculated that cells from local soft tissues may also take on an osteogenic phenotype. Myoblasts are known to adopt a bone gene program upon treatment with the osteogenic bone morphogenetic proteins (BMP-2,-4,-6,-7,-9), but their osteogenic capacity relative to other progenitor types is unclear. We further hypothesized that the sensitivity of cells to BMP-2 would correlate with BMP receptor expression.MethodsWe directly compared the BMP-2 sensitivity of myoblastic murine cell lines and primary cells with osteoprogenitors from osseous tissues and fibroblasts. Fibroblasts forced to undergo myogenic conversion by transduction with a MyoD-expressing lentiviral vector (LV-MyoD) were also examined. Outcome measures included alkaline phosphatase expression, matrix mineralization, and expression of osteogenic genes (alkaline phosphatase, osteocalcin and bone morphogenetic protein receptor-1A) as measured by quantitative PCR.ResultsBMP-2 induced a rapid and robust osteogenic response in myoblasts and osteoprogenitors, but not in fibroblasts. Myoblasts and osteoprogenitors grown in osteogenic media rapidly upregulated Bmpr-1a expression. Chronic BMP-2 treatment resulted in peak Bmpr-1a expression at day 6 before declining, suggestive of a negative feedback mechanism. In contrast, fibroblasts expressed low levels of Bmpr-1a that was only weakly up-regulated by BMP-2 treatment. Bioinformatics analysis confirmed the presence of myogenic responsive elements in the proximal promoter region of human and murine BMPR-1A/Bmpr-1a. Forced myogenic gene expression in fibroblasts was associated with a significant increase in Bmpr-1a expression and a synergistic increase in the osteogenic response to BMP-2.ConclusionThese data demonstrate the osteogenic sensitivity of muscle progenitors and provide a mechanistic insight into the variable response of different cell lineages to BMP-2.
Highlights
Osteoblasts are considered to primarily arise from osseous progenitors within the periosteum or bone marrow
This study aimed to address whether the capacity of progenitors for osteogenic conversion correlates with the expression of BMP receptors (BMPRs), and if forced myogenesis could affect BMPR expression and bone morphogenetic protein (BMP) sensitivity in fibroblasts
BMP-2 stimulates osteogenesis in myoblastic but not fibroblastic cell lines The C2C12 and NIH/3T3 cell lines were used to examine the capacity of myoblasts and fibroblasts to undergo BMP-induced osteogenic differentiation respectively
Summary
Osteoblasts are considered to primarily arise from osseous progenitors within the periosteum or bone marrow. The conventional view of bone cell differentiation is that pluripotent or multi-potent stem cells commit to an osteoprogenitor lineage and undergo a smooth, consistent, and well defined transition to produce differentiated osteoblasts. The processes of osteoprogenitor commitment and osteoblast differentiation are both facilitated by members of the bone morphogenetic protein (BMP) protein family [2]. BMP homodimers and heterodimers bind to BMP receptors (BMPRs) on the cell surface that can transduce the concentrations of extracellular BMPs into specific changes in gene expression [3]. While the expression of BMPs in bone development and repair are well described [7,8], the potential for lineage-specific control of BMP signaling by regulating BMPR expression levels has not been explored in detail
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