New insights into BMP-7 mediated osteoblastic differentiation of primary human mesenchymal stem cells

Karen Lavery, Sara Hawley, Pamela Swain, Robert Rooney, Dean Falb, Moulay Hicham Alaoui-Ismaili

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Bone Morphogenetic Proteins (BMPs) are members of the TGF-β superfamily of growth factors. Several BMPs exhibit osteoinductive bioactivities, and are critical for bone formation in both developing and mature skeletal systems. BMP-7 (OP-1) is currently used clinically in revision of posterolateral spine fusions and long bone non-unions. The current study characterizes BMP-7 induced gene expression during early osteoblastic differentiation of human mesenchymal stem cells (hMSC). Primary hMSC were treated with BMP-7 for 24 or 120 h and gene expression across the entire human genome was evaluated using Affymetrix HG-U133 Plus 2.0 Arrays. 955 probe sets representing 655 genes and 95 ESTs were identified as differentially expressed and were organized into three major expression profiles (Profiles A, B and C) by hierarchical clustering. Genes from each profile were classified according to biochemical pathway analyses. Profile A, representing genes upregulated by BMP-7, revealed strong enrichment for established osteogenic marker genes, as well as several genes with undefined roles in osteoblast function, including MFI2, HAS3, ADAMTS9, HEY1, DIO2 and FGFR3. A functional screen using siRNA suggested roles for MFI2, HEY1 and DIO2 in osteoblastic differentiation of hMSC. Profile B contained genes transiently downregulated by BMP-7, including numerous genes associated with cell cycle regulation. Follow-up studies confirmed that BMP-7 attenuates cell cycle progression and cell proliferation during early osteoblastic differentiation. Profile C, comprised of genes continuously downregulated by BMP-7, exhibited strong enrichment for genes associated with chemokine/cytokine activity. Inhibitory effects of BMP-7 on cytokine secretion were verified by analysis of enriched culture media. Potent downregulation of CHI3L1, a potential biomarker for numerous joint diseases, was also observed in Profile C. A focused evaluation of BMP, GDF and BMP inhibitor expression elucidated feedback loops modulating BMP-7 bioactivity. BMP-7 was found to induce BMP-2 and downregulate GDF5 expression. Transient knockdown of BMP-2 using siRNA demonstrated that osteoinductive properties associated with BMP-7 are independent of endogenous BMP-2 expression. Noggin was identified as the predominant inhibitor induced by BMP-7 treatment. Overall, this study provides new insight into key bioactivities characterizing early BMP-7 mediated osteoblastic differentiation.

Original languageEnglish (US)
Pages (from-to)27-41
Number of pages15
JournalBone
Volume45
Issue number1
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

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Bone Morphogenetic Protein 7
Mesenchymal Stromal Cells
Bone Morphogenetic Proteins
Genes
Bone Morphogenetic Protein 2
Down-Regulation
Small Interfering RNA
Cell Cycle
Cytokines
Gene Expression
Joint Diseases
Expressed Sequence Tags
Human Genome
Osteoblasts
Chemokines
Osteogenesis

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

New insights into BMP-7 mediated osteoblastic differentiation of primary human mesenchymal stem cells. / Lavery, Karen; Hawley, Sara; Swain, Pamela; Rooney, Robert; Falb, Dean; Alaoui-Ismaili, Moulay Hicham.

In: Bone, Vol. 45, No. 1, 01.07.2009, p. 27-41.

Research output: Contribution to journalArticle

Lavery, Karen ; Hawley, Sara ; Swain, Pamela ; Rooney, Robert ; Falb, Dean ; Alaoui-Ismaili, Moulay Hicham. / New insights into BMP-7 mediated osteoblastic differentiation of primary human mesenchymal stem cells. In: Bone. 2009 ; Vol. 45, No. 1. pp. 27-41.
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