Molecular mechanisms of FGF-2 inhibitory activity in the osteogenic context of mouse adipose-derived stem cells (mASCs)

Bone. 2008 Jun;42(6):1040-52. doi: 10.1016/j.bone.2008.01.026. Epub 2008 Feb 20.

Abstract

Adipose-derived adult stem cells (ASCs), like their bone-marrow derived counterparts, possess the ability to differentiate down osteogenic, chondrogenic, adipogenic, and myogenic pathways. For bone differentiation of mouse ASCs (mASCs), retinoic-acid mediated upregulation of BMPR-IB has been found to be necessary. Interestingly, our previous work has also shown Fibroblast Growth Factor-2 (FGF-2) to strongly inhibit this osteogenic differentiation, even in the presence of retinoic acid. In this report, we investigated the molecular mechanisms underlying FGF-2 mediated osteogenic inhibition, demonstrating that addition of exogenous FGF-2 to mASCs antagonizes upregulation of BMPR-IB gene expression in response to retinoic acid. In addition, constitutive expression of BMPR-IB, but not BMPR-IA or BMPR-II, was found to counteract the inhibitory effects of FGF-2. Finally, p53(-/-) mASCs and human ASCs, both of which express high levels of endogenous BMPR-IB, underwent normal osteogenic differentiation even in the presence of FGF-2. Collectively, our data therefore indicate that FGF-2 antagonizes the response of mASCs to retinoic acid and also suggest that threshold levels of BMPR-IB may play a crucial role both in counteracting the inhibitory role of FGF-2 and in promoting osteogenic differentiation of ASCs in the absence of retinoic acid. Moreover, the present study also indicates that differences exist between mouse and human ASCs in relationship to FGF-2 activity in the osteogenic context.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology*
  • Animals
  • Antineoplastic Agents / metabolism
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Fibroblast Growth Factor 2 / metabolism*
  • Gene Expression
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Osteogenesis / physiology*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Stem Cells / cytology
  • Stem Cells / physiology*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Tretinoin / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • BMP2 protein, human
  • BMP4 protein, human
  • Bmp2 protein, mouse
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • RNA, Small Interfering
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Fibroblast Growth Factor 2
  • Tretinoin
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II