Enhanced osteogenesis of adipose derived stem cells with Noggin suppression and delivery of BMP-2

PLoS One. 2013 Aug 15;8(8):e72474. doi: 10.1371/journal.pone.0072474. eCollection 2013.

Abstract

Bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors. However, BMPs are highly pleiotropic molecules and their supra-physiological high dose requirement leads to adverse side effects and inefficient bone formation. Thus, there is a need to develop alternative osteoinductive growth factor strategies that can effectively complement BMP activity. In this study, we intrinsically stimulated BMP signaling in adipose derived stem cells (ASCs) by downregulating noggin, a potent BMP antagonist, using an RNAi strategy. ASCs transduced with noggin shRNA significantly enhanced osteogenic differentiation of cells. The potency of endogenous BMPs was subsequently enhanced by stimulating ASCs with exogenous BMPs at a significantly reduced dose. The level of mineralization in noggin shRNA treated ASCs when treated with BMP-2 was comparable to that of control shRNA treated cell treated with 10-fold more BMP-2. The complementary strategy of noggin suppression + BMP-2 to enhance osteogenesis was further confirmed in 3D in vitro environments using scaffolds consisting of chitosan (CH), chondroitin sulfate (CS), and apatite layer on their surfaces designed to slowly release BMP-2. This finding supports the novel therapeutic potential of this complementary strategy in bone regeneration.

Publication types

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

MeSH terms

  • Adipose Tissue / cytology*
  • Alkaline Phosphatase / metabolism
  • Animals
  • Bone Morphogenetic Protein 2 / pharmacology*
  • Calcification, Physiologic / drug effects
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Chitosan / pharmacology
  • Chondroitin Sulfates / pharmacology
  • Collagen / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Mice, Inbred C57BL
  • Osteogenesis / drug effects*
  • Osteogenesis / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Proteins / pharmacology
  • Stem Cells / cytology
  • Stem Cells / enzymology
  • Stem Cells / metabolism*
  • Stem Cells / ultrastructure
  • Tissue Scaffolds
  • Transduction, Genetic
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Bone Morphogenetic Protein 2
  • Carrier Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • recombinant human bone morphogenetic protein-2
  • noggin protein
  • Chondroitin Sulfates
  • Collagen
  • Chitosan
  • Alkaline Phosphatase