Osteoinduction within adipose tissue fragments by heterodimeric bone morphogenetic Proteins-2/6 and -2/7 versus homodimeric bone morphogenetic protein-2: Therapeutic implications for bone regeneration

J Gene Med. 2021 Mar;23(3):e3311. doi: 10.1002/jgm.3311. Epub 2021 Feb 1.

Abstract

Background: Fragments of subcutaneous adipose tissue that have been genetically modified to express bone morphogenetic protein-2 (BMP-2) regenerate large segmental osseous lesions in rodents. Gene-activated adipose tissue can be implanted into osseous defects without prior cell extraction and cell culture. The present study aimed to explore whether the heterodimers BMP-2/6 or BMP-2/7 exceed the osteoinductive effect of BMP-2 on adipose tissue.

Methods: In an in vitro tissue culture system, freshly harvested rat subcutaneous adipose tissue was cultivated in the presence of either BMP-2 or BMP-2/6 or BMP-2/7 at a high (200 ng/ml) and low (50 ng/ml) concentration. Gene expression analysis as well as histological and immunohistochemical methods were applied to test for osteoinduction.

Results: A concentration of 200 ng/ml of homodimeric BMP-2 induced osteogenic differentiation most potently, showing more calcification and a higher expression level of bone markers than both concentrations of BMP-2/6 or -2/7. A concentration of 50 ng/ml of BMP-2 was a significantly stronger osteogenic inducer than both concentrations of BMP-2/6 and the low concentration of BMP-2/7. The most potent heterodimeric driver of osteoinduction was BMP-2/7 at a high concentration, demonstrating effects similar to those of BMP-2 at a low concentration.

Conclusions: Homodimeric BMP-2 evoked osteoinduction within adipose tissue more potently and at a lower concentration than heterodimeric BMP-2/6 or BMP-2/7. This result agrees well with the fact that it might be easier to translate adipose grafts activated by homodimeric BMP-2 clinically. Preclinical in vivo gene transfer studies are necessary to confirm the results of the present study.

Keywords: BMPs; adipose tissue; bone healing; gene transfer; heterodimers; osteoinduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bone Morphogenetic Protein 2 / pharmacology*
  • Bone Morphogenetic Protein 6 / pharmacology*
  • Bone Morphogenetic Protein 7 / pharmacology*
  • Bone Regeneration / drug effects*
  • Gene Expression / drug effects
  • Humans
  • Male
  • Osteogenesis / drug effects*
  • Rats
  • Rats, Inbred F344
  • Recombinant Proteins / pharmacology
  • Subcutaneous Fat / drug effects*
  • Subcutaneous Fat / metabolism*
  • Tissue Culture Techniques

Substances

  • BMP2 protein, human
  • BMP6 protein, human
  • BMP7 protein, human
  • Biomarkers
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Protein 7
  • Recombinant Proteins