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

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.

Adipose tissue in bone regeneration - stem cell source and beyond

“…In an in vitro study, genetically modified fragmented WAT overexpressing BMP-2 was shown to undergo mineralization in osteoinductive conditions[ 157 ]. The same team reported that the homodimer BMP-2 induced increased mineralization at lower doses compared to heterodimer BMP-2/6 or BMP-2/7; however, these findings need to be confirmed by in vivo studies[ 158 ]. WAT has been considered a modality to deliver micro vascular grafts to healing bone defects to prevent atrophic nonunions.…”

Osteogenic Differentiation of Human Adipose-Derived Stem Cells Seeded on a Biomimetic Spongiosa-like Scaffold: Bone Morphogenetic Protein-2 Delivery by Overexpressing Fascia

“…Therefore, in order to develop safe, expedited, single-surgery gene therapy approaches, our group has been working with gene activated autologous tissue grafts [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. The genetic modification of such tissue grafts can be accomplished within one hour or less, enabling surgeons to re-implant the grafts within the same surgical procedure.…”