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Hypertrophy is induced during the in vitro chondrogenic differentiation of human mesenchymal stem cells by bone morphogenetic protein-2 and bone morphogenetic protein-4 gene transfer
Arthritis Research & Therapy, 10/07/09

Steinert AF et al. – BMP-2 and BMP-4 were equally effective in provoking chondrogenesis by primary human MSCs in pellet culture. However, chondrogenesis triggered by BMP-2 and BMP-4 gene transfer showed considerable evidence of hypertrophic differentiation, with the cells resembling growth plate chondrocytes both morphologically and functionally. This suggests caution when using these candidate genes in cartilage repair.

• Adenoviral vectors carrying cDNA encoding human BMP-4 (Ad.BMP-4) constructed by cre-lox combination and compared to previously generated adenoviral vectors for BMP-2 (Ad.BMP-2), green fluorescent protein (Ad.GFP), or firefly luciferase (Ad.Luc)
• Cultures of human bone-marrow derived MSCs infected with 5 x 102 viral particles/cell of Ad.BMP-2, or Ad.BMP-4, seeded into aggregates and cultured for three weeks in defined, serum-free medium
• Untransduced cells or cultures transduced with marker genes served as controls
• Expression of BMP-2 and BMP-4 determined by ELISA, and aggregates were analyzed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy
  Results
  • Levels of BMP-2 and BMP-4 in media initially 30 to 60 ng/mL and declined thereafter
  • BMP-4 and BMP-2 genes equipotent inducers of chondrogenesis in primary MSCs as judged by lacuna formation, strong staining for proteoglycans and collagen type II, increased levels of GAG synthesis, and expression of mRNAs associated with chondrocyte phenotype
  • BMP-4 modified aggregates showed lower tendency to progress towards hypertrophy, as judged by expression of alkaline phosphatase, annexin 5, immunohistochemical staining for type X collagen protein, and lacunar size

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