Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair

Abstract

The extracellular matrix-associated bone morphogenetic proteins (BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their potentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell (MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted cell-type lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.

Keywords: Bone morphogenetic protein; Bone repair; Cartilage; Mesenchymal stem cells.

Figure 1

Canonical and non-canonical bone morphogenetic protein signal transduction. A: BMP canonical pathway: Upon type I and type II receptor dimerization the R-Smads 1, 5 and 8 can be phosphorylated by activated type I receptor leading to coupling with the common R-Smad4 coactivator. The heterodimers then translocate to the nucleus promoting expression of target genes; B: BMP non canonical pathways: activation of type I and type II receptors after dimerization can lead to stimulation of various intracellular transduction signals other than the R-Smads dependent ones. From left to right: Activation of the PKC/RhoA pathway through par6 recruitment by type I activated receptor; activation of the PI3K/AKT pathway through direct PI3K phosphorylation by activated type II receptor; activation of JNK/p38 pathway through TRAF6/TAK1 recruitment by activated type II receptor and finally activation of the MAPK/ERK pathway through Shc/Grb2/Sos/Ras recruitment by type II activated receptor. BMP: Bone morphogenetic protein; Par6: Partitioning defective protein 6; PKC: Protein kinase C; PI3K: Phosphoinositide-3 kinase; AKT: V-akt murine thymoma viral oncogene homolog 1; TRAF6: TNF receptor associated factor 6; TAK1: TGF-beta activated kinase 1; JNK: C-Jun N-terminal kinase; Shc: Src homology 2 domain containing; Grb2: Growth factor receptor bound protein 2; Sos: Son-of-sevenless; RAS: Rat sarcoma viral oncogene homolog; MAPK: Mitogen activated protein kinase.