Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists

Abstract

The BMPs (bone morphogenetic proteins) and the GDFs (growth and differentiation factors) together form a single family of cystine-knot cytokines, sharing the characteristic fold of the TGFbeta (transforming growth factor-beta) superfamily. Besides the ability to induce bone formation, which gave the BMPs their name, the BMP/GDFs display morphogenetic activities in the development of a wide range of tissues. BMP/GDF homo- and hetero-dimers interact with combinations of type I and type II receptor dimers to produce multiple possible signalling complexes, leading to the activation of one of two competing sets of SMAD transcription factors. BMP/GDFs have highly specific and localized functions. These are regulated in a number of ways, including the developmental restriction of BMP/GDF expression and through the secretion of several specific BMP antagonist proteins that bind with high affinity to the cytokines. Curiously, a number of these antagonists are also members of the TGF-beta superfamily. Finally a number of both the BMP/GDFs and their antagonists interact with the heparan sulphate side chains of cell-surface and extracellular-matrix proteoglycans.

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

“…Differential BMP-mediated pSmad1/5/8 signalling and Gremlin1 inhibition in kidney epithelial cells BMP binding to heterotetrameric type I/II receptor complexes leads to Smad1/5/8 phosphorylation, dimerization with co-Smad4, nuclear translocation and transcriptional activation [2]. To validate the SPR and MST protein interaction data in a cell culture system, human kidney proximal tubule epithelial cells (HK-2) were incubated with increasing concentrations of rhBMPs (BMP-2; 0.5 ng/ml-10 ng/ml, (39-790 pM), BMP-4; 0.5 ng/ml-10 ng/ml, (39-780 pM) or BMP-7; 5-50 ng/ml (325 pM-3.25 nM)).…”

“…To date, however, efforts to translate these data into BMP-7-centred treatment of fibrosis have been rather slow to develop [18,19] Canonical BMPs signalling involves the Smad pathway, where BMP dimers bind to type I and type II BMP receptors leading to the formation of a hexameric complex, triggering receptor phosphorylation. This leads to phosphorylation of R-Smads (Smad1/5/8) and complex formation with co-Smad4 which translocates to the nucleus to regulate BMP target gene expression [1,2]. BMP target genes include inhibitor of differentiation (Id 1-3) genes and inhibitory Smad 6 [1,2].…”

“…BMP target genes include inhibitor of differentiation (Id 1-3) genes and inhibitory Smad 6 [1,2]. BMP signalling is regulated on multiple levels: intracellularly by inhibitory Smads (Smad 6, 7), miRNAs, methylation and extracellularly by pseudoreceptors such as BAMBI and BMP antagonists including Gremlin (Grem1), Nogginand twisted gastrulation 1 (Twsg 1) [1,2,20].…”

“…BMPs were originally identified for their ability to induce bone formation in vivo via osteoblast differentiation [2,3]. BMPs have a key function in morphogenesis, general organogenesis, cartilage and limb formation, as well as cell proliferation, differentiation and apoptosis [1,[3][4][5].…”

Cellular and Molecular Mechanisms of Chronic Inflammation-Associated Organ Fibrosis

“…Bone morphogenic proteins (BMPs) belong to the TGFβ family and regulate proliferation and differentiation of both mesenchymal cells and epithelial cells (Rider and Mulloy, 2010). Recent studies have revealed that BMP7 prevents fibrosis by promoting epithelial regeneration, while BMP antagonists such as gremlin and ectodin drive organ fibrosis by inhibiting BMP7 signaling.…”