Bone Morphogenetic Protein (BMP) signaling in development and human diseases

Abstract

Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis. Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects, highlighting the essential functions of BMPs. In this review, we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development. A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling.

Keywords: BMP signaling; Development; Genetics; Mouse knockout; Pathogenesis; Signal transduction.

Figure 1

BMP Family and Signaling Pathways. (A) Phylogenetic analysis of the human BMP family members. The human BMP full-length precursor protein sequences and coding region sequences were analyzed using Phylogeny.fr. The branch length is proportional to the number of substitutions per site. (a) Phylogenetic analysis was performed using the amino acid sequence of human BMPs. (b) Phylogenetic analysis was carried out using the coding region of human BMPs. (B) BMPs signal via the canonical, Smad-dependent pathway or various non-canonical pathways. In the canonical pathway, BMPs initiate the signal transduction cascade by binding to type I or type II serine/threonine kinase receptors and forming a heterotetrameric complex. The constitutively active type II receptor then transphosphorylates the type I receptor, and the type I receptor phosphorylates the R-Smads (Smad1/5/8). Phosphorylated Smad1/5/8 associates with the co-Smad (Smad4), and the complex translocates to the nucleus where it further associates with coactivators or corepressors to regulate gene expression. Various non-canonical pathways, including the MAPK cascade, can also lead to regulation of gene expression. BMP signaling is modulated extracellularly (e.g., Noggin), intracellularly (e.g., FKBP12, microRNAs, phosphatases, and I-Smads), and by co-receptors in the plasma membrane (e.g., Endoglin).

Figure 2

Representative members of the BMP signaling pathway that have been demonstrated to cause or be associated with human diseases. The mutations associated with human pathologies may be gain-of-function or loss-of-function. In some instances, higher or lower gene expression is correlated with disease. Because BMP signaling is involved in multiple organ systems, there are associated pathologies with most organ systems. Abbreviations: LOF, loss-of-function; GOF: gain-of-function; CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; FOP, fibrodysplasia ossificans progressiva; OI, osteogenesis imperfecta; OA, osteoarthritis; A–M, anophthalmia–microphthalmia; PAH, pulmonary arterial hypertension; HHT, hereditary hemorrhagic telangiectasia; BE, Barrett esophagus; JP, juvenile polyposis.