BMP antagonists in tissue development and disease

Abstract

Bone morphogenic proteins (BMPs) are important growth regulators in embryogenesis and postnatal homeostasis. Their tight regulation is crucial for successful embryonic development as well as tissue homeostasis in the adult organism. BMP inhibition by natural extracellular biologic antagonists represents the most intensively studied mechanistic concept of BMP growth factor regulation. It was shown to be critical for numerous developmental programs, including germ layer specification and spatiotemporal gradients required for the establishment of the dorsal-ventral axis and organ formation. The importance of BMP antagonists for extracellular matrix homeostasis is illustrated by the numerous human connective tissue disorders caused by their mutational inactivation. Here, we will focus on the known functional interactions targeting BMP antagonists to the ECM and discuss how these interactions influence BMP antagonist activity. Moreover, we will provide an overview about the current concepts and investigated molecular mechanisms modulating BMP inhibitor function in the context of development and disease.

Keywords: ALK3, anaplastic lymphoma kinase 3; ATF2, activating transcription factor 2; ActR, activin receptor; BDB2, brachydactyly type B2; BISC, BMP-induced signalling complex; BMP antagonists; BMPER, BMP binding endothelial regulator; BMPs, bone morphogenetic proteins; Bone morphogenetic protein (BMP); CAN, cerberus and DAN; CDD, craniodiaphyseal dysplasia; CHRD domain, chordin specific domain; CUB domain, for complement C1r/C1s, Uegf, Bmp1 domain; Connective tissue disorder; Cv2, crossveinless-2; DAN, differential screening selected gene aberrative in neuroblastoma; DSD, diaphanospondylodysostosis; Dpp, decapentaplegic; ECM, extracellular matrix; ERK, extracellular signal-regulated kinases; Extracellular matrix (ECM); FMF, fibrillin microfibrils; HS, heparan sulphate; HSPGs, heparan sulphate proteoglycans; MAPKs, mitogen-activated protein kinases; MGC1, megalocornea 1; PI3K, phosphoinositide 3-kinase; PRDC, protein related to DAN and Cerberus; SOST, sclerostin; SYNS1, multiple synostoses syndrome 1; Scw, screw; Sog, short gastrulation; TCC, tarsal-carpal coalition syndrome; TGF-β, transforming growth factor- β; Tld, tolloid; Tsg, twisted gastrulation; VBCH, Van Buchem disease; Xlr/Tll, xolloid-related metalloprotease; vWC, von Willebrand factor type C; vWD, von Willebrand factor type D.

Fig. 1

Concepts to control BMP signalling: BMP growth factor and antagonist diffusion versus ECM-dependent spatio-temporal control. In early embryonic tissue, ECM production is minor, so that diffusion of BMP growth factors (GFs) and inhibitors in opposite directions is a plausible concept. By ventral expression of BMP inhibitors and dorsal expression of BMP GFs and their diffusion in opposing directions a gradient is formed, which determines the cell fate in a concentration-dependent manner. In postnatal tissues, the presence of the ECM is more pronounced. Pure gradient diffusion as explanation for BMP GFs and inhibitors to reach their place of action is therefore an insufficient model. Instead, spatio-temporal control might take place to target, locally concentrate and release BMP GFs and antagonists when needed. Several diseases have been implicated in this context. SOST mutations can lead to hyperostosis of e.g. the skull and diaphyseal cortices of the long bones. Impaired complexation of BMP GFs by chordin can result in disrupted mesoderm development, body axes malformation and craniofacial defects. In postnatal tissue, increased levels of gremlin have been associated with pulmonary fibrosis and diabetic nephropathy. Upon renal injury, chordin-like 1 was found to be upregulated. In epithelial cell cancers, BMPs are involved in proliferation, migration, and invasion.

Fig. 2

BMP antagonists and their implications in diseases. A. Phenogram of BMP antagonists based on sequence similarity adapted from Brazil et al 2015. B. Domain structure of chordin family members. Von Willebrand factor type C (vWC) domains are represented as orange ovals. Chordin specific domains are illustrated as blue rectangles, the von Willebrand factor type D domain is depicted as a green rectangle and the brown rectangle represents the TIL-domain of Cv2/BMPER. C: Domain structure of CAN family members. The purple box illustrates the relative size and position of the DAN domain in each protein. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Mechanism of BMP inhibition and release by chordin. A: Chordin binds BMP via its first and third von Willebrand factor type C (vWC) domains (orange). Likely, chordin is bound to matrix components such as BMPER, integrins or collagen IV (brown) in this process. B: Upon binding of twisted gastrulation (Tsg) to chordin, a conformational change is induced, making chordin more susceptible to cleavage by tolloid proteases. C: Tolloid cleavage of the fourth vWC domain leaves the inhibitory function of chordin intact. Tsg strengthens the remaining inhibitory complex. D: Tolloid cleavage of the first vWC domain mediates release of the BMP growth factor, which in turn can bind to a BMP receptor, activating intracellular BMP signalling. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)