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Targeting BMP signalling in cardiovascular disease and anaemia.

ABSTRACT: Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonic patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders including heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell-specific and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signalling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, as well as for anaemia of inflammation. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signalling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies.

SUBMITTER: Morrell NW

PROVIDER: S-EPMC4886232 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Targeting BMP signalling in cardiovascular disease and anaemia.

Morrell Nicholas W NW Bloch Donald B DB ten Dijke Peter P Goumans Marie-Jose T H MJ Hata Akiko A Smith Jim J Yu Paul B PB Bloch Kenneth D KD

Nature reviews. Cardiology 20151013 2

Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonic patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders including heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical an ...[more]

PMID: 26461965

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Project description:Bone morphogenetic protein (BMP) signalling has emerged as a fundamental pathway in endothelial cell biology and deregulation of this pathway is implicated in several vascular disorders. BMP signalling output in endothelial cells is highly context- and dose-dependent. Phosphorylation of the BMP intracellular effectors, SMAD1/5/9, is routinely used to monitor BMP signalling activity. To better understand the in vivo context-dependency of BMP-SMAD signalling, we investigated differences in BMP-SMAD transcriptional activity in different vascular beds during mouse embryonic and postnatal stages. For this, we used the BRE::gfp BMP signalling reporter mouse in which the BMP response element (BRE) from the ID1-promotor, a SMAD1/5/9 target gene, drives the expression of GFP.A mosaic pattern of GFP was present in various angiogenic sprouting plexuses and in endocardium of cardiac cushions and trabeculae in the heart. High calibre veins seemed to be more BRE::gfp transcriptionally active than arteries, and ubiquitous activity was present in embryonic lymphatic vasculature. Postnatal lymphatic vessels showed however only discrete micro-domains of transcriptional activity. Dynamic shifts in transcriptional activity were also observed in the endocardium of the developing heart, with a general decrease in activity over time. Surprisingly, proliferative endothelial cells were almost never GFP-positive. Patches of transcriptional activity seemed to correlate with vasculature undergoing hemodynamic alterations.The BRE::gfp mouse allows to investigate selective context-dependent aspects of BMP-SMAD signalling. Our data reveals the highly dynamic nature of BMP-SMAD mediated transcriptional regulation in time and space throughout the vascular tree, supporting that BMP-SMAD signalling can be a source of phenotypic diversity in some, but not all, healthy endothelium. This knowledge can provide insight in vascular bed or organ-specific diseases and phenotypic heterogeneity within an endothelial cell population.

Project description:From the 33,000 men in the U.S. who die from prostate cancer each year, the majority of these patients exhibit metastatic disease with bone being the most common site of metastasis. Prostate cancer bone metastases are commonly blastic, exhibiting new growth of unhealthy sclerotic bone, which can cause painful skeletal related events. Patient's current care entails androgen deprivation therapy, anti-resorptive agents, radiation, and chemotherapy to help control the spread of the cancer but little intervention is available to treat blastic bone disease. The transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) pathways are known to regulate bone growth and resorption of destructive lytic bone lesions, yet the role of TGFβ/BMP signaling in prostate cancer blastic vs lytic bone lesions are not fully understood. We hypothesized that to target the BMP/TGFβ pathway, a useful biomarker of bone lytic or blastic pathology would have superior response. We show distinct BMP vs. TGFβ signaling in clinical samples of human prostate cancer bone metastases with either lytic or blastic pathologies. BMPs exhibit distinct effects on bone homeostasis, so to examine the effect of BMP inhibition on healthy bone, we treated mice with the BMP receptor small molecule antagonist DMH1 and saw a modest temporary improvement in bone health, with increased trabecular bone. We next sought to use the BMP inhibitor DMH1 to treat bone metastasis engraftment seeded by a caudal artery injection of the lytic human prostate cell line PC3 in immunodeficient mice. The colonization by PC3 cells to the bone were restricted with DMH1 treatment and bone health was importantly preserved. We next proceeded to test BMP inhibition in an injury model of established bone metastasis via intratibial injection of the MYC-CaP mouse prostate cell line into FVBN syngeneic mice. DMH1 treated mice had a modest decrease in trabecular bone and reduced lymphocytes in circulation without affecting tumor growth. Taken together we show unique responses to BMP inhibition in metastatic prostate cancer in the bone. These studies suggest that profiling bone lesions in metastatic prostate cancer can help identify therapeutic targets that not only treat the metastatic tumor but also address the need to better treat the distinct tumor induced bone disease.

Dataset Information

Targeting BMP signalling in cardiovascular disease and anaemia.

Publications

Targeting BMP signalling in cardiovascular disease and anaemia.

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