Thesis presented October 11, 2012
Abstract:
The Bone Morphogenetic Proteins (BMPs) play an important role in many pathophysiological processes, particularly in angiogenesis. The development of sensitive and specific detection methods could be useful for potential clinical applications. This work focuses on BMP9, a molecule recently identified by our team as the physiological and specific ligand of the orphan receptor Activin Receptor-Like Kinase 1 (ALK1). BMP9 is a circulating vascular quiescence factor. These observations have allowed us to propose that BMP9 blood concentration could be a biomarker of the activation state of the vascular endothelium. To validate this hypothesis, three objectives were defined: 1 / Develop a sensitive and specific assay of circulating BMP9, 2 / characterize expression sites and circulating forms of BMP9 and 3 / evaluate the relevance of BMP9 as a biomarker for physiological and pathological angiogenesis, in particular tumor. The first part of my thesis was to develop two assays. The first is a biological method, based on the use of a reporter gene under the control of the promoter BMP Responsive Element (BRE) which responds to the activation of the BMPs. The second method is based on a "sandwich"-type immunoassay. The characteristics of these methods have been established. In a second step, using these tools, we have shown that BMP9 is a protein produced mainly by hepatocytes and circulates predominantly in an active form complexed to its pro-domain. An inactive form homo-dimeric uncleaved is also synthesized. This work also confirms the role of BMP9 in the quiescence of vascular endothelium. In the last part of this work, the rate of BMP9 was measured in biological fluids of the patient (s) with various pathophysiological situations. An increase in the blood concentration of BMP9 is observed shortly before delivery and in preeclamptic patients higher rates of BMP9 were also observed, opening perspectives in obstetrics. In tumoral pathology, our observations show that BMP9 has no value as diagnostic or prognostic marker. However, the data collected in medullary carcinoma of the thyroid treated by vandetanib suggest that the measurement of circulating BMP9 rates could have a predictive value for the efficacy of treatment. So, the use of the BMP9 assay as a predictive marker or pharmacodynamic marker of anti-angiogenic therapies should be considered. Indeed, at present, the therapeutic index of anti-angiogenic treatments could be improved if it were possible to identify and validate biomarkers that may predict early clinical efficacy or the development of resistance to treatment. This perspective appears particularly interesting since two molecules targeting the signaling pathway Alk1 have recently been developed and show promising results, especially in patients with resistance to anti-VEGF
Keywords:
BMP9, angiogenesis, ALK1