Study of kinin B1 receptor in osteogenic differentiation induced by recombinant BMP-2 and analysis of the role of this receptor in fibrodysplasia ossificans progressiva (FOP)

• Grant number: 15/05433-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2015
• End date: November 30, 2019
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: João Bosco Pesquero
• Grantee: Marina Rodrigues e Silva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Bone is a dynamic tissue, constantly refurbished, which depends on several factors to maintain the balance between bone formation and resorption. Damage on this tissue is a serious public health problem. Bone tissue is affected by several injuries, including congenital factors, metabolic diseases as well as factors external such as fractures. The Fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by progressive heterotopic ossification is one example about congenital factor. Recently it was demonstrated that ossification are due to increased expression of BMP-2 and BMP-4, a member of the bone morphogenetic proteins (BMPs). The related episodes inflammation have acute events that initiate ectopic ossification. All these commitments arouse great interest in the search for a mechanism able to repair bone injured. There are many mediators involved in the differentiation process osteogenic that seek to repair and form bone tissue, some of these mediators are the Bone morphogenetic proteins (BMPs). In addition to these, some systems are being related to the bone differentiation process such as kallikrein-kinin system. This system has been associated with the destruction of bone matrix, however, little is known yet on the true role of the various components of the system in this pathological process. Current data indicate the involvement of the kallikrein-kinin system bone metabolism which several animal models of bone disease show changes often accompanied by elevated levels of inflammatory mediators such as RANKL IL-1² and TNF-±. These mediators known to act on receptors expression of kallikrein-kinin system that is part of the cell signaling involved in FOP. The objective of this project is evaluate the functional viability of BMP-2 protein recombinant ever produced; evaluate the role of kinin B1 receptor in osteogenesis in vitro assays and in vivo using animal model of FOP injection exogenous rBMP-2 / Matrigel in knockout animals for the B1 receptor. Based on these results, pharmacological blockade of kinin receptors can become a modality interesting therapy. In addition, the main goal is to develop a therapy in which formation bone is modulated inflammation of bone tissue. Creating models animal FOP from the knockout mice to kinin receptors allow us clarify the role of inflammation in ectopic bone formation, found in this disease.Thus, with the generated models, it is possible to evaluate the role of kinins in osteogenesis mediated BMP-2.