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Importance of NFR2 on osteoclastogenis and its impact on bone metabolism

Grant number: 21/08754-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): October 01, 2021
Effective date (End): September 30, 2023
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Thiago Mattar Cunha
Grantee:Cesar Augusto Speck Hernandez
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID


Bone is a rigid tissue, but it is in continuous remodeling activity, which is essential for the renewal and maintenance of its integrity throughout the individual's life. Bone remodeling is a metabolic process characterized by a precise balance between bone matrix degradation (resorption) and synthesis, which involves the activity of several specialized cells, among which osteoclasts and osteoblasts play a fundamental role. The imbalance between osteoclastic and osteoblastic activities results in changes in bone tissue and, consequently, loss of bone mass. In this context, numerous evidences have shown that Reactive Oxygen Species (ROS) and oxidative stress are associated with the progression of bone diseases. It has been shown that ROS act as an important regulator of the fate and function of osteoblasts and osteoclasts and, consequently, alter bone homeostasis. In this context, understanding the mechanisms that regulate these processes may allow designing therapeutic strategies to control the damage caused by ROS in bone. Physiologically, cells have control mechanisms against the adverse effects of oxidative stress, such as the activation of transcription factors that lead to the induction of genes with antioxidant properties. Among them stands out a gene known as "Nuclear Factor Erythroid 2-Related Factor 2" or NFR2. The importance of this gene in controlling oxidative stress was demonstrated in NFR2 deficient animals that were highly susceptible to the negative impacts of oxidative stress. NFR2 has been described as an important protein in controlling osteoclast differentiation. Therefore, NFR2 is considered a negative regulator of osteoclast differentiation by controlling the oxidative stress produced by ROS production and, consequently, preventing bone destruction. The mechanisms by which NFR2 activity is suppressed during osteoclastogenesis include the induction of KEAP1, a protein that binds to NFR2 and promotes its degradation. Recently a work showed that the post-translational modification of KEAP1 mediated by its O-GlcNacylation promotes the degradation of NFR2. A preliminary result from our laboratory shows that pharmacological inhibition of OGT, the enzyme responsible for O-GlcNacylation, favors the translocation of NFR2 to the nucleus and this correlates with less osteoclast differentiation. In the present project, we will test the hypothesis that these two processes may be related and could explain the mechanism by which RANKL signaling is controlled by NFR2. We will further test the role of NFR2 on mitochondrial metabolism during osteoclast differentiation. In this context, this project will use different methodologies that will allow us to advance in the knowledge of the importance and mechanisms by which NFR2 acts during osteoclast differentiation. Understanding the complexity of mitochondrial metabolic control, and regulation of oxidative activity by NFR2, in addition to understanding their roles on osteoclast formation and activation is a promising field of investigation, which can bring important contributions towards curbing pathological bone destruction. (AU)

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