Investigating the role of the Brain-derived neurotrophic factor (BDNF)-Tropomyosin receptor kinase B (TrkB) axis in the bone disruption and neuropathic pain of Fibrous dysplasia of bone.

Anno
2020
Proponente Mara Riminucci - Professore Ordinario
Sottosettore ERC del proponente del progetto
LS4_1
Componenti gruppo di ricerca
Componente Categoria
Domenico Raimondo Componenti strutturati del gruppo di ricerca
Michele Dello Spedale Venti Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca
Alessandro Corsi Componenti strutturati del gruppo di ricerca
Abstract

Increased osteoclastogenesis and bone resorption are major determinants of clinical morbidity in many human genetic, metabolic and neoplastic skeletal diseases. Fibrous Dysplasia of bone (FD/MAS; OMIM#174800) ) is a severely crippling genetic disorder due to gain-of-function mutations of the GNAS gene that causes bone fractures, deformities and chronic pain, especially in pediatric patients. Excess osteoclast formation and bone remodeling disruption in FD are linked to increased expression of the osteoclastogenic factor RANKL by lesional stromal cells. By using our FD transgenic mouse model, we have previously shown that systemic inhibition of RANKL by an anti-murine RANKL antibody reverts FD lesions to hyper-mineralized, mechanically sound bone and halts the progression of the disease. Although an anti-human RANKL antibody is already available and approved for some specific bone disease, persistent inhibition of RANKL in the entire skeleton may have severe and even life-threatening undesired effects. Recently, we have observed that human FD lesions are characterized by high levels of expression of the Brain Derived Neurotrophic Factor (BDNF). Emerging evidence suggests that BDNF may play a major role in pathological conditions associated with bone remodeling disruption. For example, in Multiple Myeloma (MM) BDNF stimulates osteoclastogenesis both directly and indirectly through stimulation of RANKL expression in osteoprogenitor cells. In addition, BDNF is known to act as a key modulator of pain in MM and other pathological conditions.
In this project, we plan to use our transgenic mouse model a) to investigate the pathogenetic role of BDNF in the increased osteoclastogenesis/bone resorption associated with FD and b) to test the effect of BDNF/TrkB axis inhibition on the establishment and development of FD lesions. The results of this study may provide important informations for the pathogenesis and treatment of FD and of other high-turnover skeletal diseases.

ERC
LS3_12, LS4_8, LS7_4
Keywords:
MALATTIE RARE, ORGANISMI TRANSGENICI, ANATOMIA PATOLOGICA

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