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.
The demonstration that osteoclasts are deeply involved in the establishment, clinical expression (i.e. bone fractures, deformities and pain) and progression of FD lesions has provided a major advance in our understanding of this devastating disease (1). In human FD, as in the mouse model of the disease, the inappropriate osteoclast formation is driven by RANKL and an anti-human RANKL antibody has been already developed and approved by the FDA for the treatment of some skeletal disorders with high bone resorption. However, long term therapies based on complete inhibition of osteoclast formation in the entire skeleton are not advisable, especially in young patients, in which they would prevent the physiological processes of bone growth, modeling and remodeling. Furthermore, sporadic studies in FD patients (2) and our previous work on the FD mouse model (1) have shown that shortly after the discontinuation of the treatment with the anti-RANKL antibody, a severe recurrence of lesions occurs, which may associate with life-threatening hypercalcemia. For this reason, different strategies to inhibit osteoclast formation and/or function must be developed that specifically target the FD tissue. Our preliminary data show that BDNF, which is normally expressed in the bone marrow microenvironment along with its high affinity receptor TrkB (3, 4), is significantly upregulated in the human FD tissue. Based on the reported involvement of BDNF in the increased osteoclastogenesis occurring in Multiple Myeloma (5, 6) our data suggest that this factor could contribute to the abnormal osteoclast formation observed in FD, an effect that could be further increased by its activity as a mediator of angiogenesis (7, 8). Therefore, the studies that we propose in this project may have many important implications for FD patients, in particular for pediatric patients who often show a polyostotic, severely crippling and painful disease. Firstly, they may contribute to elucidate the molecular mechanisms underlying the pathogenesis of the disease. Secondly, they could reveal new potential therapeutic avenues to prevent/control the development of lesions and, possibly, the chronic pain that they cause. Different approaches have already been developed to inhibit the BDNF-TrkB axis in vivo including TrkB inhibitors as K252a (9) and gene silencing of BDNF through short hairpin RNA (shRNA) (10). The availability of a specific transgenic model of the disease will allow us to test their efficacy and to identify the most appropriate conditions of treatment. In addition, it must be noted that BDNF and other neurotrophins are emerging as important regulators of bone cell activities in different contexts and therefore the results of our work may provide important information not only for FD but for bone physiopathology at large.
References:
1) J Bone Miner Res 2019, 34: 2171-2182.
2) J Bone Miner Res 2012, 27:1462-1470.
3) Blood 1993, 81:1726-1738.
4) Am J Pathol 1999, 154:405-415.
5) Int J Cancer 2012, 130:827-836.
6) PLoS One 2012, 7(10):e46287.
7) Clin Cancer Res 2011, 17:3123-3133.
8) Development 2000, 127: 4531-4540.
9) Endocrinology 2010, 151:3006-3014.
10) Int J Cancer 2013, 133:1074-1085.