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Brain derived neurotrophic factor (BDNF) is a neurotrophin, expressed in the central nervous system and in peripheral tissues, that is regulated by the Gsα/cAMP pathway. In bone, it regulates osteogenesis and stimulates RANKL secretion and osteoclast formation in osteolytic tumors such as Multiple Myeloma. Fibrous dysplasia (FD) of bone is a rare genetic disease of the skeleton caused by gain-of-function mutations of the Gsα gene in which RANKL-dependent enhanced bone resorption is a major cause of bone fragility and clinical morbidity. We observed that BDNF transcripts are expressed in human FD lesions. Specifically, immunolocalization studies performed on biopsies obtained from FD patients revealed the expression of BDNF in osteoblasts and, to a lower extent, in the spindle-shaped cells within the fibrous tissue. Therefore, we hypothesized that BDNF can play a role in the pathogenesis of FD by stimulating RANKL secretion and bone resorption. To test this hypothesis, we used the EF1α-Gsα R201C mouse model of the human disease (FD mice). Western blot analysis revealed a higher expression of BDNF in bone segments of FD mice compared to WT mice and the immunolabeling pattern within mouse FD lesions was similar to that observed in human FD. Treatment of FD mice with a monoclonal antibody against BDNF reduced the fibrous tissue along with the number of osteoclasts and osteoblasts within femoral lesions. These results reveal BDNF as a new player in the pathogenesis of FD and a potential molecular mechanism by which osteoclastogenesis may be nourished within FD bone lesions. They also suggest that BDNF inhibition may be a new approach to reduce abnormal bone remodeling in FD., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aerobic exercise has many beneficial effects on human health. One of them, is to influence positively bone remodeling through, however, incompletely understood mechanisms. Given its recently demonstrated role as a mediator of the bone to muscle to bone crosstalk during exercise, we hypothesized that interleukin-6 (IL-6) signaling in bone may contribute to the beneficial effect that exercise has on bone homeostasis. In this study, we first show that aerobic exercise increases the expression of Il6r in bones of WT mice. Then, we analyzed a mutant mouse strain that lacks the IL-6 receptor alpha specifically in osteoblasts (Il6r osb -/- mice, in sedentary conditions, bone mass and remodeling were normal in adult Il6r -/- mice, in sedentary conditions, bone mass and remodeling were normal in adult Il6r osb mice that were subjected to aerobic exercise did not show the increase in bone mass and remodeling parameters that control littermates demonstrated. Moreover, Il6r -/- mice undergoing aerobic exercise showed a severe impairment in bone formation, indicating that activation of bone-forming cells is defective when IL-6 signaling in osteoblasts is disrupted. In sum, this study provides evidence that a function of IL-6 signaling in osteoblasts is to promote high bone turnover during aerobic exercise.osb -/- mice that were subjected to aerobic exercise did not show the increase in bone mass and remodeling parameters that control littermates demonstrated. Moreover, Il6r osb -/- mice undergoing aerobic exercise showed a severe impairment in bone formation, indicating that activation of bone-forming cells is defective when IL-6 signaling in osteoblasts is disrupted. In sum, this study provides evidence that a function of IL-6 signaling in osteoblasts is to promote high bone turnover during aerobic exercise., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)