Elucidating the role of mast cell-released Midkine in the pathologies of osteoporosis and osteoporotic fracture healing

• Applicant: Dr. Verena Fischer
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523603345

Osteoporosis is a major metabolic bone disease that affects approximately 25 million women across Europe and is characterized by bone loss and microarchitecture deterioration, often resulting in an increased fracture risk. Fracture healing in osteoporotic patients is significantly delayed and accompanied by severe medical complications, implant failure, increased mortality and high economic costs. Experimental studies revealed an increased local and systemic inflammatory response and impaired bone formation in osteoporotic rodents. However, the molecular mechanisms underlying these findings are mostly unclear. Therefore, there is a considerable clinical need for new therapeutic options to both impede the development of osteoporosis and improve osteoporotic fracture healing. For that, a more in-depth understanding of the molecular and cellular pathomechanisms of both conditions are essential. During recent years, we and others revealed a crucial role of mast cells in osteoporosis development and in the regulation of fracture healing. In preliminary work of this proposal, we demonstrated that mast cells drive the fracture-induced inflammatory response and regulate osteoclastogenesis during callus remodeling and in ovariectomy (OVX)-induced bone loss. However, molecular and mast-cell mediator specific effects have not been investigated so far. Of note, our preliminary results indicate that mast cell-released Midkine (MDK), a pro-inflammatory and osteoclast stimulating factor, might play a key role in the pathologies of osteoporosis and compromised bone repair under estrogen-deficient conditions, however the final mechanistic is still missing. Therefore, the primary goal of this project is to elucidate the role of mast cell-released MDK in both pathologies, and to determine its impact on immune and bone cells and involved molecular signaling pathways. Our central hypothesis is that mast cell-released MDK is a key molecule regulating inflammatory, osteo-catabolic and osteo-anabolic processes under estrogen-deficient conditions. Based on that, we hypothesize that the specific deletion of Mdk in mast cells protects against OVX-induced bone loss and compromised bone repair. Open question which should be addressed by the proposed project are how mast cell-released MDK stimulates immune cell recruitment, activation and functions (e.g., neutrophils, T cells), and how it regulates osteoblast and osteoclast numbers and functions under estrogen-deficient conditions. On the molecular level, we will identify underlying pathways and targets genes and proteins of mast cell and MDK signaling in osteoporotic bone and during fracture healing. The results of the proposed project might be clinically relevant to establish new treatment options for osteoporosis and related fracture healing complications.

• DFG Programme: Research Grants