Role and function of mechanical ADAM10/17 activation in alveolar bone remodeling

• Applicants: Professor Dr. Andreas Ludwig; Professor Dr. Michael Wolf
• Subject Area: Pharmacology ; Dentistry, Oral Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559483338

Bone remodeling is a continuous process throughout life and serves to adjust bone architecture to meet changing mechanical needs. The induced bone remodeling by mechanical forces is also an underlying principle of orthodontic tooth movement. The mechanosensitive ion channel Piezo1 has been implicated in sensing mechanical forces in bone tissue. Bone remodeling is mediated by osteoblast that build up new bone matrix and osteoclasts that resorb bone tissue. Differentiation into osteoclasts is stimulated by Macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) that are locally produced by osteoblasts. M-CSF promotes survival and proliferation of myeloid lineage precursor cells by signaling through its receptor CSF1R. In addition, the signaling of RANK needs to be triggered by RANKL for complete osteoclast differentiation and activation. Recent joint research of our departments of Molecular Pharmacology and Orthodontics revealed that the constitutive function of the metalloproteinases ADAM10 and ADAM17 on osteoclast precursor cells limits osteoclast development by cleavage of cell surface expressed RANK and CSF1R and thereby reducing the cellular responsiveness of the cells. Our preliminary data also indicate that ADAM17 is further activated via the mechanosensitive ion channel Piezo1 leading to enhanced receptor shedding thereby further reducing induction of osteoclast differentiation. Also on osteoblasts, we found that Piezo1 activates ADAM10 leading to enhanced release of RANKL. This implies that less transmembrane RANKL is available on osteoblasts for cell-to-cell stimulation of osteoblasts. We therefore propose that activation of ADAM10 and ADAM17 via mechanosensitive ion channels (Piezo1 and also TRPV4) regulate alveolar bone remodeling in response to mechanical stress. To address this issue, we will continue our established collaboration to translate our molecular oriented research of ADAM proteases into experimental and clinical orthodontics. First in vitro experiments with chemical or mechanical activation of Piezo1 will be performed to study how this influences osteoclast differentiation. We will then analyze ADAM activation via mechanosensitive ion channels in osteoblasts and osteocytes. To study how ADAM proteases regulate the cell-to-cell interaction of osteoclasts and osteoblasts, coculture experiments will be performed. Next, we will study the role of Piezo1 and ADAM17 in our established mouse model of orthodontic bone remodeling. To link our findings to clinical data, we will analyze gingival cervical fluids from patients undergoing orthodontic treatments for the presence of soluble mediators generated by ADAM proteases. By this we hope to demonstrate a new mechanistic link from force perception via Piezo1 to enhanced proteolytic activity of ADAM10 and ADAM17 and finally to alveolar bone remodeling.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Aaron Babendreyer; Privatdozent Dr. Rogerio Bastos Craveiro