Role of Ror2 signaling in bone health and disease

• Applicant: Dr. Hiroaki Saito
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464546685

Aging-related loss of bone mass often leads to osteoporosis and fragility fractures, which represent a major burden for patients and the healthcare system. Bone mass is maintained by the balanced activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Differentiation and function of bone cells is governed by signaling molecules, receptors and downstream pathways. In osteoblasts, Wnt signaling, which comprises a canonical- and non-canonical branch, plays a pivotal role. While great insights exist on the canonical branch, much less is known about the role of non-canonical Wnt signaling in osteoblast biology and bone mass maintenance. Our preliminary data demonstrate that targeted genetic ablation of the non-canonical Wnt-related Receptor tyrosine kinase-like orphan receptor 2 (Ror2), but not of its family member Ror1, in the osteoblast lineage increases bone formation and bone mass by interfering with IL-6/SOCS3/IGF signaling. This observation is novel, original and has a translational value. Thus, we propose in this grant application to further investigate the Role of Ror2 signaling in bone health and disease. In the first scientific Aim, we intend to perform a comprehensive structure-function analysis of Ror2 in osteoblasts to identify activating ligands, co-receptors, intracellular domains and associating factors that transmit the activation signal. In the second Aim, we will further dissect the Ror2/IL-6/SOCS3/IGF signal transduction cascade. To confirm the in vivo relevance of the mechanism under disease conditions, pharmacological inhibition of Ror2 will be used to treat gonadectomy-induced osteoporosis in mice of both genders within the framework of the third Aim. In summary, this project will further explore the role of non-canonical Wnt signaling in physiological and pharmacological regulation of bone mass maintenance. The findings will expand the understanding of bone biology and may lead to novel opportunities for the treatment of metabolic bone diseases.

• DFG Programme: Research Grants