Osteoporosis, a prevalent age-related disease, is characterized by impaired bone formation and an increased risk of fractures. Current anabolic treatments primarily rely on biologics, which are costly and require inconvenient administration. Identifying regulators of osteoblastogenesis that are amenable to small-molecule targeting is essential for developing more accessible therapies. Through an unbiased kinome-wide RNAi screen in primary murine calvarial osteoblasts, we identified two kinases, CDK5 and Axl as negative regulators of bone formation. Cdk5 knockdown by siRNA, genetic deletion using the Cre-loxP system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro and roscivitine application enhanced bone mass in mice. The Axl tyrosine receptor kinase was found most highly expressed undifferentiated and early differentiated osteoblasts, with a rapid decline in expression during osteoblast maturation. Here siRNA-mediated knockdown of Axl or pharmacological inhibition with the small molecule BGB324 significantly enhanced osteoblast differentiation and mineralization in vitro and BGB324 treatment increased bone mass by promoting bone formation. Collectively, our study identifies Axl as a promising therapeutic target for osteoporosis and other bone-related disorders.

Biography: Prof. Jan Tuckermann received his PhD from at the German Cancer Research Center (DKFZ), Heidelberg, University of Karlsruhe, Karlsruhe, Germany and was trained in molecular and cellular biology (DKFZ, Heidelberg) and bone biology (FLI, Jena). Currently, he is a professor and a director of the Institute of Comparative Molecular Endocrinology, Ulm University, Ulm. He has an excellent publication track record and he is a a well-recognized expert in the field of bone physiology and the holder of several prestigues grants and awards. His research is focused on the glucocorticoid receptor signaling in bone immunometabolism, especially investigating the cross-talk of immune and stromal cells during osteoarthritis and diabetes and how resolution of inflammation can be fine tuned to alleviate disease and to allow repair of tissue integrity. Studying the GR signaling pathway opens up opportunities for new therapeutic concepts to tackle the metabolic and inflammatory diseases associated with the aging process. His recent research is focused on studying the role of tyrosine receptor kinase in the regulation of osteoblast function and bone formation.

IPHYS contact person: Michaela Tencerová, Laboratory of Molecular Physiology of Bone, michaela.tencerova@fgu.cas.cz