A novel function of cyclin-dependent kinase 5 (Cdk5) in bone integrity - a potential therapeutic target to treat osteoporosis
Final Report Abstract
We characterized in this project the role of CDK5 in bone integrity. Our initial hypothesis that inhibition of CDK5, e.g. by siRNA, Roscovitine or conditional deletion of CDK5 enhances bone formation was confirmed. Indeed Roscovitine treatment enhanced bone mass in total, and also the conditional knockout increased bone formation and cortical bone mass. However we could not confirm that inhibition of CDK5 in all considered bone disease models improves bone mass via elevation of bone formation. Glucocorticoid mediated bone loss was improved, but not via increase of bone formation, rather decrease of bone resorption. Ovariectomy mediated bone loss on the contrary was even worse after Roscovitine treatment concerning bone mass. By eliminating CDK5 in the osteoblast lineage we observed a strong decrease of trabecular bone mass, despite an increase in bone formation and decrease of osteoclast numbers. We could not solve yet this phenomenon, but discovered that inhibition of CDK5 strongly affects survival of osteocytes. We are currently exploiting, whether this explains the decrease trabecular bone mass observed in CDK5Runx2Cre mice. We bred and are currently investigating CDK5Dmp1Cre mice to see whether they phenocopy the CDK5Runx2Cre phenotype in part and thus the action of CDK5 in osteocytes is decisive for bone mass. We therefore omitted the initial planned studies targeting CDK5 at the skeletal stem cell level, since we currently do not believe that this influences the complex effects of CDK5 inhibition in vivo. Overall our work revealed a complex role of CDK5 in bone integrity, which should also being considered in patients receiving CDK5 inhibiting drugs for other disease conditions, such as leukemia. Therefore also complex effects on bone can be expected. We will continue our research on the role of CDK5 in bone with now the new hypothesis that CDK5 in osteocytes contributes to trabecular bone mass.
Publications
- (2018). Cell-based RNAi screening and high-content analysis in primary calvarian osteoblasts applied to identification of osteoblast differentiation regulators. Sci. Rep. 8, 14045
Ahmad, M., Kroll, T., Jakob, J., Rauch, A., Ploubidou, A., and Tuckermann, J.
(See online at https://doi.org/10.1038/s41598-018-32364-8) - (2019) A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunology. Front Immunol 10, 2460
Ahmad M, Hachemi Y, Paxian K, Mengele F, Koenen M, Tuckermann J
(See online at https://doi.org/10.3389/fimmu.2019.02460) - (2019). RNAi-Screening in Knochenbildenden Zellen. Biospektrum 25, 523–526
Kroll, T., Ahmad, M., Ploubidou, A., and Tuckermann, J.
(See online at https://doi.org/10.1007/s12268-019-1091-1) - (2020). PPARδ-mediated mitochondrial rewiring of osteoblasts determines bone mass. Sci. Rep. 10, 8428
Müller, D.I.H., Stoll, C., Palumbo-Zerr, K., Böhm, C., Krishnacoumar, B., Ipseiz, N., Taubmann, J., Zimmermann, M., Böttcher, M., Mougiakakos, D., et al.
(See online at https://doi.org/10.1038/s41598-020-65305-5) - (2020). RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk. Cell Death Differ 3, 1–15
Najafova, Z., Liu, P., Wegwitz, F., Ahmad, M., Tamon, L., Kosinsky, R.L., Xie, W., Johnsen, S.A., and Tuckermann, J.
(See online at https://doi.org/10.1038/s41418-020-00614-w) - (2021). Leukemia inhibitory factor treatment attenuates the detrimental effects of glucocorticoids on bone in mice. Bone 115843
Lee, S., Liu, P., Ahmad, M., and Tuckermann, J.P.
(See online at https://doi.org/10.1016/j.bone.2021.115843) - (2021). The endothelium–bone axis in development, homeostasis and bone and joint disease. Nat Rev Rheumatol 1–13
Tuckermann, J., and Adams, R.H.
(See online at https://doi.org/10.1038/s41584-021-00682-3)
