A novel function of cyclin-dependent kinase 5 (Cdk5) in bone integrity - a potential therapeutic target to treat osteoporosis

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Osteoporosis, a major disease of the elderly population is frequently treated with anti-resorptive agents that fail to restore bone formation. Thus, bone quality is not fully restored. Increase in bone formation is currently achieved by costly biologicals. Pathways that can be targeted by cost-effective small molecules are still ill-explored. Cdk5, a proline-directed serine/threonine kinase, can be inhibited with small molecules, such as Roscovitine. We discovered that Cdk5 is a negative regulator of differentiation of osteoblasts, the bone forming cells. In our preliminary work we demonstrate that either siRNA knockdown of Cdk5 or inhibition with Roscovitine in primary murine osteoprogenitor cells potently enhance osteoblast differentiation and maturation. Similarly, knockdown of Cdk5 interacting proteins modulate osteoblast differentiation, suggesting a Cdk5 signaling network that had not been described in bone cells before. High dose exposure of dexamethasone inhibits osteoblast differentiation, an underlying cause of bone loss in glucocorticoid-induced osteoporosis (GIO). Intriguingly, knockdown of Cdk5 by siRNA or inhibition of CDK5 with Roscovitine abrogates the deleterious effects of dexamethasone, suggesting that this might ameliorate GIO in vivo. Finally, we have first preliminary evidence that application of Roscovitine in unchallenged mice elevates trabecular bone mass. In this proposal we aim to unravel the function of Cdk5 in mesenchymal progenitor cells to inhibit osteoblastogenesis in vivo by lineage tracing in conditional Cdk5 knockout mice. We will analyze the impact of loss of CDK5 in mesenchymal cells and osteoblast lineage in conditional Cdk5 knockout mice by state-of-the-art bone integrity analyses (micro computer tomography, dynamic bone histomorphometry and biomechanical tests). We further aim to biochemically characterize the signaling network of Cdk5 in primary osteoblasts that leads to inhibition of differentiation. Finally, we will determine to which extent small molecules interfering with Cdk5 activity rescue osteoporosis models in mice. Since CDK5 inhibitors are already applied in clinical trials, our proposed study will provide the rationale to assess bone metabolic parameters in patient cohorts to validate CDK5 as a target to increase bone formation for treatment of osteoporosis.