Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing

Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis,a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5(Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by si RNA, genetic deletion using the Cre-lox P system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing.

Could a phase model help to improve translational animal research?

Background:Animal models are widely applied in medical research for different purposes.In particular,results from translational experiments may be used for subsequent clinical development.However,transferability of these findings to the human organism is controversial.Among other factors,this may be traced back to a lack of clear differentiation of the evidence(explorative vs.confirmatory)provided by such experimental results.In general,inferential statistics(i.e.p values)should not be interpreted in as confirmatory unless crucial methodological requirements are met.Methods:Therefore,we propose a phase model which reflects the well-established process of clinical research,and we discuss its potential to improve decision making in translational research.The model aims to clarify the reliability of results derived from animal models.Results:The phase model proposes subdividing translational,pre-clinical research into pilot,exploration,and confirmation phases.Experiments for which there is no valid estimation of the expected effect size are designated as pilot studies.Based on these data,experiments in subsequent phases may be planned using both appropriate design and statistical methods.Conclusion:Separating the entire process of translational animal research into three phases could contribute to improved transparency of the evidence derived from such experiments.