| Cdk6 is an important player in the G1 phase of the cell cycle. It is best known as a negative regulator of pRB. While it is primarily associated with the cell cycle control, recent decade has yielded body of evidence that extends the function of Cdk6 beyond the cell cycle regulation. Here, we show that Cdk6 inhibits bone formation in vivo as well as mineralization of osteoblasts in vitro, which it accomplishes at least in part via regulation of Runx2 activity. Importantly, both cdk6 knockout (KO) and loss-of-function (K43M) mutations render animals insensitive to ovariectomy -- induced bone loss. These findings, we believe, shed light on a novel Cdk6 function, underline its uniqueness and provide a compelling therapeutic target.;It was previously shown that Cdk6 is overexpressed in several malignancies, including glioma, glioblastoma multiforme (GBM) and squamous cell carcinoma. Additionally, it was recently demonstrated that pRB and p53 loss cooperate to produce very aggressive, metastatic osteosarcomas in mice with phenotypes closely resembling that of the human disease. We hypothesized that Cdk6 being a direct regulator of pRB might also have an impact on the malignancy of bone.;Here we show that, indeed, Cdk6 is necessary for the transformation of osteoblasts in vitro as well as tumor formation in vivo. This effect is independent of proliferation and is at least in part through Cdk6 regulation of the number of self-renewing cells. Additionally, preliminary observations show that Cdk6 inhibition-insensitive mutation on the background of p53 bone-specific loss leads to the accelerated onset of tumor-formation, albeit at low penetrance. Overall, our data strongly supports the involvement of Cdk6 in the malignancy of bone tissue. |
