For normal skeletal growth and development the relationship between cell proliferation and differentiation must be tightly regulated. Osteoblasts are committed to enter the cell cycle and proliferate under specific regulatory signals, then differentiate and product mineralized matrix. Various cyclins and cyclin dependent kinases (CDKs) have been postulated to play a role in osteoblast proliferation and differentiation. Among these kinases is CDK4, a cell cycle protein that plays a major role in the transition of cells from Go-phase (quiescent) to S-phase (DNA synthesis) of the cell cycle. The proposed studies will examine the role of CDK4 deficiency on osteoblast development and function using a mouse model null for CDK4. Previous studies showed that CDK4-/-mice compared to age-matched, wild-type (+/+) mice. Densitometry by peripheral quantitative computerized tomography (pQCT) showed a reduction in trabecular bone density in CDK4 -/- compared to +/+ mice.
Aim 1 will confirm and extend these preliminary findings in CDK4 -/- and +/+ mice at different ages.
Aim 2 will examine the expression of osteoblast-related genes and the role of CDK4 on cell proliferation and apoptosis in vivo and in primary osteoblast cultures derived from +/+ and -/- mice.
Aim 3 will determine to what extent the diabetic condition exacerbates the bone abnormalities in CDK4 -/- mice, especially in older animals. Experiments will attempt to rescue the CDK4 -/- mice by treating them with insulin and also determine what role IGF-I may play in mediating these bone defects. We hypothesize that CDK4 plays a direct role in regulating osteoblast development and function, and the diabetes may accelerate the bone loss in older CDK4 -/- mice. Information generated from the proposed studies may be useful in developing novel therapeutic strategies to modulate or increase bone formation in certain osteopenic conditions or during fracture repair.
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