Systems level analysis of osteoclastogenesis reveals intrinsic and extrinsic regulatory interactions

Osteoclasts are bone-resorbing cells derived from the myeloid lineage that play a central role in bone remodeling and inflammatory bone erosion diseases. The receptor activator of NF-kappaB ligand (RANKL) produced by osteoblasts and activated immune cells initiates the development of osteoclasts in the bone marrow. Using time series gene expression data, the intrinsic processes and the extrinsic factors that control osteoclastogenesis were identified. The gene expression profiles display distinct commitment and differentiation phases. Analysis of the time course revealed several mechanistic details, including the complex role of cholesterol in osteoclast development. Epistatic interactions and the coordination between cellular processes that regulate development were inferred from the coexpression network. The coexpression network indicated that osteoclasts induce angiogenesis and recruit T-cells to the site of osteoclastogenesis early in the commitment phase. The resulting model provides an essential framework for a better understanding of the epigenetic program of osteoclastogenesis.