Commitment and differentiation of stem cells to the osteoclast lineage

Osteoclasts are hematopoietic cells which play important roles in bone remo deling and resorption. They have phenotypic characteristics of the monocyte /macrophage lineages. In this review we first describe the phylogeny of ost eoclasts. Osteoclast generation is closely linked to the presence of bone t issues. The formation of bone cavities in aquatic animals is underdeveloped , even though they have cells which have the potential to differentiate int o osteoclasts. Next we describe recent advances in our understanding of ost eoclastogenesis that have resulted from the identification of critical mole cules and mutated genes of osteopetrotic mice. Reports that transcriptional factors PU.1 and c-Fos are essential for commitment and (or) differentiati on into the osteoclast lineage and novel culture systems, which have clarif ied some characteristics of osteoclast precursors, are also described. We a re now able to induce mature osteoclasts from hematopoietic stem cells and even from totipotent embryonic stem cells. Cell lines that differentiate in to osteoclasts are also available. Using these culture systems and cell lin es, the interactions of osteoclasts with osteoblastic stromal cells, which produce critical molecules for osteoclastogenesis, have been studied. Very recently, one of these critical molecules, osteoclast differentiation facto r/osteoprotegerin-ligand, was cloned. The presence of this factor and macro phage-colony-stimulating factor is sufficient to induce osteoclast developm ent in cultures inoculated only with an osteoclast precursor cell line. We review the present status and the remaining questions in osteoclast biology .