Deficiency of these two cytokines or their cognate receptors eliminates osteoclast formation and causes severe osteopetrosis in humans and rodents.2, 3, 4, 5, 6 Although M-CSF stimulates the proliferation of macrophages and the survival of osteoclasts by activating extracellular signal-regulated kinase (ERK) and phosphoinositide-3-kinase/Akt (PI3K/AKT) pathways, RANKL is a major, if not the only, osteoclast differentiation factor. The gene discussed is AKT1; the disease is osteopetrosis.