A proposed model for the pathogenesis of PD. Mutations that enhance basal osteoclastogenesis predispose patients to PD by creating a permissive environment for its development. A second factor, such as expression of certain viral proteins, may further alter signaling pathways or expression of specific transcription factors, resulting in the abnormal characteristics of pagetic osteoclasts. For example, the increased sensitivity of osteoclast precursors to low levels of 1,25-(OH)₂D₃ and RANKL (RL) enhances osteoclast formation. Further, the increased numbers of osteoclasts would secrete high levels of IL-6, which would further enhance osteoclast formation. Since osteoclast and osteoblast activity remain coupled in PD, the increased osteoclast activity would result in increased osteoblast numbers and rapid formation of new bone. The increased numbers of immature osteoblasts expressing high levels of RANKL and M-CSF would further increase osteoclast formation. As more and more bone is formed, the lesion would eventually become sclerotic.