Cell biology of Paget's disease

Paget's disease is characterized by markedly increased osteoclast formation and bone resorption followed by excessive new bone formation. Osteoclasts in Paget's disease are increased both in number and size, contain paramyxov iral-like nuclear inclusions, and can have up to 100 nuclei per cell. Marro w culture studies have identified several abnormalities in osteoclast forma tion in Paget's disease. Osteoclast-like multinucleated cells formed more r apidly in marrow cultures from patients with Paget's disease, produced incr eased levels of interleukin-6 (IL-6), and expressed high levels of IL-6 rec eptors compared to normals. IL-6 levels were also increased in bone marrow and peripheral blood of patients with Paget's disease. In addition, osteocl ast precursors from patients with Paget's disease are hyperresponsive to 1, 25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) and calcitonin, The increased sens itivity of osteoclast precursors to 1,25(OH)(2)D-3 is mediated through the vitamin D receptor (VDR), since 24-hydroxylase activity is also up-regulate d at concentrations of 1,25(OH)(2)D-3 that are one log less than that neede d to induce 24-hydroxylase activity in osteoclast precursors from normals. However, VDR numbers and affinity for 1,25(OH)(2)D-3 do not differ in osteo clast precursors from Paget's patients compared to those from normals. Syne rgistic interactions between cytokines such as IL-6 and 1,25(OH)(2)D-3 also cannot explain the enhanced sensitivity of osteoclast precursors from pati ents with Paget's disease to 1,25(OH)(2)D-3. Interestingly, coculture studi es of osteoclast precursors and cells from the marrow:microenvironment of p atients with Paget's disease and normals have demonstrated that the marrow microenvironment is more osteoclastogenic than normal. Thus, studies of the cell biology of osteoclasts in Paget's disease have demonstrated an increa sed rate of osteoclast formation and abnormalities in both osteoclast precu rsors and the marrow microenvironment, Enhanced IL-6 production by osteocla sts in Paget's disease may further amplify the increased osteoclast formati on already ongoing in the pagetic lesion, and may explain the increased bon e turnover at uninvolved sites distant from the pagetic lesion.