Paget's disease-a VDR coactivator disease?

Paget's disease is the most exaggerated example of bone remodeling with increased osteoclastic bone resorption followed by excessive bone formation. One of the earliest findings in our studies of Paget's disease is that pagetic osteoclast (OCL) precursors are hyper-responsive to 1,25-(OH)(2)D(3) and form OCL at concentrations of 1,25-(OH)(2)D(3) that are physiologic rather than pharmacologic. The increased responsivity to 1,25-(OH)(2)D(3) is not due to increased levels of the Vitamin D receptor (VDR) or to increased infinity of 1,25-(OH)(2)D(3) for VDR. We have recently shown using GST-VDR chimeric protein pull-down assays that TAF(II)-17, a member of the TAF(II)-D transcription complex, is increased in OCL precursors from patients with Paget's disease compared to normals. We further showed that TAF(II)-17 can enhance VDR mediated gene transcription and allow formation of the transcription complex at very low levels of 1,25-(OH)(2)D(3). In addition, coactivators of VDR including CPB300 and DRIP205 are also increased in OCL precursors from Paget's patients. These data suggest that the enhanced sensitivity of OCL precursors for 1,25-(OH)(2)D(3) in Paget's disease results from increased expression of coactivators of VDR and suggest that part of the pathophysiology underlying OCL formation in Paget's disease may result from enhanced expression of VDR coactivators.Journal ArticleReviewinfo:eu-repo/semantics/publishe

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 paramyxoviral-like nuclear inclusions, and can have up to 100 nuclei per cell. Marrow culture studies have identified several abnormalities in osteoclast formation in Paget's disease. Osteoclast-like multinucleated cells formed more rapidly in marrow cultures from patients with Paget's disease, produced increased levels of interleukin-6 (IL-6), and expressed high levels of IL-6 receptors compared to normals. IL-6 levels were also increased in bone marrow and peripheral blood of patients with Paget's disease. In addition, osteoclast precursors from patients with Paget's disease are hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and calcitonin. The increased sensitivity of osteoclast precursors to 1,25(OH)2D3 is mediated through the vitamin D receptor (VDR), since 24-hydroxylase activity is also up-regulated at concentrations of 1,25(OH)2D3 that are one log less than that needed to induce 24-hydroxylase activity in osteoclast precursors from normals. However, VDR numbers and affinity for 1,25(OH)2D3 do not differ in osteoclast precursors from Paget's patients compared to those from normals. Synergistic interactions between cytokines such as IL-6 and 1,25(OH)2D3 also cannot explain the enhanced sensitivity of osteoclast precursors from patients with Paget's disease to 1,25(OH)2D3. Interestingly, coculture studies of osteoclast precursors and cells from the marrow microenvironment of patients 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 increased rate of osteoclast formation and abnormalities in both osteoclast precursors and the marrow microenvironment. Enhanced IL-6 production by osteoclasts in Paget's disease may further amplify the increased osteoclast formation already ongoing in the pagetic lesion, and may explain the increased bone turnover at uninvolved sites distant from the pagetic lesion.SCOPUS: cp.jFLWINinfo:eu-repo/semantics/publishe