Insights into the pathogenesis of Paget's disease.
Paget's disease (PD) affects approximately 1.5 million persons in the United States and is characterized by grossly distorted bone remodeling, with increases in bone resorption and formation. Both environmental and genetic factors may contribute to the pathogenesis of PD. Mutations in sequestosome-1 (p62) occur in 25-30% of patients with familial PD, and in approximately 10% of patients with sporadic PD. Preclinical studies suggest that the p62(P392L) mutation predisposes patients to developing PD rather than causing it. Other studies have suggested that PD results from a chronic paramyxoviral infection. Transgenic mice expressing the measles virus nucleocapsid gene (MVNP) in osteoclasts (OCLs) develop pagetic bone lesions. Further, approximately 70% of patients harboring the p62(P392L) mutation we studied have detectable MVNP transcripts, and inhibiting MVNP expression in bone marrow cultures from those patients blocked pagetic OCL formation. These studies suggest that both genetic and environmental factors contribute to PD.
Roodman
G David
GD
University of Pittsburgh, School of Medicine/Hematology-Oncology, Pittsburgh, PA, USA. roodmangd@upmc.edu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010001:Osteitis Deformans / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000071456:Sequestosome-1 Protein; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D007375:Interleukin-1; D053245:RANK Ligand; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014409:Tumor Necrosis Factor-alpha