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Pathobiology of Paget's Disease of Bone.

ABSTRACT: Paget's disease of bone is characterized by highly localized areas of increased bone resorption accompanied by exuberant, but aberrant new bone formation with the primary cellular abnormality in osteoclasts. Paget's disease provides an important paradigm for understanding the molecular mechanisms regulating both osteoclast formation and osteoclast-induced osteoblast activity. Both genetic and environmental etiologies have been implicated in Paget's disease, but their relative contributions are just beginning to be defined. To date, the only gene with mutations in the coding region linked to Paget's disease is sequestosome-1 (SQSTM1), which encodes the p62 protein, and these mutations lead to elevated cytokine activation of NF-B in osteoclasts but do not induce a "pagetic osteoclast" phenotype. Further, genetic mutations linked to Paget's appear insufficient to cause Paget's disease and additional susceptibility loci or environmental factors may be required. Among the environmental factors suggested to induce Paget's disease, chronic measles (MV) infection has been the most studied. Expression of the measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic-like osteoclasts and bone lesions in mice. Further, mice expressing both MVNP in osteoclasts and germline mutant p62 develop dramatic pagetic bone lesions that were strikingly similar to those seen in patients with Paget's disease. Thus, interactions between environmental and genetic factors appear important to the development of Paget's disease. In this article we review the mechanisms responsible for the effects of mutant p62 gene expression and MVNP on osteoclast and osteoblast activity, and how they may contribute to the development of Paget's disease of bone.

SUBMITTER: Galson DL

PROVIDER: S-EPMC4075272 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Pathobiology of Paget's Disease of Bone.

Galson Deborah L DL Roodman G David GD

Journal of bone metabolism 20140531 2

Paget's disease of bone is characterized by highly localized areas of increased bone resorption accompanied by exuberant, but aberrant new bone formation with the primary cellular abnormality in osteoclasts. Paget's disease provides an important paradigm for understanding the molecular mechanisms regulating both osteoclast formation and osteoclast-induced osteoblast activity. Both genetic and environmental etiologies have been implicated in Paget's disease, but their relative contributions are j ...[more]

PMID: 25025000

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Project description:Paget's disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemic dissemination. Despite many years of intense research, the etiology of PDB has still to be conclusively determined. Based on a detailed review of genetic and viral factors incriminated in PDB, we propose a unifying hypothesis from which we can suggest emerging strategies and therapies. PDB results in weakened bone strength and abnormal bone architecture, leading to pain, deformity or, depending on the bone involved, fracture in the affected bone. The diagnostic assessment includes serum total alkaline phosphatase, total body bone scintigraphy, skull and enlarged view pelvis x-rays, and if needed, additional x-rays. The ideal therapeutic option would eliminate bone pain, normalize serum total alkaline phosphatase with prolonged remission, heal radiographic osteolytic lesions, restore normal lamellar bone, and prevent recurrence and complications. With the development of increasingly potent bisphosphonates, culminating in the introduction of a single intravenous infusion of zoledronic acid 5 mg, these goals of treatment are close to being achieved, together with long-term remission in almost all patients. Based on the recent pathophysiological findings, emerging strategies and therapies are reviewed: ie, pulse treatment with zoledronic acid; denosumab, a fully human monoclonal antibody directed against RANK ligand; tocilizumab, an interleukin-6 receptor inhibitor; odanacatib, a cathepsin K inhibitor; and proteasome and Dickkopf-1 inhibitors.

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Pathobiology of Paget's Disease of Bone.

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Pathobiology of Paget's Disease of Bone.

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