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Pathobiology of Paget’s Disease of Bone

Deborah L. Galson|G. David Roodman
대한골대사학회 (The Korean Society of Bone Metabolism)|2014.05|대한골대사학회지 (Journal of Bone Metabolism)|제21권 제2호|pp. 85-97

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참고문헌

키워드

OsteoclastsOsteoblastsPaget's disease
주제분류정형외과학

초록

Paget’s disease of bone is characterized by highly localized areas of increasedbone resorption accompanied by exuberant, but aberrant new bone formationwith the primary cellular abnormality in osteoclasts. Paget’s disease provides animportant paradigm for understanding the molecular mechanisms regulatingboth osteoclast formation and osteoclast-induced osteoblast activity. Both genet-ic and environmental etiologies have been implicated in Paget’s disease, but theirrelative contributions are just beginning to be defined. To date, the only genewith mutations in the coding region linked to Paget’s disease is sequestosome-1(SQSTM1), which encodes the p62 protein, and these mutations lead to elevatedcytokine activation of NF-B in osteoclasts but do not induce a “pagetic osteoclast”phenotype. Further, genetic mutations linked to Paget’s appear insufficient tocause Paget’s disease and additional susceptibility loci or environmental factorsmay be required. Among the environmental factors suggested to induce Paget’sdisease, chronic measles (MV) infection has been the most studied. Expression ofthe measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic-likeosteoclasts and bone lesions in mice. Further, mice expressing both MVNP in os-teoclasts and germline mutant p62 develop dramatic pagetic bone lesions thatwere strikingly similar to those seen in patients with Paget’s disease. Thus, interac-tions between environmental and genetic factors appear important to the devel-opment of Paget’s disease. In this article we review the mechanisms responsiblefor the effects of mutant p62 gene expression and MVNP on osteoclast and osteo-blast activity, and how they may contribute to the development of Paget’s diseaseof bone.

Abstract

Paget’s disease of bone is characterized by highly localized areas of increasedbone resorption accompanied by exuberant, but aberrant new bone formationwith the primary cellular abnormality in osteoclasts. Paget’s disease provides animportant paradigm for understanding the molecular mechanisms regulatingboth osteoclast formation and osteoclast-induced osteoblast activity. Both genet-ic and environmental etiologies have been implicated in Paget’s disease, but theirrelative contributions are just beginning to be defined. To date, the only genewith mutations in the coding region linked to Paget’s disease is sequestosome-1(SQSTM1), which encodes the p62 protein, and these mutations lead to elevatedcytokine activation of NF-B in osteoclasts but do not induce a “pagetic osteoclast”phenotype. Further, genetic mutations linked to Paget’s appear insufficient tocause Paget’s disease and additional susceptibility loci or environmental factorsmay be required. Among the environmental factors suggested to induce Paget’sdisease, chronic measles (MV) infection has been the most studied. Expression ofthe measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic-likeosteoclasts and bone lesions in mice. Further, mice expressing both MVNP in os-teoclasts and germline mutant p62 develop dramatic pagetic bone lesions thatwere strikingly similar to those seen in patients with Paget’s disease. Thus, interac-tions between environmental and genetic factors appear important to the devel-opment of Paget’s disease. In this article we review the mechanisms responsiblefor the effects of mutant p62 gene expression and MVNP on osteoclast and osteo-blast activity, and how they may contribute to the development of Paget’s diseaseof bone.

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