RANKing the importance of measles virus in Paget’s disease
Authors: F. Patrick Ross
Journal: Journal of Clinical Investigation (2000)

Paget's disease, a common, multifocal skeletal disorder, provides a paradigm of bone remodeling gone awry.Both bone resorption and formation occur at an increased pace in pagetic bone, but the pathology arises in osteoclasts, cells that continuously migrate through and degrade the mineralized extracellular matrix of the bone.Reflecting its increased resorptive activity, the pagetic osteoclast is large and hypernucleated.Early clues regarding pathogenesis came with recognition that the nuclei and cytosol of pagetic osteoclasts contain inclusions reminiscent of structures seen in virus-infected cells.Subsequent studies demonstrated mRNA for measles, respiratory syncytial, or canine distemper virus -all members of the paramyxovirus family -in the osteoclasts of a majority of pagetic patients (1).A recent report that erythroid cells from patients with Paget's disease express viral mRNA (2), along with the delayed and unpredictable expression of the phenotype, suggests that some generally quiescent hematopoietic stem cell serves as the primary host for viral infection.However, the presence of viral mRNA in mesenchymal cells in bone (3) raises the possibility that nonhematopoietic cells also play a role in the disease.Reddy et al. have documented 2 major alterations in the milieu in pagetic bone that are likely to have mechanistic implications.First, unlike their normal counterparts, pagetic osteoclasts and their precursors secrete high levels of IL-6.Second, bone marrow aspirates from patients are hypersensitive to the effects of 1,25 dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and differentiate to form osteoclast-like cells when treated with doses of this compound 10-fold lower than needed to induce this transition in healthy cells (4).The presence of viral mRNA in osteoclasts first suggested that 1 or more viral proteins prime cells to undergo these phenotypic changes, and the report by Kurihara et al. in this issue of the JCI (5) confirms that expression of measles virus nucleocapsid protein (MVNP) in normal, marrow-derived CD34 + cells promotes increased bone resorption, enhances secretion of IL-6 by osteoclasts, and increases their sensitivity to 1,25(OH) 2 D 3 .Introduction of the measles virus membrane (MVM) protein causes different responses, suggesting that the latter protein plays a distinct role in inducing deranged bone turnover.In addition, the authors document that osteoclast precursors transduced with either MVNP-or MVM-enhanced activation of the NFκB transcription factor complex, a central aspect of osteoclast biology.As discussed below, and of considerable interest, these findings suggest that the causative agents of Paget's disease circumvent the currently accepted pathway for osteoclast formation and activation (summarized in Figure 1).The key elements in this pathway are the receptor for activation of NFκB (RANK), which is found on osteoclasts and their precursors; the RANK ligand (RANK-L; also referred to in the literature as TRANCE, OPGL, and ODF), produced in both soluble and membrane-bound forms by osteoblasts and stromal cells in bone marrow; osteoprotegerin (OPG), a soluble product of osteoblasts and stromal cells, which acts as a decoy receptor for RANK-L; and macrophage colony-stimulating factor (M-CSF), a product of stromal cells or monocytes, which binds to the receptor c-fms on osteoclasts to promote their differentiation, survival, and proliferation (6).As predicted by this model, purified murine or human monocytes and macrophages treated