Paget's disease of bone (PDB) is one of the most common bone disorders in the western world. PDB is characterized by focal areas of increased osteoclastic bone resorption and bone formation, which leads to the formation of poorly structured bone. These abnormalities of bone turnover and structure predispose affected individuals to various complications including bone pain, deformity, pathological fracture, and an increased risk of osteosarcoma. One of the main mechanisms of osteoclast formation and activation involves the receptor activator of nuclear factor -kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway, where binding of RANKL to RANK results in the differentiation of osteoclast precursors. OPG, on the other hand, acts as an inhibitor of osteoclastogenesis by serving as a decoy receptor for RANKL. Recently, mutations in the RANK gene have been shown to cause familial expansile osteolysis, a rare bone disorder showing great similarity to PDB. We performed mutation analysis in the RANK and OPG genes in 28 PDB patients to investigate whether mutations in these genes could be responsible for PDB. Our data suggest that RANK is not directly involved in PDB in our set of patients, as no mutations in the RANK coding region could be identified and allele frequencies of RANK polymorphisms did not differ in PDB patients as compared with the random population. Also, in the OPG gene, we could not detect PDB-causing mutations. However, of the several polymorphisms identified, one (400 + 4 C/T in intron 2), showed a statistically significant increased frequency for the C allele in PDB patients, suggesting that individuals harboring this allele may be more susceptible for developing PDB.
The cause of Paget's disease of bone (PDB) is unknown. In an attempt to ascertain the proportion of familial cases and evaluate the influence of genetic factors on the occurrence of the disease, a study was undertaken based on 35 PDB patients from our Unit. Their families were investigated, with the participation of a total of 128 first-degree relatives. Fourteen (40%) of these 35 index cases had at least one other first-degree relative affected with PDB and were defined as "familial." The remaining 21 (60%) were considered "sporadic." The frequency of males in the familial cases (79%) was significantly higher than among the sporadics (29%; p < or = 0.01). Mean age at diagnosis (63.1 +/- 12.6 vs. 71.3 +/- 8.7; p < or = 0.02), proportion of polyostotic cases (85.7% vs. 52.4%, p < or = 0.05), and mean number of involved bones per patient (4.36 +/- 2.50 vs. 2.33 +/- 1.93, p < or = 0.01) differ significantly in the familial and sporadic groups. The disease appears to be transmitted via both paternal and maternal sides, and pedigree analysis suggested an autosomal dominant inheritance or multifactorial mechanism. Apart from green-and-blue eye color, which was clearly associated with familial grouping (OR 6.25, 95% CI 1.15-37.16, p < or = 0.01), crude analysis on several genetically based traits and environmental variables revealed no other significant differences between the groups. The adjusted odds ratio estimated for green-and-blue eye color was 2.92 (95% CI 0.38-22.74).(ABSTRACT TRUNCATED AT 250 WORDS)
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone‐inducing agents. To date, there is no cure for FOP. The further development of FOP patient‐derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood‐derived endothelial colony‐forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial‐to‐mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Metaphyseal bony outgrowths are a well-recognized feature of fibrodysplasia ossificans progressiva (FOP) phenotype, but its genuine frequency, topographic distribution, morphological aspect, and potential implications are not fully established. To better ascertain the frequency and characteristics of osteocartilaginous exostoses in FOP disease, we conducted a cross-sectional radiological study based on all the traceable cases identified in a previous comprehensive national research. Metaphyseal exostoses were present in all the 17 cases of FOP studied. Although most often arising from the distal femoral (where metaphyseal exostoses adopt a peculiar not yet reported appearance) and proximal tibial bones, we have found that they are not restricted to these areas, but rather can be seen scattered at a variety of other skeletal sites. Using nuclear magnetic resonance imaging, we show that these exophytic outgrowths are true osteochondromas. As a whole, these results are in agreement with data coming from the literature review. Our study confirms the presence of metaphyseal osteochondromas as a very frequent trait of FOP phenotype and an outstanding feature of its anomalous skeletal developmental component. In line with recent evidences, this might imply that dysregulation of BMP signaling, in addition to promoting exuberant heterotopic ossification, could induce aberrant chondrogenesis and osteochondroma formation. Unveiling the molecular links between these physiopathological pathways could help to illuminate the mechanisms that govern bone morphogenesis.
To identify animal-related factors associated with Paget's disease of bone (osteitis deformans), we conducted a case-control study in two geographical areas of Spain characterized by different socioeconomic profiles. The analysis presented here is based on 149 cases and 150 controls, frequency matched by sex, age, study area, and place of residence in youth (urban/rural). From a logistic regression analysis, we found that contact with bovine cattle [odds ratio (OR) = 2.14; 95% confidence interval (CI) = 1.16-3.94], consumption of meat traceable to sick livestock (OR = 2.70; 95% CI = 0.98-7.43), and frequent consumption during youth of brains (OR = 1.77; 95% CI = 1.05-2.98) and other viscera increased the risk for Paget's disease of bone. Contact with bovine cattle and consumption during youth of bovid viscera exhibited a dose-response effect as regards length of exposure and frequency of consumption, respectively. A life-style shared with dogs showed itself to be differentially linked to the disease in one study area. Overall, our results support the hypothesis that various animal species are carriers of etiologic agents of Paget's disease of bone.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.