Stuart H Ralston

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..Illness representations are examined using Leventhal's Common Sense Self-Regulation Model while cognitions about treatment behaviours (acceptance of testing and treatment uptake) are conceptualised within the Theory of Planned Behaviour...

..The Theory of Planned Behaviour is a theoretical model that predicts behaviours from people's beliefs about the consequences, social pressures and perceived control over the behaviour, including uptake of treatment...

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..No firm evidence as yet exists to show that bisphosphonates can prevent the development of complications of Paget's disease of bone, and further work is needed to address the effects of treatment on long-term clinical outcome...

..Several advances have been made over recent years in understanding the genetic basis of susceptibility to osteoporosis. This paper will review recent developments in this area...

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..This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci...

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..Anecdotal reports indicate that osteoclast inhibitors such as bisphosphonates are effective for suppressing bone turnover and improving symptoms in these disorders, although the long-term effects on clinical outcomes are unclear...

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..Although there has been extensive progress in this area over the past 10 years, most of the genetic variants that regulate susceptibility to osteoporosis remain to be discovered...

..Although there has been extensive progress in identifying the genes and loci that contribute to the regulation of BMD and fracture over the past 15 yr, most of the genetic variants that regulate these phenotypes remain to be discovered...

..These increase the risk of PDB individually by 1.3- to 1.7-fold, but have combined effects that account for about 86% of the population-attributable risk of PDB in SQSTM1 negative patients...

..This could lead to reduced compliance and reduced therapeutic effectiveness, which might offset the cost savings of using the generic formulation...

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..This is consistent with a model whereby increased COL1A1 transcription predisposes to osteoporosis, probably by increasing production of the alpha 1 chain and disrupting the normal ratio of collagen type 1 alpha 1 and alpha 2 chains...

..40, P = 7.38 × 10(-17)) with PDB. These seven loci explained ∼13% of the familial risk of PDB. These studies provide new insights into the genetic architecture and pathophysiology of PDB...

..We conclude that pharmacological blockade of TRPV1 ion channels by capsazepine inhibits osteoclastic bone resorption and protects against ovariectomy induced bone loss in mice, but also inhibits osteoblast activity and bone formation...

..These studies indicate that the CB2 regulates osteoblast differentiation in vitro and bone formation in vivo...

..The results indicate that biphenyl carboxylates like ABD328 are oral candidate drugs for the treatment of diseases characterized by increased bone resorption, such as postmenopausal osteoporosis...

..The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1...

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..Accordingly, IKK inhibitors may be of value in the prevention and treatment of bone diseases characterized by increased bone loss such as postmenopausal osteoporosis...

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..09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility...

..In conclusion, the LRP5 A1330V polymorphism is associated with hip BMD in osteoporotic men, but allelic variations in LRP5 do not appear to be associated with response to bisphosphonate treatment...

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..They could be developed as diagnostic genetic tests or form molecular targets for design of new drugs for the prevention and treatment of osteoporosis and other bone diseases...

..These data indicate that cannabinoid receptors and the enzymes responsible for ligand synthesis and breakdown play important roles in bone remodeling and in the pathogenesis of joint disease...

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..The long-term clinical effects of treatment on the natural history of the bone disease remain uncertain however, and this will require further study...

..As RANKL, TNF and IL1 are all important mediators of inflammation and joint destruction, compounds like HCT1026 could represent a novel class of anti-inflammatory compounds...

..Neither management strategy had a significant beneficial impact on pain or quality of life (Clinical trial registration number ISRCTN12989577)...

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..These studies demonstrate that SQSTM1 mutations can cause a PDB-like skeletal disorder in the absence of an additional trigger and provide a new disease model for PDB...

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..This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage...

..In light of the molecular defects that have been identified thus far, it seems likely that these genes will also be involved in the RANK-NF-kappaB signaling pathway or its interactions with the ubiquitin-proteasome system...

..A major susceptibility locus for PDB was identified on chromosome 10p13 by a genome-wide linkage scan in families of British descent, which accounted for the vast majority of cases not caused by SQSTM1 mutations...

..SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes...

..The low level of nNOS expression in bone and the in vitro behavior of nNOS KO bone cells indicate that these actions are indirect and possibly mediated by a neurogenic relay...

..In summary, our work supports the view that allelic variation in the 3'UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD...

..In summary, we have found that XX homozygotes may have higher BMD and also a decreased risk of fractures when compared with carriers of the x allele, whereas the PvuII polymorphism is not associated with either BMD or fracture risk...

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..Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity...

..We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes...

..Estrogen receptor alpha (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results...

..012). Subjects with the CC genotype had significantly lower BMD (mean +/- SD: TT, 0.7 +/- 0.16; CC, 0.6 +/- 0.08 g/cm(2); P = 0.006). In conclusion, both CYP 17 and CYP 19 are candidate genes for osteoporosis in postmenopausal women...

..Information from these studies is being used to design new drugs for osteoporosis and to develop genetic markers for fracture risk assessment...

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..The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED...

..Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear...

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..We studied five common polymorphisms of TGFB1 in relation to osteoporosis-related phenotypes in a population-based cohort of 2975 British women, but found no significant association with bone mass, bone loss, bone markers, or fracture...

..In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption...

..Here we show that the most common disease-causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin...

..Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner...

..Under these circumstances it is an invaluable investigation that can be used to differentiate infiltrative disorders from primary abnormalities of osteoblast or osteoclast function...

..006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD...

..Polymorphisms in the apolipoprotein E (APOE) gene are associated with fracture risk, and a potential mechanism is through vitamin K transport...

..Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia...

..Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population...

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..Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects...

..002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach...

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..0001). These studies confirm that mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget's disease of bone...

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..A particularly striking feature was involvement of the mandible and maxilla, but it remains to be seen if this is a specific feature of the 75dup27 mutation until further kindreds with this mutation are reported...

..We observed no association in men, but a highly significant association was found in women, and this was confirmed in a population from the United Kingdom...

..Functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin-binding properties of the mutant UBA domain peptides...

..Glutamine variants and an alanine insertion were identified within the group. These data suggest that the RUNX2 alleles are associated with BMD in a menopause- and weight-dependent manner...

..We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB...

..Our data indicate that the mutations in the signal peptide and latency-associated peptide facilitate TGF-beta1 signaling, thus causing Camurati-Engelmann disease...