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Since the identification of LRP5 as the causative gene for the osteoporosis pseudoglioma syndrome (OPPG) as well as the high bone mass (HBM) phenotype, LRP5 and the Wnt/beta-catenin signaling have been extensively studied for their role in the differentiation and proliferation of osteoblasts, in the apoptosis of osteoblasts and osteocytes and in the response of bone to mechanical loading. However, more recently the direct effect of LRP5 on osteoblasts and bone formation has been questioned. Gene expression studies showed that mice lacking lrp5 have increased expression of tph1, the rate limiting enzyme for the production of serotonin in the gut: furthermore mice lacking either tph1 or htr1B, the receptor for serotonin on the osteoblasts, were reported to have an increased bone mass due to increased bone formation. This led to the still controversial hypothesis that LRP5 influences bone formation indirectly by regulating the expression of thp1 and as a consequence influencing the production of serotonin in the gut. Based on these data we decided to evaluate the role of TPH1 and HTR1B in the development of craniotubular hyperostoses, a group of monogenic sclerosing bone dysplasias. We screened the coding regions of both genes in 53 patients lacking a mutation in the known causative genes LRP5, LRP4 and SOST. We could not find disease-causing coding variants in neither of the tested genes and therefore, we cannot provide support for an important function of TPH1 and HTR1B in the pathogenesis is of sclerosing bone dysplasias in our tested patient cohort. (C) 2013 Elsevier Inc. All rights reserved.

Because of the importance of the Wnt pathway in the development and maintenance of both adipose and bone tissue, we wanted to evaluate the involvement of WNT10B, a Wnt pathway activator, in adipogenesis and osteoblastogenesis in humans. Genetic association between WNT10B polymorphisms and adiposity parameters as well as bone mineral density (BMD) measurements was analysed in two independent populations. The first is a population of 1,228 Danish men (702 aged 20-29 years; 532 aged 60-74 years) from the Odense Androgen Study (OAS), which was designed as a cross-sectional, population-based study. The second population, called SIBLOS, includes 922 Belgian men (34 +/- A 5 years old) and contains siblings selected from over 500 families. Four tagSNPs (rs833840, rs833841, rs10875902 and rs4018511) that capture variation of ten SNPs (MAF > 5 %) in a 15.2 kb region spanning the WNT10B gene and its flanking regions were genotyped. Although no association with body mass index was found, we found all tagSNPs to be associated with BMD parameters (BMD whole body, total hip and femoral neck) and height in the OAS population. The association of rs10875902 was most prominent (nominal p = 0.012) and confirmed a previously shown negative effect on BMD. No significant associations were observed in the SIBLOS population. In the present study, no association between WNT10B polymorphisms and adiposity parameters was found. However, our results clearly illustrate a role for WNT10B variants in determining human BMD. The effect of WNT10B polymorphisms on height should be evaluated in additional populations.

Introduction Sclerosteosis (OMIM 269500 ) is a rare autosomal recessive condition characterized by increased bone density associated with syndactyly. It is linked to a genetic defect in the SOST gene coding for sclerostin. So far, six different loss-of-function mutations in SOST have been reported in patients with sclerosteosis. Our objective was to sequence and identify mutation in the SOST and LRP5 genes which are known to be causal for craniotubular hyperostosis in a patient from India. Patient and methods A 22 year old woman presented with typical features of sclerosteosis in form of progressive visual and hearing loss, syndactyly and radiographs revealing increased density of bone. Genomic sequencing of the SOST gene as well as exons 2, 3 and 4 of the LRP5 gene was performed. Results We identified a novel homozygous mutation in the SOST gene, characterized as one nucleotide insertion resulting in a frame shift mutation and loss of functional sclerostin. Her parents were also found to have a similar but heterozygous mutation in the SOST gene. Conclusion A novel frame shift mutation in the SOST gene causing loss of functional sclerostin was identified in a patient with sclerosteosis and her parents.

In the last decade, the low-density lipoprotein receptor-related protein 5 (LRP5) gene, coding for a coreceptor in the canonical Wnt signalling pathway, has been shown to play an important role in regulating bone mass and to be involved in the pathogenesis of several bone disorders. Here we describe a patient who presented with a clinical picture of Autosomal Dominant Osteopetrosis type I (ADO I), in whom we could identify the first deletion in the LRP5 gene causing increased bone mass. This mutation caused the in-frame deletion of two amino acids in the fourth blade of the first propeller of the protein, namely the highly conserved glycine at position 171 and the following glutamate residue. In vitro studies suggested that the pathogenic effect of this novel mutation could be due to a decreased inhibition of Wnt signalling by the antagonistic proteins sclerostin and Dickkopf-1, encoded respectively by the SOST and DKK1 genes, in the presence of mutated LRP5. Our results highlight an increasing molecular heterogeneity in LRP5-related bone diseases., Highlights ► We report the first deletion of 2 amino acid residues in LRP5 in an ADO I patient. ► This suggests an increasing molecular heterogeneity in LRP5-related bone diseases. ► This deletion causes decreased inhibition of Wnt signalling by sclerostin and DKK1. ► ADO I and ADO II are clinically and molecularly distinct entities. ► No impairment of the immune system has been documented in ADO I patients.

Udgivelsesdato: 2010-Apr LRP5 was recently confirmed as an important susceptibility gene for osteoporosis. Our objective was to evaluate the effect of DKK1 polymorphisms on bone mineral density (BMD), hip geometry, and bone turnover. DKK1 is a secreted protein that binds to LRP5/6 receptors and inhibits canonical Wnt signaling. Using HapMap, we selected three SNPs covering the genetic variation in a 13.53-kb region comprising DKK1. The Odense Androgen Study is a population-based study comprising 783 Caucasian men aged 20-29 years. BMD and hip structural parameters were available for study. Bone turnover markers were used as a secondary end point. All analyses were repeated after adjusting for covariables and in subgroups according to physical activity. We found no significant association between DKK1 and BMD or markers of bone turnover; however, a significant association (P = 0.012) was found for rs1569198 with hip axis length (HAL), independent of BMD and height. Moreover, the association seemed to be driven by the nonsedentary subgroup (P = 0.004). Haplotype analysis further confirmed the association of rs1569198 with HAL. Furthermore, we obtained indications for interaction between DKK1 and LRP5 genotypes for different hip geometry parameters. As almost all variance within the DKK1 gene was covered, we conclude that common variation in this gene does not markedly influence BMD or bone turnover markers in young men. In this population, however, a common SNP in DKK1 does have a significant effect on HAL, implying a possible effect on hip fracture risk in the general population. This finding could be of interest but needs replication in independent populations.

Wnt signaling plays a central role in many processes during embryonic development and in later stages of life. At least three distinct wnt signaling pathways have been described. In 2001, evidence was obtained from genetic studies on some rare hereditary conditions, that the canonical wnt signaling pathway plays an important role in bone formation. Functional studies and experimental analysis of relevant animal models confirmed the anabolic effect of wnt signaling by modulating the differentiation, the proliferation, the activity and finally the apoptosis of (pre)osteoblasts and osteocytes. More recently, also non-canonical wnt signaling was shown to play a role in bone formation. Since there is currently a major lack of anabolic therapeutic agents for the prevention and treatment of osteoporosis this signaling pathway deserves major attention. A big concern, however, is the pleiotropic function of the pathway that needs to be taken into account in order to avoid unwanted side-effects. Preliminary data are already indicating that this might be achieved by targeting sclerostin, a bone-specific extracellular antagonist of canonical wnt signaling.