Rony Sapir-Koren

Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-β-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechan...

In order to identify genetic effects of allelic variation on bone mineral density (BMD), association studies have been performed recently. Examining the relation between PvuII and XbaI restriction fragment length polymorphism (RFLPs) at the estrogen receptor (ER alpha) gene and BMD, in women or men, have yielded conflicting results. We analyzed the association between this polymorphism and BMD Z score values of cancellous bone at the 3rd finger in 344 members of nuclear families of European population, Chuvasha, living in Russia. The population sample included 183 males, aged 18-84, and 161 females, aged 23-79. The analysis has been performed separately for both sexes and for both generations (parents and offspring). We used a novel direct haplotyping method, which determines simultaneously each of the PvuII and XbaI RFLPs and their relation to each other. The haplotypes were represented as the combination of both polymorphic sites on the same chromosome, by using P/p and X/x for PvuII and XbaI restriction sites, respectively. The subjects were classified into 3 groups of genotypes: A = PXPX (homozygote for the PX haplotype); B = PXPx, PXpx (the heterozygotes for the PX haplotype); C = PxPx, Pxpx, pxpx (genotypes that are lacking the PX haplotype). The PXPX genotype (A) was associated with higher BMD Z score values in comparison to the genotypes that are lacking the PX haplotype (C), in total males [0.618 vs. -0.133 (p = 0.004)] and for the "sons" generation [0.724 vs. -0.198 (p = 0.02)]. Similar tendency was observed for the "fathers" generation (0.539 vs. -0.085), though the difference did not approach statistical significance (p = 0.087). These findings were not found in the female samples, nor in the "mothers" or "daughters" generations. The question if there are differences in the mode of action of estrogen through its receptor on bone mass, between the genders or between the males' generations, have to be further investigated.

Body phosphate homeostasis is regulated by a hormonal counter-balanced intestine-bone-kidney axis. The major systemic hormones involved in this axis are parathyroid hormone (PTH), 1,25-dihydroxyvitamin-D, and fibroblast growth factor-23 (FGF23). FGF23, produced almost exclusively by the osteocytes, is a phosphaturic hormone that plays a major role in regulation of the bone remodeling process. Remodeling composite components, bone mineralization and resorption cycles create a continuous influx-efflux loop of the inorganic phosphate (Pi) through the skeleton. This "bone Pi loop," which is formed, is controlled by local and systemic factors according to phosphate homeostasis demands. Although FGF23 systemic actions in the kidney, and for the production of PTH and 1,25-dihydroxyvitamin-D are well established, its direct involvement in bone metabolism is currently poorly understood. This review presents the latest available evidence suggesting two aspects of FGF23 bone local ac...

Estrogen receptor alpha (ER alpha) and collagen IA1 (COLIA1) genes have been suggested as possibly implicated in reduced bone mineral density (BMD). The present study investigated the occurrence of association and linkage disequilibrium between radiographic hand BMD and polymorphic alleles of ER alpha and COLIA1 genes, in human pedigrees of a Chuvasha population in Russia. The study sample included 463 members of 113 pedigrees, mostly nuclear families. We performed association and transmission disequilibrium test (TDT) analyses of the combined PvuII and XbaI RFLPs alleles on the same chromosome (haplotype) of the ER alpha gene with BMD Z scores of cancellous or cortical bone in the hand phalanges. The association analyses were performed separately for both genders in the parental generation, i.e., 'fathers' (n = 114; average age 64.2 y) and 'mothers' (n = 122; average age 62.7 y). The Px haplotype was associated significantly with lower BMD Z scores in 'mothers' only. The difference between subjects who carried one or two copies of the Px haplotype and those lacking it was 0.68 Z scores, P = 0.003 and 0.51 Z scores, P = 0.025 for cancellous and cortical bone, respectively. Multiple linear regression model with age, height, weight, and Px haplotype status as predictors explained 26.7% and 28.3% of the total observed variance in BMD with Px haplotype as independent predictor explaining 5.9%; P = 0.002 and 3%; P = 0.028 (cancellous and cortical bone, respectively). Results of t-TDT for triads of two parents and just one of their female offspring (but not male offspring) suggested the existence of linkage disequilibrium between the two loci of Px haplotype and BMD trait (P = 0.047). No association was found between polymorphic alleles of COLIA1 gene and BMD, but 'mothers' with combined genotypes of Px haplotype of ER alpha gene and "s" allele of COLIA1 gene had the lowest mean Z scores (-0.944 and -0.788 for cancellous and cortical bone, respectively). We conclude that the Px haplotype of the ER alpha gene is associated with low BMD values in females, as the phenotype is gender dependent (the association was not observed in males), and the "s" allele of COLIA1 gene in combination with this haplotype contributes to reduced BMD.