Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles?

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-ß-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by "mineralization-related genes" (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an "external unit", ensuring transition from bone resorption to bone formation.Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical loading, or to unloading, leading correspondingly to bone formation or resorption. This review shows a key role of the osteocyte-produced sclerostin as a major mediator of the molecular mechanisms involved in the process of adaptive bone remodeling.

Is interaction between age-dependent decline in mechanical stimulation and osteocyte-estrogen receptor levels the culprit for postmenopausal-impaired bone formation?

Declining estrogen levels during menopause are widely considered to be a major cause of age-dependent bone loss, which is primarily manifested by increased bone resorption by osteoclasts. We present accumulating evidence supporting another aspect of metabolic bone loss, suggesting that the combined interaction between age-dependent factors, namely, estrogen deficiency and reduced day-by-day activity/mechanical stimulation, directly leads to a reduction in anabolic processes. Such decreased bone formation results in diminished bone strength and failure to maintain the load-bearing competence of a healthy skeleton and to postmenopausal osteoporosis disorder. Estrogen receptors (ERs), as mediators of estrogenic actions, are essential components of bone osteocyte and osteoblast mechano-adaptive responses. ER expression appears to be upregulated by adequate circulating estrogen levels. ERα signaling pathways participate in the mechanotransduction response through obligatory "non-genomic" actions that occur independently of estrogen binding to ER and by a potentially "genomic", estrogen-dependent mode. The experimental data indicate that cross talk between the ERα-"non-genomic" and Wnt/ß-catenin signaling pathways constitutes the major regulatory mechanism. This interaction uses mechanically and ER-induced prostaglandin E2 as a mediator for the downregulation of osteocyte production of sclerostin. Sclerostin suppression, in turn, is a central prerequisite for load-induced formation and mineralization of the bone matrix. It is therefore plausible that future strategies for preventing and treating postmenopausal osteoporosis may use estrogenic compounds (such as selective estrogen receptor modulators or phytoestrogens) with physical activity, to complement antiresorptive therapy, aimed at stopping further bone loss and possibly even reversing it by stimulation of bone gain.

Association and linkage disequilibrium analyses suggest genetic effects of estrogen receptor alpha and collagen IA1 genes on bone mineral density in Caucasian women.

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.

Genetic effects of estrogen receptor alpha and collagen IA1 genes on the relationships of parathyroid hormone and 25 hydroxyvitamin D with bone mineral density in Caucasian women.

There is a growing body of evidence that estrogen receptor alpha (ERalpha) and collagen IA1 (COLIA1) genes may affect bone mineral density (BMD) levels in postmenopausal women. In a recent study we found that the Px haplotype of the ERalpha gene (resulting from combined PvuII and XbaI restriction fragment-length polymorphisms [RFLPs] in intron 1) was associated with low radiographic phalangeal hand BMD in elderly women (62.7 +/- 6.5 years of age), of European origin. The combination of the Px haplotype and "s" allele of the COLIA1 gene (MscI RFLP in Sp1 locus) decreased BMD in these women. The major aim of the present study was to investigate whether the genetic effects of these genotypes on cancellous and cortical hand BMD, in the same elderly women (N = 122), are possibly mediated through circulating levels of parathyroid hormone (PTH) and/or 25 hydroxyvitamin D [25(OH)D], and may be related to biochemical markers of bone turnover (propeptide of type I procollagen [PICP] and osteocalcin). Multiple regression analyses of age-adjusted cancellous BMD revealed that ERalpha polymorphism and circulating levels of PTH were independent predictors of about 12.9% of its variation. Some 17.9% of cortical BMD variations were attributable to the combined effects of ERalpha polymorphism and plasma concentrations of 25(OH)D, estradiol, and PTH. The significant inverse association between PTH and BMD of both types was further confirmed by association analysis according to categorical subgroups of BMD values, as well by haplotype status. The mean difference in PTH concentrations between subjects carrying the Px haplotype (higher mean) and those lacking it (lower mean) reached 0.59 SD (P =.01). The difference in PTH levels further increased when explored in the 4 subgroups formed by combinations of polymorphic ERalpha and COLIA1 genotypes. Mean PTH of subjects carrying both the Px haplotype and "s" allele was higher by 1.52 SD (P =.001) than in subjects lacking both the Px haplotype and "s" allele. Those carrying both Px haplotype and "s" allele were also characterized by highest mean value of PICP and lowest means of 25(OH)D and BMD (both tissue types). We conclude that in the studied elderly women, the Px haplotype may be involved in causing the phenotypic expression of higher circulating levels of PTH and higher bone turnover, which, in turn, may lead to bone loss.

Bone mineral density is associated with estrogen receptor gene polymorphism in men.

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.