Missense polymorphisms of the WNT16 gene are associated with bone mass, hip geometry and fractures

García-Ibarbia, Carmen; Pérez-Núñez, María Isabel; Olmos, José M.; Valero, Carmen; Pérez-Aguilar, M.D.; Hernández, José L.; Zarrabeitia, Marı́a T.; González‐Macías, Jesús; Riancho, José A.

doi:10.1007/s00198-013-2302-0

Cited by 70 publications

(52 citation statements)

References 24 publications

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“…37,36 Furthermore, recent studies have further demonstrated that several novel genetic variations in and around the WNT16 locus are strongly associated with BMD at different skeletal sites and have concluded that WNT16 positively affect BMD and bone strength, particularly at cortical sites. 33,34,35 Therefore, all these studies indicated that WNT16 is a key determinant of cortical bone mass and is associated with risk of fracture in humans. In addition, WNT16 might have a role in determining bone accrual and peak bone mass, known to be important determinants for the risk of osteoporosis in adulthood.…”

Section: Genome-wide Association Studies Of Skeletal Phenotypes Reveamentioning

confidence: 99%

A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures

Gori¹,

Lerner²,

Ohlsson³

et al. 2015

BoneKEy Reports

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The last decade has provided abundant data implicating the WNT pathway in bone development and in the regulation of skeletal homeostasis. Rare human mutations together with gain-and loss-of-function approaches in mice have clearly demonstrated that disrupted regulation of this pathway leads to altered bone mass. In addition to these rare human and mice mutations, large population-based genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in B60 loci strongly associated with variations in bone mineral density (BMD) at different skeletal sites. Among the loci/genes identified by BMD GWAS, components of the WNT signaling pathway are numerous and have been shown to contribute to skeletal development and homeostasis. Within the components of WNTsignaling, the gene coding for WNT16, one of the 19 WNT ligands of the human genome, has been found strongly associated with specific bone traits such as cortical bone thickness, cortical porosity and fracture risk. Recently, the first functional characterization of Wnt16 has confirmed the critical role of Wnt16 in the regulation of cortical bone mass and bone strength in mice. These reports have extended our understanding of Wnt16 function in bone homeostasis and have not only confirmed the unique association of Wnt16 with cortical bone and fracture susceptibility, as suggested by GWAS in human populations, but have also provided novel insights into the biology of this WNT ligand and the mechanism(s) by which it regulates cortical but not trabecular bone homeostasis. Most interestingly, Wnt16 appears to be a strong anti-resorptive soluble factor acting on both osteoblasts and osteoclast precursors. WNT Signaling and Skeletal HomeostasisSkeletal homeostasis is maintained throughout life by the balance between bone formation by osteoblasts (which derive from mesenchymal cells) and bone resorption by osteoclasts (which have hematopoietic origin), regulated in part by the third bone cell type, the osteocyte, itself derived from osteoblasts. The adult skeleton continuously undergoes remodeling, and failure to balance these two processes can lead to skeletal diseases, such as osteoporosis, characterized by decreased bone mass, altered bone micro-structure and increased risk of fragility fractures.1 Most studies have, however, focused on trabecular bone remodeling despite the fact that 80% of the skeleton is constituted by cortical bone. [2][3][4] The findings that with aging 80% of fractures are associated with cortical bone (non-vertebral fractures) indicate that cortical bone mass is a key determinant of bone strength. [2][3][4] Although the risk of vertebral fractures, which arise mainly at trabecular sites, is significantly decreased by the currently available anti-resorptive or anabolic treatments, the risk of non-vertebral fractures is reduced only by B20%, confirming a dichotomy between the homeostatic regulation of the trabecular and cortical bone compartments 1,[5][6][7][8]

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Section: Genome-wide Association Studies Of Skeletal Phenotypes Reveamentioning

confidence: 99%

A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures

Gori¹,

Lerner²,

Ohlsson³

et al. 2015

BoneKEy Reports

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“…In the brain, estrogen signaling activates WNT by down-regulating dickkopf-1 (Dkk1), a WNT antagonist, to prevent neurodegeneration (27). In the uterus, estrogen prompts the canonical WNT signaling pathway in the uterine epithelium to induce uterine epithelial cell growth (28), and in breast cancer, ERα activation enhances cell growth via WNT signaling (29).Human genetic studies followed by subsequent mechanistic studies have recently revealed that WNT16 is a key physiological regulator of cortical bone mass and nonvertebral fracture risk (4,5,(30)(31)(32)(33). We recently demonstrated that WNT16 is osteoblast-derived and inhibits osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts (3).…”

mentioning

confidence: 99%

“…Human genetic studies followed by subsequent mechanistic studies have recently revealed that WNT16 is a key physiological regulator of cortical bone mass and nonvertebral fracture risk (4,5,(30)(31)(32)(33). We recently demonstrated that WNT16 is osteoblast-derived and inhibits osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts (3).…”

mentioning

confidence: 99%

The bone-sparing effects of estrogen and WNT16 are independent of each other

Movérare‐Skrtic

Henning

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16 −/− mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. OblWnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L 3 . Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx OblWnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16 −/− mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16 −/− and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.WNT16 | estrogen | cortical bone | trabecular bone | transgenic mice B oth estrogen and wingless-type MMTV integration site family (WNT)16 are crucial regulators of bone mass in women (1-5). The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα) (6). Estrogen-deficiency leads to rapid bone loss and contributes significantly to the development of postmenopausal osteoporosis that can be prevented by estradiol treatment. However, this treatment is associated with side effects such as breast cancer and thromboembolism (7,8).The WNTs are a family of secreted glycoproteins that consists of 19 members in mammals, and which mediates autocrine and paracrine effects by binding to frizzled (Fzd) receptors and LDL-related protein 5/6 (LRP5/6) coreceptors (9). During the last decade, several lines of clinical and preclinical evidence have indicated that WNT signaling is critical in bone development and in the regulation of adult bone homeostasis (10-20) and modulation of WNT signaling has emerged as a promising strategy for increasing bone mass (21-23). Crosstalk and synergy between ERα signaling and the WNT pathways have been described (24-26). In the brain, estrogen signaling activates WNT by down-regulating dickkopf-1 (Dkk1), a WNT antagonist, to pr...

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“…[26][27][28][29][30][31] These findings suggested that Wnt16 regulated bone formation and resorption to maintain bone mass in humans. Mové rare-Skrtic et al 32 recently discussed the roles of Wnt16 in bone metabolism.…”

Section: Wnt/b-catenin Signals In Osteoblastsmentioning

confidence: 98%

The regulation of osteoclast differentiation by Wnt signals

et al. 2015

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Wnt ligands activate β-catenin-dependent canonical and -independent noncanonical signaling pathways. Wnt regulates many physiological events such as the development of organs and bone metabolism. In contrast, failed signaling leads to pathological conditions including cancer and osteoporosis. Analyses of loss-of-function mutations in the low-density lipoprotein receptor-related protein (Lrp) 5 gene revealed that Lrp5 acted as a co-receptor of Wnt/β-catenin signals and positively regulated bone mass in humans and mice. Many players in Wnt signals including sclerostin, an osteocyte-derived Wnt antagonist, also have since been found to influence bone mass. Bone mass is regulated by the activities of bone-forming osteoblasts, -resorbing osteoclasts and matrix-embedded osteocytes. The roles of Wnt/β-catenin signals in osteoblastogenesis and osteoclastogenesis have been established by the findings of a large number of in vitro and in vivo studies. In contrast, the roles of noncanonical Wnt signals in bone metabolism are only now being examined. In this review, we introduced and discussed recent information on the roles of Wnt signals in bone resorption.

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Missense polymorphisms of the WNT16 gene are associated with bone mass, hip geometry and fractures

Cited by 70 publications

References 24 publications

A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures

A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures

The bone-sparing effects of estrogen and WNT16 are independent of each other

The regulation of osteoclast differentiation by Wnt signals

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