The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.

The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-α (ERα), encoded by the Esr1 gene. ERα in osteoclasts is crucial for the trabecular bonesparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ERα in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ERα flox/flox mice to generate mice lacking ERα protein expression specifically in osteocytes (Dmp1-ERα −/− ). Male Dmp1-ERα −/− mice displayed a substantial reduction in trabecular bone volume (−20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (−45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ERα −/− mice. The male Dmp1-ERα −/− mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2, Sp7, and Dmp1 (P < 0.05). Gonadal intact Dmp1-ERα −/− female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ERα −/− female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ERα −/− mice of both genders had unaffected cortical bone. In conclusion, ERα in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone-sparing effect of estrogen is mediated via ERα in osteocytes in males, but via ERα in osteoclasts in females.

Background: Tissue-specific mouse model for Hutchinson-Gilford progeria syndrome (HGPS). Results: Dysfunctional osteoblast maturation and impacts DNA damage and Wnt signaling, which lead to abnormal bone mineralization and impaired skeletal and dental structures. Conclusion: Resemble clinical features of HGPS and normal bone aging.Significance: Provides insights to the molecular mechanisms of HGPS and will be useful to further elucidate the processes that contribute to general bone aging.

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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Molecular dynamics simulations of liquid ethylene glycol described by the OPLS-AA force field were performed to gain insight into its hydrogen-bond structure. We use the population correlation function as a statistical measure for the hydrogen-bond lifetime. In an attempt to understand the complicated hydrogen-bonding, we developed new molecular visualization tools within the Vish Visualization shell and used it to visualize the life of each individual hydrogen-bond. With this tool hydrogen-bond formation and breaking as well as clustering and chain formation in hydrogen-bonded liquids can be observed directly. Liquid ethylene glycol at room temperature does not show significant clustering or chain building. The hydrogen-bonds break often due to the rotational and vibrational motions of the molecules leading to an H-bond half-life time of approximately 1.5 ps. However, most of the H-bonds are reformed again so that after 50 ps only 40% of these H-bonds are irreversibly broken due to diffusional motion. This hydrogen-bond half-life time due to diffusional motion is 80.3 ps. The work was preceded by a careful check of various OPLS-based force fields used in the literature. It was found that they lead to quite different angular and H-bond distributions.

It has generally been assumed that bone mass is controlled by endocrine mechanisms and the local bone environment. Recent findings demonstrate that central pathways are involved in the regulation of bone mass. Estrogen is involved in the regulation of bone homeostasis and the CNS is also a target for estrogen actions. The aim of this study was to investigate in vivo the role of central estrogen receptor-α (ERα) expression for bone mass. Nestin-Cre mice were crossed with ERα flox mice to generate mice lacking ERα expression specifically in nervous tissue (nestin-ERα). Bone mineral density was increased in both the trabecular and cortical bone compartments in nestin-ERα −/− mice compared with controls. Femoral bone strength was increased in nestin-ERα −/− mice, as demonstrated by increased stiffness and maximal load of failure. The high bone mass phenotype in nestin-ERα −/− mice was mainly caused by increased bone formation. Serum leptin levels were elevated as a result of increased leptin expression in white adipose tissue (WAT) and slightly increased amount of WAT in nestin-ERα −/− mice. Leptin receptor mRNA levels were reduced in the hypothalamus but not in bone. In conclusion, inactivation of central ERα signaling results in increased bone mass, demonstrating that the balance between peripheral stimulatory and central inhibitory ERα actions is important for the regulation of bone mass. We propose that the increased bone mass in nestin-ERα −/− mice is mediated via decreased central leptin sensitivity and thereby increased secretion of leptin from WAT, which, in turn, results in increased peripheral leptin-induced bone formation.

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