| 1. |
- Moverare-Skrtic, Sofia, et al.
(författare)
-
Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans
- 2019
-
Ingår i: Faseb Journal. - 0892-6638. ; 33:10, s. 11163-11179
-
Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible Notum-inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage-specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.-Moverare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P. P. C., Lerner, U. H., Ohlsson, C. Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans.
|
|
| 2. |
- Nilsson, Karin H., et al.
(författare)
-
RSPO3 is important for trabecular bone and fracture risk in mice and humans
- 2021
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here, the authors show that RSPO3 exerts an important role for vertebral trabecular bone mass and bone strength in mice and fracture risk in humans. With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.
|
|
| 3. |
- Windahl, Sara H, 1971, et al.
(författare)
-
Estrogen receptor-alpha in osteocytes is important for trabecular bone formation in male mice
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 110:6, s. 2294-2299
-
Tidskriftsartikel (refereegranskat)abstract
- The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-alpha (ER alpha), encoded by the Esr1 gene. ER alpha in osteoclasts is crucial for the trabecular bone-sparing 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 ER alpha 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 ER alpha(flox/flox) mice to generate mice lacking ER alpha protein expression specifically in osteocytes (Dmp1-ER alpha(-/-)). Male Dmp1-ER alpha(-/-) 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-ER alpha(-/-) mice. The male Dmp1-ER alpha(-/-) mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2, Sp7, and Dmp1 (P < 0.05). Gonadal intact Dmp1-ER alpha(-/-) female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ER alpha(-/-) female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ER alpha(-/-) mice of both genders had unaffected cortical bone. In conclusion, ER alpha 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 ER alpha in osteocytes in males, but via ER alpha in osteoclasts in females.
|
|
| 4. |
- Wu, Jianyao, et al.
(författare)
-
Androgen receptor SUMOylation regulates bone mass in male mice
- 2019
-
Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 479:January, s. 117-122
-
Tidskriftsartikel (refereegranskat)abstract
- The crucial effects of androgens on the male skeleton are at least partly mediated via the androgen receptor (AR). In addition to hormone binding, the AR activity is regulated by post-translational modifications, including SUMOylation. SUMOylation is a reversible modification in which Small Ubiquitin-related MOdifier proteins (SUMOs) are attached to the AR and thereby regulate the activity of the AR and change its interactions with other proteins. To elucidate the importance of SUMOylation of AR for male bone metabolism, we used a mouse model devoid of the two AR SUMOylation sites (AR(SUM-);K381R and K500R are substituted). Six-month-old male AR(SUM-) mice displayed significantly reduced trabecular bone volume fraction in the distal metaphyseal region of femur compared with wild type (WT) mice (BV/TV, -19.1 +/- 4.9%, P < 0.05). The number of osteoblasts per bone perimeter was substantially reduced (-60.5 +/- 7.2%, P < 0.001) while no significant effect was observed on the number of osteoclasts in the trabecular bone of male AR(SUM-) mice. Dynamic histomorphometric analysis of trabecular bone revealed a reduced bone formation rate (-32.6 +/- 7.4%, P < 0.05) as a result of reduced mineralizing surface per bone surface in AR(SUM-) mice compared with WT mice (-24.3 +/- 3.6%, P < 0.001). Furthermore, cortical bone thickness in the diaphyseal region of femur was reduced in male AR(SUM-) mice compared with WT mice (-7.3 +/- 2.0%, P < 0.05). In conclusion, mice devoid of AR SUMOylation have reduced trabecular bone mass as a result of reduced bone formation. We propose that therapies enhancing AR SUMOylation might result in bone-specific anabolic effects with minimal adverse effects in other tissues.
|
|
| 5. |
- Börjesson, Anna E, et al.
(författare)
-
SERMs have substance-specific effects on bone, and these effects are mediated via ER alpha AF-1 in female mice
- 2016
-
Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 310:11
-
Tidskriftsartikel (refereegranskat)abstract
- The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)alpha, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ER alpha AF-1 for the estradiol (E-2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ER alpha AF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ER alpha AF-1 (ER alpha AF-1(0)) with E-2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ER alpha AF-1(0) mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ER alpha AF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.
|
|
| 6. |
- Movérare-Skrtic, Sofia, et al.
(författare)
-
The bone-sparing effects of estrogen and WNT16 are independent of each other
- 2015
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:48, s. 14972-14977
-
Tidskriftsartikel (refereegranskat)abstract
- 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 isWNT16-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. Obl- Wnt16 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 L3. 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 Obl- Wnt16 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.
|
|
