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Sökning: WFRF:(Gustafsson Karin L. 1987)

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1.
  • 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.
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2.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • A tissue-specific role of membrane-initiated ERα signaling for the effects of SERMs
  • 2022
  • Ingår i: Journal of Endocrinology. - 0022-0795. ; 253:2, s. 75-84
  • Tidskriftsartikel (refereegranskat)abstract
    • Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To dete rmine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451 A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza), or estradi ol (E2), and various tissues were evaluated. Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on the uterus was predominantly mER α-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were abse nt in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in th e skeleton are mERα- dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrati ng mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating the ability of these treatments to affect fat tissue in the absence of functional mER α signaling. In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manne r. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.
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3.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • Arginine site 264 in murine estrogen receptor alpha is dispensable for the regulation of the skeleton.
  • 2021
  • Ingår i: American journal of physiology. Endocrinology and metabolism. - 1522-1555. ; 320:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen protects against bone loss, but is not a suitable treatment due to adverse effects in other tissues. Increased knowledge regarding estrogen signaling in estrogen-responsive tissues is therefore warranted to aid the development of bone-specific estrogen treatments. Estrogen receptor alpha (ERα), the main mediator of estrogenic effects in bone, is widely subjected to posttranslational modifications (PTMs). In vitro studies have shown that methylation at site R260 in the human ERα affects receptor localization and intracellular signaling. The corresponding amino acid R264 in murine ERα has been shown to have a functional role in endothelium in vivo; albeit the methylation of R264 in the murine gene is yet to be empirically demonstrated. The aim of this study was to investigate if R264 in ERα is involved in the regulation of the skeleton in vivo. DXA analysis at three, six, nine, and twelve months of age showed no differences in total body areal BMD between R264A and WT in either female or male mice. Furthermore, analyses using CT demonstrated that trabecular bone mass in tibia and vertebra, and cortical thickness in tibia, were similar between R264A and WT mice. In addition, R264A females displayed a normal estrogen treatment response in trabecular bone mass, as well as in cortical thickness. Furthermore, uterus, thymus, and adipose tissue responded similarly in R264A and WT female mice after estrogen treatment. In conclusion, our novel finding that mutation of R264 in ERα does not affect the regulation of the skeleton, together with the known role of R264 for ERα-mediated endothelial effects, supports the concept that R264 determines tissue specificity of ERα.
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4.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • ER alpha expression in T lymphocytes is dispensable for estrogenic effects in bone
  • 2018
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 238:2, s. 129-136
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERa) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERa expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERa expression specifically in T lymphocytes (Lck-ERa-/-) and ERaflox/flox littermate (control) mice. Deletion of ERa expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERa-/compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERa-/- mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERa-/- led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERa in T lymphocytes. In conclusion, ERa expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice.
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5.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • The role of membrane ER alpha signaling in bone and other major estrogen responsive tissues
  • 2016
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen receptor a (ER alpha) signaling leads to cellular responses in several tissues and in addition to nuclear ER alpha-mediated effects, membrane ER alpha (mER alpha) signaling may be of importance. To elucidate the significance, in vivo, of mER alpha signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ER alpha to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mER alpha signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mER alpha (<35% reduction in estrogen response in NOER mice). In conclusion, mER alpha signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ER alpha actions may provide means to develop new selective estrogen receptor modulators with improved profiles.
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6.
  • Lawenius, Lina, et al. (författare)
  • Development of a synbiotic that protects against ovariectomy-induced trabecular bone loss
  • 2022
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 322:4
  • Tidskriftsartikel (refereegranskat)abstract
    • The gut microbiome has the capacity to regulate bone mass. The aim of this study was to develop a nutritional synbiotic dietary assemblage at an optimal dose to maintain bone mass in ovariectomized (Ovx) mice. We performed genomic analyses and in vitro experiments in a large collection of bacterial and fungal strains (>4,000) derived from fresh fruit and vegetables to identify candidates with the synergistic capacity to produce bone-protective short-chain fatty acids (SCFA) and vitamin K2. The candidate SBD111-A, composed of Lactiplantibacillus plantarum, Levilactobacillus brevis, Leuconostoc mesenteroides, Pseudomonas fluorescens, and Pichia kudriavzevii together with prebiotic dietary fibers, produced high levels of SCFA in vitro and protected against Ovx-induced trabecular bone loss in a dose-dependent manner in mice. Metagenomic sequencing revealed that SBD111-A changed the taxonomic composition and enriched specific pathways for synthesis of bone-protective SCFA, vitamin K2, and branched-chain amino acids in the gut microbiome. NEW & NOTEWORTHY We performed genomic analyses and in vitro experiments in a collection of bacterial and fungal strains. We identified a combination (SBD111-A) that produced high levels of SCFA in vitro and protected against ovariectomy-induced bone loss in a dose-dependent manner in mice. Metagenomic sequencing revealed that SBD111-A changed the taxonomic composition and function of the gut microbiome and enriched pathways for synthesis of bone-protective SCFA, vitamin K2, and branched-chain amino acids.
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7.
  • Lawenius, Lina, et al. (författare)
  • Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss
  • 2020
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 318:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (pAkk) could prevent ovx-induced bone loss. Mice were treated with vehicle or pAkk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with pAkk reduced fat mass accumulation confirming earlier findings. However, treatment with pAkk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with pAkk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with pAkk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and pAkk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with pAkk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with pAkk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.
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8.
  • 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.
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9.
  • Nilsson, Karin H., et al. (författare)
  • Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other
  • 2022
  • Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 322:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Osteoporosis is an age-dependent serious skeletal disease that leads to great suffering for the patient and high social costs, especially as the global population reaches higher age. Decreasing estrogen levels after menopause result in a substantial bone loss and increased fracture risk, whereas estrogen treatment improves bone mass in women. RSPO3, a secreted protein that modulates WNT signaling, increases trabecular bone mass and strength in the vertebrae of mice, and is associated with trabecular density and risk of distal forearm fractures in humans. The aim of the present study was to determine if RSPO3 is involved in the bone-sparing effect of estrogens. We first observed that estradiol (E2) treatment increases RSPO3 expression in bone of ovariectomized (OVX) mice, supporting a possible role of RSPO3 in the bone-sparing effect of estrogens. As RSPO3 is mainly expressed by osteoblasts in the bone, we used a mouse model devoid of osteoblast-derived RSPO3 (Runx2-creRspo3flox/flox mice) to determine if RSPO3 is required for the bone-sparing effect of E2 in OVX mice. We confirmed that osteoblast-specific RSPO3 inactivation results in a substantial reduction in trabecular bone mass and strength in the vertebrae. However, E2 increased vertebral trabecular bone mass and strength similarly in mice devoid of osteoblast-derived RSPO3 and control mice. Unexpectedly, osteoblast-derived RSPO3 was needed for the full estrogenic response on cortical bone thickness. In conclusion, although osteoblast-derived RSPO3 is a crucial regulator of vertebral trabecular bone, it is required for a full estrogenic effect on cortical, but not trabecular, bone in OVX mice. Thus, estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other.NEW & NOTEWORTHY Osteoblast-derived RSPO3 is known to be a crucial regulator of vertebral trabecular bone. Our new findings show that RSPO3 and estrogen regulate trabecular bone independent of each other, but that RSPO3 is necessary for a complete estrogenic effect on cortical bone.
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10.
  • Ohlsson, Claes, 1965, et al. (författare)
  • Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice.
  • 2018
  • Ingår i: The Journal of endocrinology. - 1479-6805. ; 237:2, s. 113-122
  • Tidskriftsartikel (refereegranskat)abstract
    • Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of cortical bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult cortical bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in cortical bone were reduced and cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, cortical thickness and cortical bone strength with no effect on trabecular bone volume fraction. Mechanistic studies demonstrated that the reduced cortical bone thickness was caused by a combination of increased bone resorption and reduced periosteal bone formation. In conclusion, WNT16 is a crucial regulator of cortical bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at cortical bone sites.
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11.
  • Ohlsson, Claes, 1965, et al. (författare)
  • The effects of estradiol are modulated in a tissue-specific manner in mice with inducible inactivation of ERα after sexual maturation.
  • 2020
  • Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 318:5, s. 646-654
  • Tidskriftsartikel (refereegranskat)abstract
    • Mouse models with lifelong inactivation of estrogen receptor α (ERα) show that ERα is the main mediator of estrogenic effects in bone, thymus, uterus, and fat. However, ERα inactivation early in life may cause developmental effects that confound the adult phenotypes. To address the specific role of adult ERα expression for estrogenic effects in bone and other non-skeletal tissues, we established a tamoxifen-inducible ERα-inactivated model by crossing CAG-Cre-ER and ERαflox/flox mice. Tamoxifen-induced ERα-inactivation after sexual maturation substantially reduced ERα mRNA levels in cortical bone, trabecular bone, thymus, uterus, gonadal fat, and hypothalamus, in CAG-Cre-ERαflox/flox (inducible ERαKO) compared to ERαflox/flox (control) mice. 17β-estradiol (E2) treatment increased trabecular bone volume fraction (BV/TV), cortical bone area and uterine weight, while it reduced thymus weight and fat mass in ovariectomized control mice. The estrogenic responses were substantially reduced in inducible ERαKO mice compared to control mice on BV/TV (-67%), uterine weight (-94%), thymus weight (-70%), and gonadal fat mass (-94%). In contrast, the estrogenic response on cortical bone area was unaffected in inducible ERαKO compared to control mice. In conclusion, using an inducible ERαKO model, not confounded by lack of ERa during development, we demonstrate that ERα expression in sexually mature female mice is required for normal E2 responses in most, but not all tissues. The finding that cortical, but not trabecular bone, responds normally to E2 treatment in inducible ERαKO mice strengthens the idea of cortical and trabecular bone being regulated by estrogen via different mechanisms.
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12.
  • Ohlsson, Claes, 1965, et al. (författare)
  • WNT16 overexpression partly protects against glucocorticoid-induced bone loss
  • 2018
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 314:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Therapeutic use of glucocorticoids (GCs) is a major cause of secondary osteoporosis, but the molecular mechanisms responsible for the deleterious effects of GCs in bone are only partially understood. WNT16 is a crucial physiological regulator of bone mass and fracture susceptibility, and we hypothesize that disturbed WNT16 activity might be involved in the deleterious effects of GC in bone. Twelve-week-old female Obl-Wnt16 mice (WNT16 expression driven by the rat procollagen type I alpha 1 promoter) and wild-type (WT) littermates were treated with prednisolone (7.6 mg.kg(-1).day(-1)) or vehicle for 4 wk. We first observed that GC treatment decreased the Wnt16 mRNA levels in bone of female mice (-56.4 +/- 6.1% compared with vehicle, P < 0.001). We next evaluated if WNT16 overexpression protects against GC-induced bone loss. Dual-energy X-ray absorptiometry analyses revealed that GC treatment decreased total body bone mineral density in WT mice (-3.9 +/- 1.2%, P = 0.028) but not in Obl-Wnt16 mice (+1.3 +/- 1.4%, nonsignificant). Microcomputed tomography analyses showed that GC treatment decreased trabecular bone volume fraction (BV/TV) of the femur in WT mice (P = 0.019) but not in Obl-Wnt16 mice. Serum levels of the bone formation marker procollagen type I N-terminal propeptide were substantially reduced by GC treatment in WT mice (-50.3 +/- 7.0%, P = 0.008) but not in Obl-Wnt16 mice (-3.8 +/- 21.2%, nonsignificant). However, the cortical bone thickness in femur was reduced by GC treatment in both WT mice and Obl-Wnt16 mice. In conclusion. GC treatment decreases Wnt16 mRNA levels in bone and WNT16 overexpression partly protects against GC-induced bone loss.
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13.
  • Scheffler, Julia M., et al. (författare)
  • ER alpha Signaling in a Subset of CXCL12-Abundant Reticular Cells Regulates Trabecular Bone in Mice
  • 2022
  • Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 6:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen has pronounced effects on the immune system, which also influences bone homeostasis. In recent years, stromal cells in lymphoid organs have gained increasing attention as they not only support the regulation of immune responses but also affect bone remodeling. A conditional knockout mouse model where estrogen receptor alpha (ER alpha) is deleted in CCL19-expressing stromal cells (Ccl19-Cre ER alpha(fl/fl) mice) was generated and bone densitometry was performed to analyze the importance of stromal cell-specific ER alpha signaling on the skeleton. Results showed that female Ccl19-Cre ER alpha(fl/fl) mice display reduced total bone mineral density and detailed X-ray analyses revealed that ER alpha expression in CCL19-expressing stromal cells is important for trabecular but not cortical bone homeostasis. Further analysis showed that the trabecular bone loss is caused by increased osteoclastogenesis. Additionally, the bone formation rate was reduced; however, the expression of osteoprogenitor genes was not altered. Analysis of the bone marrow stromal cell compartment revealed a deletion of ER alpha in a subgroup of CXCL12-abundant reticular (CAR) cells resulting in increased secretion of the pro-osteoclastogenic chemokine CXCL12. In conclusion, this study reveals the importance of ER alpha signaling in CAR cells for bone health. (c) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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14.
  • Colldén, Hannah, et al. (författare)
  • Comprehensive Sex Steroid Profiling in Multiple Tissues Reveals Novel Insights in Sex Steroid Distribution in Male Mice
  • 2022
  • Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 163:3
  • Tidskriftsartikel (refereegranskat)abstract
    • A comprehensive atlas of sex steroid distribution in multiple tissues is currently lacking, and how circulating and tissue sex steroid levels correlate remains unknown. Here, we adapted and validated a gas chromatography tandem mass spectrometry method for simultaneous measurement of testosterone (T), dihydrotestosterone (DHT), androstenedione, progesterone (Prog), estradiol, and estrone in mouse tissues. We then mapped the sex steroid pattern in 10 different endocrine, reproductive, and major body compartment tissues and serum of gonadal intact and orchiectomized (ORX) male mice. In gonadal intact males, high levels of DHT were observed in reproductive tissues, but also in white adipose tissue (WAT). A major part of the total body reservoir of androgens (T and DHT) and Prog was found in WAT. Serum levels of androgens and Prog were strongly correlated with corresponding levels in the brain while only modestly correlated with corresponding levels in WAT. After orchiectomy, the levels of the active androgens T and DHT decreased markedly while Prog levels in male reproductive tissues increased slightly. In ORX mice, Prog was by far the most abundant sex steroid, and, again, WAT constituted the major reservoir of Prog in the body. In conclusion, we present a comprehensive atlas of tissue and serum concentrations of sex hormones in male mice, revealing novel insights in sex steroid distribution. Brain sex steroid levels are well reflected by serum levels and WAT constitutes a large reservoir of sex steroids in male mice. In addition, Prog is the most abundant sex hormone in ORX mice.
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15.
  • Corciulo, Carmen, et al. (författare)
  • Pulsed administration for physiological estrogen replacement in mice
  • 2021
  • Ingår i: F1000Research. - : F1000 Research Ltd. - 2046-1402 .- 1759-796X. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid.
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16.
  • Farman, Helen H., 1983, et al. (författare)
  • Extra-nuclear effects of estrogen on cortical bone in males require ERαAF-1
  • 2017
  • Ingår i: Journal of Molecular Endocrinology. - 0952-5041. ; 58:2, s. 105-111
  • Tidskriftsartikel (refereegranskat)abstract
    • Estradiol (E2) signaling via estrogen receptor alpha (ERα) is important for the male skeleton as demonstrated by ERα inactivation in both mice and man. ERα mediates estrogenic effects not only by translocating to the nucleus and affecting gene transcription but also by extra-nuclear actions e.g., triggering cytoplasmic signaling cascades. ERα contains various domains, and the role of activation function 1 (ERαAF-1) is known to be tissue specific. The aim of this study was to determine the importance of extra-nuclear estrogen effects for the skeleton in males and to determine the role of ERαAF-1 for mediating these effects. Five-month-old male wild-type (WT) and ERαAF-1-inactivated (ERαAF-10) mice were orchidectomized and treated with equimolar doses of 17β-estradiol (E2) or an estrogen dendrimer conjugate (EDC), which is incapable of entering the nucleus and thereby only initiates extra-nuclear ER actions or their corresponding vehicles for 3.5 weeks. As expected, E2 treatment increased cortical thickness and trabecular bone volume per total volume (BV/TV) in WT males. EDC treatment increased cortical thickness in WT males, whereas no effect was detected in trabecular bone. In ERαAF-10 males, E2 treatment increased cortical thickness, but did not affect trabecular bone. Interestingly, the effect of EDC on cortical bone was abolished in ERαAF-10 mice. In conclusion, extra-nuclear estrogen signaling affects cortical bone mass in males, and this effect is dependent on a functional ERαAF-1. Increased knowledge regarding estrogen signaling mechanisms in the regulation of the male skeleton may aid the development of new treatment options for male osteoporosis.
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17.
  • Farman, Helen H., 1983, et al. (författare)
  • Membrane estrogen receptor alpha is essential for estrogen signaling in the male skeleton
  • 2018
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 239:3, s. 303-312
  • Tidskriftsartikel (refereegranskat)abstract
    • The importance of estrogen receptor alpha (ER alpha) for the regulation of bone mass in males is well established. ERa mediates estrogenic effects both via nuclear and membraneinitiated ER alpha (mER alpha) signaling. The role of mERa signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERa signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ER alpha to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (mu CT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mER alpha is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.
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18.
  • Grahnemo, Louise, et al. (författare)
  • Increased bone mass in a mouse model with low fat mass.
  • 2018
  • Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 315:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Mice with impaired acute inflammatory responses within adipose tissue display reduced diet-induced fat mass gain associated with glucose intolerance and systemic inflammation. Therefore, acute adipose tissue inflammation is needed for a healthy expansion of adipose tissue. Because inflammatory disorders are associated with bone loss, we hypothesized that impaired acute adipose tissue inflammation leading to increased systemic inflammation results in a lower bone mass. To test this hypothesis, we used mice overexpressing an adenoviral protein complex - the receptor internalization and degradation (RID) complex that inhibits pro-inflammatory signaling - under the control of the aP2-promotor (RID tg mice), resulting in suppressed inflammatory signaling in adipocytes. As expected, RID tg mice had a lower high-fat diet-induced weight and fat mass gain and higher systemic inflammation than their littermate wild type controls. Contrary to our hypothesis, the RID tg mice had increased bone mass in long bones and vertebrae, affecting trabecular and cortical parameters, as well as improved humeral biomechanical properties. We did not find any differences in bone formation or resorption parameters as determined by histology or enzyme immunoassay. However, bone marrow adiposity, often negatively associated with bone mass, was decreased in male RID tg mice as determined by histological analysis of tibia. In conclusion, mice with reduced fat mass, due to impaired adipose tissue inflammation, have increased bone mass.
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19.
  • Lagerquist, Marie K, et al. (författare)
  • Acute fat loss does not affect bone mass
  • 2021
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity has previously been thought to protect bone since high body weight and body mass index are associated with high bone mass. However, some more recent studies suggest that increased adiposity negatively impacts bone mass. Here, we aimed to test whether acute loss of adipose tissue, via adipocyte apoptosis, alters bone mass in age-related obese mice. Adipocyte apoptosis was induced in obese male FAT-ATTAC mice through AP20187 dimerizer-mediated activation of caspase 8 selectively in adipocytes. In a short-term experiment, dimerizer was administered to 5.5 month-old mice that were terminated 2 weeks later. At termination, the total fat mass weighed 58% less in dimerizer-treated mice compared with vehicle-treated controls, but bone mass did not differ. To allow for the detection of long-term effects, we used 9-month-old mice that were terminated six weeks after dimerizer administration. In this experiment, the total fat mass weighed less (- 68%) in the dimerizer-treated mice than in the controls, yet neither bone mass nor biomechanical properties differed between groups. Our findings show that adipose tissue loss, despite the reduced mechanical loading, does not affect bone in age-related obese mice. Future studies are needed to test whether adipose tissue loss is beneficial during more severe obesity.
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20.
  • Lionikaite, Vikte, et al. (författare)
  • Clinically relevant doses of Vitamin A decrease cortical bone mass in mice
  • 2018
  • Ingår i: Journal of Endocrinology. - 0022-0795 .- 1479-6805. ; 239:3, s. 389-402
  • Tidskriftsartikel (refereegranskat)abstract
    • Excess vitamin A has been associated with decreased cortical bone thickness and increased fracture risk. While most studies in rodents have employed high dosages of vitamin A for short periods of time, we investigated the bone phenotype in mice after longer exposure to more clinically relevant doses. For 1, 4 and 10 weeks, mice were fed a control diet (4.5µg retinyl acetate/g chow), a diet modeled from the human upper tolerable limit (UTL; 20µg retinyl acetate/g chow) and a diet three times UTL (supplemented; 60µg retinyl acetate/g chow). Time-dependent decreases in periosteal circumference and bone mineral content were noted with the supplemented dose. These reductions in cortical bone resulted in a significant time-dependent decrease of predicted strength and a non-significant trend toward reduced bone strength as analyzed by three-point bending. Trabecular bone in tibiae and vertebrae remained unaffected when vitamin A was increased in the diet. Dynamic histomorphometry demonstrated that bone formation was substantially decreased after 1 week of treatment at the periosteal site with the supplemental dose. Increasing amount of vitamin A decreased endocortical circumference, resulting in decreased marrow area, a response associated with enhanced endocortical bone formation. In the presence of bisphosphonate, vitamin A had no effect on cortical bone, suggesting that osteoclasts are important, even if effects on bone resorption were not detected by osteoclast counting, genes in cortical bone or analysis of serum TRAP5b and CTX. In conclusion, our results indicate that even clinically relevant doses of vitamin A have a negative impact on the amount of cortical bone. © 2018 The authors Published by Bioscientifica Ltd.
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21.
  • Liphardt, Anna-Maria, et al. (författare)
  • Changes in mechanical loading affect arthritis-induced bone loss in mice.
  • 2020
  • Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 131
  • Tidskriftsartikel (refereegranskat)abstract
    • Arthritis induces bone loss by inflammation-mediated disturbance of bone homeostasis. On the other hand, pain and impaired locomotion are highly prevalent in arthritis and result in reduced general physical activity and less pronounced mechanical loading. Bone is affected by mechanical loading, directly through impact with the ground during movement and indirectly through muscular activity. Mechanical loading in its physiological range is essential for maintaining bone mass, whereas disuse leads to bone loss. The aim of this study was to investigate the impact of mechanical loading on periarticular bone as well as inflammation during arthritis. Mechanical loading was either blocked by botulinum neurotoxin A (Botox) injections before induction of arthritis, or enhanced by cyclic compressive loading, three times per week during arthritis induction. Arthritis was verified and evaluated histologically. Trabecular and cortical bone mass were investigated using micro-computed tomography (μCT), subchondral osteoclastogenesis and bone turnover was assessed by standard methods. Inhibition of mechanical loading enhanced arthritis-induced bone loss while it did not affect inflammation. In contrast, enhanced mechanical loading mitigated arthritis-induced bone loss. Furthermore, the increase in bone resorption markers by arthritis was partly blocked by mechanical loading. In conclusion, enhanced arthritic bone loss after abrogation of mechanical loading suggests that muscle forces play an essential role in preventing arthritic bone loss. In accordance, mechanical loading of the arthritic joints inhibited bone loss, emphasizing that weight bearing activities may have the potential to counteract arthritis-mediated bone loss.
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22.
  • Nordqvist, Jauqueline, 1988, et al. (författare)
  • A tissue-selective estrogen complex as treatment of osteoporosis in experimental lupus
  • 2022
  • Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 31:2, s. 143-154
  • Tidskriftsartikel (refereegranskat)abstract
    • Osteoporosis is a common secondary complication in patients with systemic lupus erythematosus (SLE). Current osteoporosis treatment with bisphosphonates has some negative side effects and there is a lack of data regarding newer treatments options for SLE associated osteoporosis. The tissue-selective estrogen complex (TSEC) containing conjugated estrogens and the selective estrogen receptor modulator bazedoxifene (Bza) is approved for treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis. However, it has not been evaluated for treatment of osteoporosis in postmenopausal SLE patients. Ovariectomized MRL/lpr mice constitute a model for postmenopausal lupus that can be used for osteoporosis studies. We used this model in a set of experiments where the mice were treated with different doses of 17β-estradiol-3-benzoate (E2), Bza, or TSEC (E2 plus Bza), administered in the early or late phases of disease development. The skeleton was analyzed by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and high-resolution microcomputed tomography. The lupus disease was assessed by determination of proteinuria, hematuria, and lupus disease markers in serum. Treatment with medium dose TSEC administered in early disease protected ovariectomized MRL/lpr mice from trabecular bone loss, while there were no differences in lupus disease parameters between treatments. This is the first experimental study to investigate TSEC as a potential new therapy for osteoporosis in postmenopausal SLE. © The Author(s) 2022.
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23.
  • Ohlsson, Claes, 1965, et al. (författare)
  • Mild stimulatory effect of a probiotic mix on bone mass when treatment is initiated 1.5 weeks after ovariectomy in mice
  • 2021
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Studies in humans and rodents show that probiotic bacteria can protect from bone loss caused by sex steroid deficiency. We showed earlier that a mixture of three probiotic bacteria, Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312, and DSM 15313 (L. mix), protects mice from ovariectomy (ovx)-induced bone loss when treatment was started 2 wk before sham and ovx surgery. In addition, the same probiotic treatment protected against lumbar spine bone loss in early postmenopausal women. In the present study, we wanted to evaluate the therapeutic potential of L. mix by starting treatment 1.5 wk after ovx when most of the rapid bone loss as a result of estrogen deficiency has already occurred. Treatment with L. mix for 5.5 wk increased the trabecular thickness but not the trabecular number in the proximal metaphyseal region of tibia compared with vehicle treatment. Cortical thickness and cortical area of the middiaphyseal part of the tibia were significantly decreased in ovx mice but not in L. mix-treated ovx mice. The bone-protective effects of L. mix in ovx mice were associated with a protection against ovx-induced reduction of the frequency of regulatory T-cells and of the expression of Tgfb in the bone marrow. In conclusion, the probiotic L. mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that L. mix may exert beneficial effects on bone mass when treatment is started after ovariectomy. NEW & NOTEWORTHY The probiotic L. mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that L. mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.
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24.
  • Ohlsson, Claes, 1965, et al. (författare)
  • Phosphorylation site S122 in estrogen receptor α has a tissue-dependent role in female mice
  • 2020
  • Ingår i: FASEB Journal. - 0892-6638 .- 1530-6860. ; 34, s. 15991-16002
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen treatment increases bone mass and reduces fat mass but is associated with adverse effects in postmenopausal women. Knowledge regarding tissue-specific estrogen signaling is important to aid the development of new tissue-specific treatments. We hypothesized that the posttranslational modification phosphorylation in estrogen receptor alpha (ERα) may modulate ERα activity in a tissue-dependent manner. Phosphorylation of site S122 in ERα has been shown in vitro to affect ERα activity, but the tissue-specific role in vivo is unknown. We herein developed and phenotyped a novel mouse model with a point mutation at the phosphorylation site 122 in ERα (S122A). Female S122A mice had increased fat mass and serum insulin levels but unchanged serum sex steroid levels, uterus weight, bone mass, thymus weight, and lymphocyte maturation compared to WT mice. In conclusion, phosphorylation site S122 in ERα has a tissue-dependent role with an impact specifically on fat mass in female mice. This study is the first to demonstrate in vivo that a phosphorylation site in a transactivation domain in a nuclear steroid receptor modulates the receptor activity in a tissue-dependent manner.
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25.
  • Scheffler, Julia M., et al. (författare)
  • Interleukin 17A: a Janus-faced regulator of osteoporosis
  • 2020
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Interleukin (IL)-17A is a well-described mediator of bone resorption in inflammatory diseases, and postmenopausal osteoporosis is associated with increased serum levels of IL-17A. Ovariectomy (OVX) can be used as a model to study bone loss induced by estrogen deficiency and the role of IL-17A in osteoporosis development has previously been investigated using various methods to inhibit IL-17A signaling in this model. However, the studies show opposing results. While some publications reported IL-17A as a mediator of OVX-induced osteoporosis, others found a bone-protective role for IL-17 receptor signaling. In this study, we provide an explanation for the discrepancies in previous literature and show for the first time that loss of IL-17A has differential effects on OVX-induced osteoporosis; with IL-17A being important for cortical but not trabecular bone loss. Interestingly, the decrease in trabecular bone after OVX in IL-17A knock-out mice, was accompanied by increased adipogenesis depicted by elevated leptin levels. Additionally, the bone marrow adipose tissue expanded, and the bone-turnover decreased in ovariectomized mice lacking IL-17A compared to ovariectomized WT mice. Our results increase the understanding of how IL-17A signaling influences bone remodeling in the different bone compartments, which isof importance for the development of new treatments of post-menopausal osteoporosis. © 2020, The Author(s).
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