| 1. |
- Börjesson, Anna E, et al.
(författare)
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The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice
- 2012
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 302:11
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Tidskriftsartikel (refereegranskat)abstract
- Borjesson AE, Windahl SH, Karimian E, Eriksson EE, Lagerquist MK, Engdahl C, Antal MC, Krust A, Chambon P, Savendahl L, Ohlsson C. The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice. Am J Physiol Endocrinol Metab 302: E1381-E1389, 2012. First published March 13, 2012; doi:10.1152/ajpendo.00646.2011.-High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-alpha stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ER alpha and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ER alpha (ER alpha(-/-)) or ER alpha AF-1 (ER alpha AF-1(0)) were evaluated. Old (16- to 19-mo-old) female ER alpha(-/-) mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ER alpha AF-1(0) mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ER alpha AF-1(0) mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ER alpha(-/-) mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ER alpha or aromatase. In contrast, ER alpha AF-1 deletion results in a hyperactive ER alpha, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ER alpha that do not require AF-1 and that ER alpha AF-1 opposes growth plate closure.
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| 2. |
- Iravani, M., et al.
(författare)
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Effects of the selective GPER1 agonist G1 on bone growth
- 2019
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Ingår i: Endocrine Connections. - 2049-3614. ; 8:9, s. 1302-1309
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens may affect bone growth locally or systemically via the known estrogen receptors ESR1, ESR2 and G protein-coupled estrogen receptor 1 (GPER1). Mouse and human growth plate chondrocytes have been demonstrated to express GPER1 and ablation of this receptor increased bone length in mice. Therefore, GPER1 is an attractive target for therapeutic modulation of bone growth, which has never been explored. To investigate the effects of activated GPER1 on the growth plate, we locally exposed mouse metatarsal bones to different concentrations of the selective GPER1 agonist G1 for 14 days ex vivo. The results showed that none of the concentrations of G1 had any direct effect on metatarsal bone growth when compared to control. To evaluate if GPER1 stimulation may systemically modulate bone growth, ovariectomized C57BL/6 mice were treated with G1 or beta-estradiol (E2). Similarly, G1 did not influence tibia and femur growth in treated mice. As expected, E2 treatment suppressed bone growth in vivo. We conclude that ligand stimulation of GPER1 does not influence bone growth in mice.
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| 3. |
- Sjögren, Klara, 1970, et al.
(författare)
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Body fat content can be predicted in vivo in mice using a modified dual-energy X-ray absorptiometry technique.
- 2001
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Ingår i: The Journal of nutrition. - : Elsevier BV. - 0022-3166. ; 131:11, s. 2963-6
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Tidskriftsartikel (refereegranskat)abstract
- The introduction of transgenic mice as animal models in medical research has increased the need for methods to study the phenotype of mice. The aim of the present study was to develop and evaluate a method for in vivo prediction of fat content in living mice. We combined a modified dual-energy X-ray technique with an image analysis procedure. This combined procedure calculates the percentage of fat area, defined as the percentage of the total area of the mice consisting of >50% fat. A high correlation between the percentage of fat area and dissected adipose tissue was seen in both male and female mice (males, r = 0.92, P < 0.001; females, r = 0.88, P < 0.001). A high correlation was also seen between the percentage of fat area and serum levels of leptin (males, r = 0.95, P < 0.001; females, r = 0.86, P < 0.001). An additional experiment demonstrated a very strong correlation between the percentage of fat area and total body fat as determined by chemical extraction (r = 0.97, P < 0.001). In summary, the percentage of fat area, as measured with the dual-energy X-ray/image combined procedure, provides a good in vivo estimation of total body fat content in mice.
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| 4. |
- Velentza, L., et al.
(författare)
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Pharmacological inhibition of BCL-2 with the FDA-approved drug venetoclax impairs longitudinal bone growth
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Treatment-related skeletal complications are common in childhood cancer patients and survivors. Venetoclax is a BCL-2 inhibitor that has shown efficacy in hematological malignancies in adults and is being investigated in pediatric cancer clinical trials as a promising therapeutic modality. Venetoclax triggers cell death in cancer cells, but whether it exerts similar effects in normal bone cells, is unknown. Chondrogenic ATDC5 cells, E20 fetal rat metatarsal bones, and human growth plate biopsies were treated with different concentrations of venetoclax. Female NMRI nu/nu mice were treated with venetoclax or vehicle for 15 days. Mice were X-rayed at baseline and at the end of the experiment to assess longitudinal bone growth and body weight was monitored throughout the study. Histomorphometric and immunohistochemical analyses were performed to evaluate treatment effects on the growth plate cartilage. Venetoclax decreased the viability of chondrocytes and impaired the growth of ex vivo cultured metatarsals while reducing the height of the resting/proliferative zone and the hypertrophic cell size. When tested in vivo, venetoclax suppressed bone growth and reduced growth plate height. Our experimental data suggest that venetoclax directly targets growth plate chondrocytes suppressing bone growth and we, therefore, encourage careful monitoring of longitudinal bone growth if treating growing children with venetoclax.
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| 5. |
- Zaman, F., et al.
(författare)
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Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid-induced bone growth impairment
- 2019
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Ingår i: Faseb Journal. - 0892-6638. ; 33:4, s. 4962-4974
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are frequently used to treat chronic disorders in children, including inflammation and cancer. Prolonged treatment with GCs is well known to impair bone growth, an effect linked to increased apoptosis and suppressed proliferation in growth plate chondrocytes. We hypothesized that the endogenous antiapoptotic protein humanin (HN) may prevent these effects. Interestingly, GC-induced bone growth impairment and chondrocyte apoptosis was prevented in HN overexpressing mice, HN-treated wild-type mice, and in HN-treated cultured rat metatarsal bones. GC-induced suppression of chondrocyte proliferation was also prevented by HN. Furthermore, GC treatment reduced Indian Hedgehog expression in growth plates of wild-type mice but not in HN overexpressing mice or HN-treated wild-type animals. A Hedgehog (Hh) antagonist, vismodegib, was found to suppress the growth of cultured rat metatarsal bones, and this effect was also prevented by HN. Importantly, HN did not interfere with the desired anti-inflammatory effects of GCs. We conclude that HN is a novel regulator of Hh signaling preventing GC-induced bone growth impairment without interfering with desired effects of GCs. Our data may open for clinical studies exploring a new possible strategy to prevent GC-induced bone growth impairment by cotreating with HN.
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