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1
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Lipsey CC, Harbuzariu A, Daley-Brown D, Gonzalez-Perez RR. Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer. World J Methodol 2016; 6:43-55. [PMID: 27019796 PMCID: PMC4804251 DOI: 10.5662/wjm.v6.i1.43] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/11/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Obesity is a global pandemic characterized by high levels of body fat (adiposity) and derived-cytokines (i.e., leptin). Research shows that adiposity and leptin provide insight on the link between obesity and cancer progression. Leptin’s main function is to regulate energy balance. However, obese individuals routinely develop leptin resistance, which is the consequence of the breakdown in the signaling mechanism controlling satiety resulting in the accumulation of leptin. Therefore, leptin levels are often chronically elevated in human obesity. Elevated leptin levels are related to higher incidence, increased progression and poor prognosis of several human cancers. In addition to adipose tissue, cancer cells can also secrete leptin and overexpress leptin receptors. Leptin is known to act as a mitogen, inflammatory and pro-angiogenic factor that induces cancer cell proliferation and tumor angiogenesis. Moreover, leptin signaling induces cancer stem cells, which are involved in cancer recurrence and drug resistance. A novel and complex signaling crosstalk between leptin, Notch and interleukin-1 (IL-1) [Notch, IL-1 and leptin crosstalk outcome (NILCO)] seems to be an important driver of leptin-induced oncogenic actions. Leptin and NILCO signaling mediate the activation of cancer stem cells that can affect drug resistance. Thus, leptin and NILCO signaling are key links between obesity and cancer progression. This review presents updated data suggesting that adiposity affects cancer incidence, progression, and response to treatment. Here we show data supporting the oncogenic role of leptin in breast, endometrial, and pancreatic cancers.
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2
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Wang QS, Zhang XC, Li RX, Sun JG, Su WH, Guo Y, Li H, Zhang XZ. A comparative study of mechanical strain, icariin and combination stimulations on improving osteoinductive potential via NF-kappaB activation in osteoblast-like cells. Biomed Eng Online 2015; 14:46. [PMID: 25994935 PMCID: PMC4455701 DOI: 10.1186/s12938-015-0039-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 04/16/2015] [Indexed: 11/28/2022] Open
Abstract
Background The combination of drugs and exercise was the effective treatment in bone injure and rebuilding in clinic. As mechanical strain has potential in inducing the differentiation of osteoblasts in our previous study, the further research to investigate the combination of mechanical strain and icariin stimulation on inducing osteoblast proliferation, differentiation and the possible mechanism in MC3T3-E1 cell line. Methods A whole cell enzyme-linked immunosorbent assay that detects the bromodeoxyuridine incorporation during DNA synthesis was applied to evaluate the proliferation. The mRNA expression of alkaline phosphatase (ALP), osteocalcin (OCN), type I collagen (Col I), bone morphogenetic protein-2 (BMP-2) and BMP-4 was detected by real-time reverse-transcription polymerase chain reaction. The activity of ALP was analyzed by ELISA and the protein expression of OCN, Col I and BMP-2 was assessed by western blot. Moreover, the activity of nuclear transcription factor kappa-B (NF-κB) signaling pathway was investigated with the expression of inhibitor of κB (IκB) α, phosphorylation of IκB-α (P-IκB-α), p65, P-p65 by western blot. Results We observed that compared to single mechanical strain or icariin stimulation, the mRNA and protein expressions of ALP (P < 0.05 or P < 0.01), OCN (P < 0.01) and Col I (P < 0.05 or P < 0.01) were increased significantly by the combination of mechanical strain and icariin stimulation. Moreover, the combination of mechanical strain and icariin stimulation could up-regulate the expression of BMP-2 (P < 0.01) and BMP-4 compared to single mechanical strain or icariin stimulation. The combination of mechanical strain and icariin stimulation could activate NF-κB signaling pathway by increasing the expression of IκB α, P-IκB-α, p65, P-p65 (P < 0.01). Conclusion The combination of mechanical strain and icariin stimulation could activate the NF-κB pathway to improve the proliferation, differentiation of osteoblast-like cells.
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Affiliation(s)
- Qiang-Song Wang
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
| | - Xin-Chang Zhang
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
| | - Rui-Xin Li
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
| | - Jing-Gong Sun
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
| | - Wei-Hua Su
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
| | - Yong Guo
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
| | - Hao Li
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
| | - Xi-Zheng Zhang
- Tianjin Institute of Medical Equipment, Academy of Military Medical Sciences, No. 106 Wandong Road, Hedong District, Tianjin, 300162, People's Republic of China.
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3
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FSH and TSH in the regulation of bone mass: the pituitary/immune/bone axis. Clin Dev Immunol 2013; 2013:382698. [PMID: 23818914 PMCID: PMC3683445 DOI: 10.1155/2013/382698] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 05/17/2013] [Accepted: 05/17/2013] [Indexed: 11/21/2022]
Abstract
Recent evidences have highlighted that the pituitary hormones have profound effects on bone, so that the pituitary-bone axis is now becoming an important issue in the skeletal biology. Here, we discuss the topical evidence about the dysfunction of the pituitary-bone axis that leads to osteoporotic bone loss. We will explore the context of FSH and TSH hormones arguing their direct or indirect role in bone loss. In addition, we will focus on the knowledge that both FSH and TSH have influence on proinflammatory and proosteoclastogenic cytokine expression, such as TNFα and IL-1, underlining the correlation of pituitary-bone axis to the immune system.
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4
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Seitz S, Keller J, Schilling AF, Jeschke A, Marshall RP, Stride BD, Wintermantel T, Beil FT, Amling M, Schütz G, Tuckermann J, Schinke T. Pharmacological estrogen administration causes a FSH-independent osteo-anabolic effect requiring ER alpha in osteoblasts. PLoS One 2012; 7:e50301. [PMID: 23209701 PMCID: PMC3507728 DOI: 10.1371/journal.pone.0050301] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 10/18/2012] [Indexed: 11/18/2022] Open
Abstract
Postmenopausal osteoporosis is characterized by declining estrogen levels, and estrogen replacement therapy has been proven beneficial for preventing bone loss in affected women. While the physiological functions of estrogen in bone, primarily the inhibition of bone resorption, have been studied extensively, the effects of pharmacological estrogen administration are still poorly characterized. Since elevated levels of follicle-stimulating hormone (FSH) have been suggested to be involved in postmenopausal bone loss, we investigated whether the skeletal response to pharmacological estrogen administration is mediated in a FSH-dependent manner. Therefore, we treated wildtype and FSHβ-deficicent (Fshb−/−) mice with estrogen for 4 weeks and subsequently analyzed their skeletal phenotype. Here we observed that estrogen treatment resulted in a significant increase of trabecular and cortical bone mass in both, wildtype and Fshb−/− mice. Unexpectedly, this FSH-independent pharmacological effect of estrogen was not caused by influencing bone resorption, but primarily by increasing bone formation. To understand the cellular and molecular nature of this osteo-anabolic effect we next administered estrogen to mouse models carrying cell specific mutant alleles of the estrogen receptor alpha (ERα). Here we found that the response to pharmacological estrogen administration was not affected by ERα inactivation in osteoclasts, while it was blunted in mice lacking the ERα in osteoblasts or in mice carrying a mutant ERα incapable of DNA binding. Taken together, our findings reveal a previously unknown osteo-anabolic effect of pharmacological estrogen administration, which is independent of FSH and requires DNA-binding of ERα in osteoblasts.
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Affiliation(s)
- Sebastian Seitz
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Keller
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Arndt F. Schilling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Plastic and Hand Surgery, Technische Universität München, Munich, Germany
| | - Anke Jeschke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Robert P. Marshall
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Brenda D. Stride
- Division Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
| | - Tim Wintermantel
- Division Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
| | - Frank T. Beil
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Günther Schütz
- Division Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
| | - Jan Tuckermann
- Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany
- * E-mail: (JT); (TS)
| | - Thorsten Schinke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- * E-mail: (JT); (TS)
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5
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Wu XY, Yu SJ, Zhang H, Xie H, Luo XH, Peng YQ, Yuan LQ, Dai RC, Sheng ZF, Liu SP, Wu XP, Liao EY. Early bone mineral density decrease is associated with FSH and LH, not estrogen. Clin Chim Acta 2012; 415:69-73. [PMID: 23063515 DOI: 10.1016/j.cca.2012.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Revised: 09/17/2012] [Accepted: 10/04/2012] [Indexed: 10/27/2022]
Abstract
BACKGROUND It remains unclear whether gonadotropins or estrogen is responsible for early bone mineral density (BMD) decrease in Chinese women. METHODS A cross-sectional study was conducted on 368 healthy adult women, aged 35-60 years. We measured BMD, calculated BMD decrease rates (BDRs) and assessed serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E(2)) levels. RESULTS BDR was significantly negatively correlated with serum FSH (r=-0.429 to -0.622, all p=0.000) and LH (r=-0.359 to -0.526, all p=0.000). After adjustment for age and body mass index, the negative correlations of serum FSH and LH with BDR persisted, but there was no overall correlation between serum E(2) and BDR. Multiple linear stepwise regression analysis suggested that serum FSH is a negative determinant of BDR. Serum E(2) seems to be a positive determinant of BDR in a few parts of the skeleton. CONCLUSIONS The decrease of BMD during the menopause is associated with FSH and LH levels, rather than E(2) in Chinese women.
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Affiliation(s)
- Xi-Yu Wu
- Institute of Metabolism and Endocrinology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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6
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Yan YX, Gong YW, Guo Y, Lv Q, Guo C, Zhuang Y, Zhang Y, Li R, Zhang XZ. Mechanical strain regulates osteoblast proliferation through integrin-mediated ERK activation. PLoS One 2012; 7:e35709. [PMID: 22539993 PMCID: PMC3335094 DOI: 10.1371/journal.pone.0035709] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 03/20/2012] [Indexed: 01/21/2023] Open
Abstract
Mechanical strain plays a critical role in the proliferation, differentiation and maturation of bone cells. As mechanical receptor cells, osteoblasts perceive and respond to stress force, such as those associated with compression, strain and shear stress. However, the underlying molecular mechanisms of this process remain unclear. Using a four-point bending device, mouse MC3T3-E1 cells was exposed to mechanical tensile strain. Cell proliferation was determined to be most efficient when stimulated once a day by mechanical strain at a frequency of 0.5 Hz and intensities of 2500 µε with once a day, and a periodicity of 1 h/day for 3 days. The applied mechanical strain resulted in the altered expression of 1992 genes, 41 of which are involved in the mitogen-activated protein kinase (MAPK) signaling pathway. Activation of ERK by mechanical strain promoted cell proliferation and inactivation of ERK by PD98059 suppressed proliferation, confirming that ERK plays an important role in the response to mechanical strain. Furthermore, the membrane-associated receptors integrin β1 and integrin β5 were determined to regulate ERK activity and the proliferation of mechanical strain-treated MC3T3-E1 cells in opposite ways. The knockdown of integrin β1 led to the inhibition of ERK activity and cell proliferation, whereas the knockdown of integrin β5 led to the enhancement of both processes. This study proposes a novel mechanism by which mechanical strain regulates bone growth and remodeling.
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Affiliation(s)
- Yu-xian Yan
- Institute of Medical Equipment, Academy of Military Medical Science, Tianjin, China
- Experiment Management Center of Medical College of People's Armed Police Forces, TianJin, China
| | - Yuan-wei Gong
- Institute of Medical Equipment, Academy of Military Medical Science, Tianjin, China
| | - Yong Guo
- Institute of Medical Equipment, Academy of Military Medical Science, Tianjin, China
| | - Qi Lv
- Experiment Management Center of Medical College of People's Armed Police Forces, TianJin, China
| | - Chun Guo
- Institute of Medical Equipment, Academy of Military Medical Science, Tianjin, China
| | - Yan Zhuang
- Experiment Management Center of Medical College of People's Armed Police Forces, TianJin, China
| | - Yuan Zhang
- Experiment Management Center of Medical College of People's Armed Police Forces, TianJin, China
| | - Ruixin Li
- Institute of Medical Equipment, Academy of Military Medical Science, Tianjin, China
| | - Xi-zheng Zhang
- Institute of Medical Equipment, Academy of Military Medical Science, Tianjin, China
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7
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Rouach V, Katzburg S, Koch Y, Stern N, Somjen D. Bone loss in ovariectomized rats: Dominant role for estrogen but apparently not for FSH. J Cell Biochem 2011; 112:128-37. [DOI: 10.1002/jcb.22908] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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8
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Abstract
Elevated follicle-stimulating hormone (FSH) activity is proposed to directly cause bone loss independent of estradiol deficiency in aging women. Using transgenic female mice expressing human FSH (TgFSH), we now reveal that TgFSH dose-dependently increased bone mass, markedly elevating tibial and vertebral trabecular bone volume. Furthermore, TgFSH stimulated a striking accrual of bone mass in hypogonadal mice lacking endogenous FSH and luteinizing hormone (LH) function, showing that FSH-induced bone mass occurred independently of background LH or estradiol levels. Higher TgFSH levels increased osteoblast surfaces in trabecular bone and stimulated de novo bone formation, filling marrow spaces with woven rather than lamellar bone, reflective of a strong anabolic stimulus. Trabecular bone volume correlated positively with ovarian-derived serum inhibin A or testosterone levels in TgFSH mice, and ovariectomy abolished TgFSH-induced bone formation, proving that FSH effects on bone require an ovary-dependent pathway. No detectable FSH receptor mRNA in mouse bone or cultured osteoblasts or osteoclasts indicated that FSH did not directly stimulate bone. Therefore, contrary to proposed FSH-induced bone loss, our findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism, which is independent of LH activity, and does not involve direct FSH actions on bone cells.
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9
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Lana MBP, Straminsky V, Onetto C, Amuchastegui JM, Blanco G, Galluzzo L, Provenzano S, Nolting M. What is really responsible for bone loss in spontaneous premature ovarian failure? A new enigma. Gynecol Endocrinol 2010; 26:755-9. [PMID: 20504091 DOI: 10.3109/09513590.2010.487599] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To determine if there is a relation between the follicle-stimulating hormone (FSH) and oestradiol levels with values found in bone mineral density, at lumbar spinal and femoral neck levels, in patients with spontaneous premature ovarian failure (POF) as at the time of diagnosis. METHOD Cross-sectional study. Eighty-five patients were selected with a diagnosis of POF. Inclusion criteria. Forty women with bone mineral density (BMD) in any of the regions, that is, lumbar spine column or femoral neck. Forty-two age-matched healthy women were included as controls. RESULTS The average FSH value found was 80.11 mUI/ml, while the oestradiol average value was 37.2 pg/ml. The FSH values were correlated with the BMD values at the lumbar spinal column (p < 0.002) and the femoral neck (p < 0.002). The oestradiol values did not bear any relation with the BMD values in L2-L4 (p = 0.420) nor with the femoral neck (p = 0.868). CONCLUSIONS High FSH concentrations, but not oestradiol, are positively associated with bone mass loss in both skeletal regions, in patients with spontaneous POF.
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Affiliation(s)
- Maria Belen Perez Lana
- CLINICAS' Hospital, Gynecology Division, Gynaecological Endocrinology Section, Buenos Aires, República Argentina.
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10
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DuSell CD, Nelson ER, Wang X, Abdo J, Mödder UI, Umetani M, Gesty-Palmer D, Javitt NB, Khosla S, McDonnell DP. The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis. Endocrinology 2010; 151:3675-85. [PMID: 20501668 PMCID: PMC2940523 DOI: 10.1210/en.2010-0080] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, and the identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydroxycholesterol (27HC), suggests a mechanism by which nutritional/metabolic status can influence bone biology. With its levels directly correlated with cholesterol, a new possibility emerges wherein 27HC links estrogen and cholesterol signaling to bone homeostasis. In these studies, we found that increasing concentrations of 27HC, both by genetic and pharmacological means, led to decreased bone mineral density that was associated with decreased bone formation and increased bone resorption. Upon manipulation of endogenous estrogen levels, many of the responses to elevated 27HC were altered in such a way as to implicate ER as a likely mediator. In a model of postmenopausal bone loss, some pathologies associated with elevated 27HC were exacerbated by the absence of endogenous estrogens, suggesting that 27HC may act both in concert with and independently from classic ER signaling. These data provide evidence for interactions between estrogen signaling, cholesterol and metabolic disease, and osteoporosis. Patients with high cholesterol likely also have higher than average 27HC, perhaps putting them at a higher risk for bone loss and fracture. More studies are warranted to fully elucidate the mechanism of action of 27HC in bone and to identify ways to modulate this pathway therapeutically.
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Affiliation(s)
- Carolyn D DuSell
- Department of Pharmacology, Duke University Medical Center, Pharmacology and Cancer Biology, Durham, North Carolina 27710, USA
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11
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Abstract
Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates secretion of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which directly regulate ovarian function. Pituitary FSH can modulate osteoclast development, and thereby influence bone turnover. Pituitary oxytocin and prolactin effects on the skeleton are not merely limited to pregnancy and lactation; oxytocin stimulates osteoblastogenesis and bone formation, whereas prolactin exerts skeletal effects in an age-dependent manner. Cyclic levels of inhibins and estrogen suppress FSH and LH, respectively, and also suppress bone turnover via their suppressive effects on osteoblast and osteoclast differentiation. However, continuous exposure to inhibins or estrogen/androgens is anabolic for the skeleton in intact animals and protects against gonadectomy-induced bone loss. Alterations of one hormone in the hypothalamic-pituitary-gonadal (HPG) axis influence other bone-active hormones in the entire feedback loop in the axis. Thus, we propose that the action of the HPG axis should be extended to include its combined effects on the skeleton, thus creating the HPG skeletal (HPGS) axis.
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Affiliation(s)
- Kristy M Nicks
- Departments of Physiology and Biophysics and Orthopaedic Surgery, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 505, Little Rock, AR, 72205, USA.
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12
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Sowers MR, Zheng H, Jannausch ML, McConnell D, Nan B, Harlow S, Randolph JF. Amount of bone loss in relation to time around the final menstrual period and follicle-stimulating hormone staging of the transmenopause. J Clin Endocrinol Metab 2010; 95:2155-62. [PMID: 20215399 PMCID: PMC2869543 DOI: 10.1210/jc.2009-0659] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND OBJECTIVE The objective of the study was to describe bone loss rates across the transmenopause related to FSH staging and the final menstrual period (FMP). DESIGN AND SETTING This was a population-based cohort of 629 women (baseline age 24-44 yr) with annual data points over 15 yr. MEASUREMENTS Measures were bone mineral density (BMD), FSH to define four FSH stages, and menstrual bleeding cessation to define the FMP. Bone loss rates were reported by obesity status. RESULTS Annualized rates of lumbar spine bone loss began in FSH stage 3, which occurs approximately 2 yr prior to the FMP (1.67%/yr); bone loss continued into FSH stage 4 (1.21%/yr). Mean spine BMD in FSH stage 4 was 6.4% less than spine BMD value in FSH stage 1. Annualized rates of femoral neck (FN) bone loss began in FSH stage 3 (0.55%/yr) and continued into FSH stage 4 (0.72%/yr). The FN difference between mean values in FSH stage 1 and FSH stage 4 was 5%. Annualized rates of spine bone loss in the 2 yr prior to the FMP were 1.7%/yr, 3.3%/yr in the 2 yr after the FMP, and 1.1%/yr in the 2- to 7-yr period after the FMP. Nonobese women had lower BMD levels and greater bone loss rates. CONCLUSIONS Spine and FN bone loss accelerates in FSH stage 3. Bone loss also began to accelerate 2 yr before the FMP with the greatest loss occurring in the 2 yr after the FMP. Bone loss rates in both spine and FN BMD were greater in nonobese women than obese women.
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Affiliation(s)
- MaryFran R Sowers
- Department of Epidemiology, School of Public Health, University of Michigan, 109 Observatory Street, Ann Arbor, Michigan 48109, USA.
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13
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Protective Effects of Follicle-stimulating Hormone Inhibitor on Alveolar Bone Loss Resulting from Experimental Periapical Lesions in Ovariectomized Rats. J Endod 2010; 36:658-63. [DOI: 10.1016/j.joen.2010.01.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Revised: 01/09/2010] [Accepted: 01/15/2010] [Indexed: 11/17/2022]
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14
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Liu S, Cheng Y, Fan M, Chen D, Bian Z. FSH aggravates periodontitis-related bone loss in ovariectomized rats. J Dent Res 2010; 89:366-71. [PMID: 20139335 DOI: 10.1177/0022034509358822] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Alveolar bone loss is one of the prominent pathologic and clinical features of periodontitis. Recently, the direct effect of follicle-stimulating hormone (FSH) on bone resorption has been demonstrated. However, the effect of FSH on alveolar bone loss remains unknown. This study tested the hypothesis that FSH would exacerbate periodontitis-related alveolar bone loss. Experimental periodontitis was induced in ovariectomized rats, and the rats were treated with extrinsic FSH or its inhibitor, leuprorelin. After mandibles were collected, we performed morphological examinations to evaluate bone loss, enzyme histochemical tests for osteoclasts, and immunohistochemical examinations for FSH receptor (FSHR). The results showed that FSH significantly increased alveolar bone resorption compared with non-FSH-treated ovariectomized rats (P < 0.05), and the number of FSHR-positive cells was positively correlated with alveolar bone loss area (r = 0.682, P < 0.01). Our results suggested that FSH can aggravate alveolar bone loss by FSHR, independent of estrogen.
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Affiliation(s)
- S Liu
- Key Lab for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, Hubei, 430079, P.R. China
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15
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Is there an association between vasomotor symptoms and both low bone density and cardiovascular risk? Menopause 2009; 16:219-23. [PMID: 19188853 DOI: 10.1097/gme.0b013e318199404a] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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16
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Buday B, Kulcsár E, Literáti Nagy B, Horváth T, Vitai M, Vecsei I, Bezzegh K, Kiss J, Péterfai É, Koltay L, Korányi L. The role of osteocalcin in the connection of bone and glucose metabolism in humans. Orv Hetil 2008; 149:2453-61. [DOI: 10.1556/oh.2008.28518] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Egerekben az osteocalcin hiányakor csökken a pancreas β-sejtjeinek proliferációja, és bennük az
inzulin
, a zsírsejtekben pedig az
adiponektin
génexpressziója.
Módszer:
Az inzulinérzékenység, a csontállapot, illetve az osteocalcin kapcsolatát 45 egészséges (nő: 20, férfi: 25) és 92 glükózintoleráns (nő: 51, férfi: 41) egyén esetében vizsgálták. Nemenként elkülönítve mérték a testösszetételt, a csontok denzitását, a csontbontás és a csontépítés markereit és hyperinsulinaemiás-normoglykaemiás teszttel az inzulinérzékenységet tükröző cukorfelhasználást.
Eredmények:
Az osteocalcinszintek a két nemben hasonlóak voltak, de a glükózintoleráns férfi betegek osteocalcinszintje alacsonyabb volt, mint az egészségeseké (24,5±11 vs. 18,1±9 ng/ml,
p
< 0,05). Az egészséges csoportban, mindkét nemben pozitív volt a korreláció az osteocalcin és az izomszövet cukorfelhasználása között (M-érték: nők:
r
= +0,319,
p
< 0,05, férfiak:
r
= 0,481,
p
< 0,01), de a glükózintoleráns csoportokban ez a kapcsolat eltűnt. Az osteocalcin egyik nemben sem mutatott korrelációt az adiponektinszinttel. Többváltozós lineáris regresszió alapján az osteocalcin szignifikáns független prediktora
az összes nő
esetében az éhomi vércukor, a teljes test és az izomtömeg cukorfelhasználása, a cukorfelhasználás sebessége, az ösztradiol és az LDL-koleszterin-vérszint (92%-os determináció), míg az
összes férfi
esetében a szérumkalcium, az OGTT során mért glükózszintek görbe alatti területe, a szabadzsírsav-szint, az inzulogenikus index, a HOMA-IR és a has/csípő körfogat (95%-os determináció) volt. A csontbontást-csontépítést jellemző BMU-index csak nők esetében korrelált szignifikánsan az M-értékekkel.
Következtetés:
Vizsgálatunk egészségesek esetében megerősítette az inzulinérzékenység–osteocalcin kapcsolatot emberi vonatkozásban is, de a csontanyagcsere–energia-háztartás közötti kapcsolatban jelentős nemi különbséget talált, amely nem az osteocalcin szintjén alakult ki.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - László Koltay
- 3 Pannon Egyetem Matematikai és Számítástechnikai Tanszék Veszprém
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17
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Mansell JP. Bone phenotypes in response to gonadotropin misexpression: the role for gonadotropins in postmenopausal osteoporosis. Int J Gen Med 2008; 1:51-7. [PMID: 20428406 PMCID: PMC2840536 DOI: 10.2147/ijgm.s3879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Scant attention has been paid to the potential role of gonadotropins in bone tissue homeostasis. The focus on estrogen and estrogen replacement therapy for osteoporosis as far back as the 1940's may account for the paucity of gonadotropin studies in bone biology. It is conceivable that prevailing dogma may have subconsciously steered us away from addressing whether gonadotropins have a place in skeletal physiology. However an examination of bone tissue catabolism in ovariectomized (OVX) and luteinizing hormone-releasing hormone (LHRH) agonist (Zoladex((R)))-treated rats generated some interesting and conflicting data; Zoladex-treated rats, unlike the OVX group, failed to exhibit increased bone collagen catabolism despite clear evidence for estrogen deficiency. The findings, although controversial, supported the possibility that elevated gonadotropins in the OVX model were in some way accountable for increased bone catabolism. In response to these initial findings further studies were performed to determine if altered LH status may in some way impact on the skeleton To this end an investigation of bone mass and histomorphometry were conducted in LH receptor nullizygous mice and human chorionic gonadotropin (hCG) overexpressing mice. There were clear phenotypic differences; the LH receptor knockout mice displayed reduced bone mass whereas the hCG overexpressing animals had stark increases in bone mass. Much more recently the team of the Mount Sinai Bone Program have made a significant discovery that bone-resorbing osteoclasts express receptors for follicle-stimulating hormone (FSH) and that mice nullizygous for FSH receptor are resistant to bone loss despite severe estrogen deficiency. Details of these fascinating models will be presented together with additional findings that give credence for exploring gonadotropin action on the skeleton as we enter the twilight of this Decade of the Bone and Joint.
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Affiliation(s)
- Jason P Mansell
- Department of Oral and Dental Sciences, Division of Oral Medicine, University of Bristol Dental School, Lower Maudlin Street, Bristol, BS1 2LY, UK
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18
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Affiliation(s)
- Graham R Williams
- Molecular Endocrinology Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
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19
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Gao J, Tiwari-Pandey R, Samadfam R, Yang Y, Miao D, Karaplis AC, Sairam MR, Goltzman D. Altered ovarian function affects skeletal homeostasis independent of the action of follicle-stimulating hormone. Endocrinology 2007; 148:2613-21. [PMID: 17332067 DOI: 10.1210/en.2006-1404] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Osteoporosis is a leading public health problem. Although a major cause in women is thought to be a decline in estrogen, it has recently been proposed that FSH or follitropin is required for osteoporotic bone loss. We examined the FSH receptor null mouse (FORKO mouse) to determine whether altered ovarian function could induce bone loss independent of FSH action. By 3 months of age, FORKO mice developed age-dependent declines in bone mineral density and trabecular bone volume of the lumbar spine and femur, which could be partly reversed by ovarian transplantation. Bilateral ovariectomy reduced elevated circulating testosterone levels in FORKO mice and decreased bone mass to levels indistinguishable from those in ovariectomized wild-type controls. Androgen receptor blockade and especially aromatase inhibition each produced bone volume reductions in the FORKO mouse. The results indicate that ovarian secretory products, notably estrogen, and peripheral conversion of ovarian androgen to estrogen can alter bone homeostasis independent of any bone resorptive action of FSH.
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Affiliation(s)
- Jianjun Gao
- Calcium Research Laboratory, McGill University Health Centre, 687 Pine Avenue West, Montreal, Quebec, Canada
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20
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Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, Hogue WR, Nicks KM, Pierson TM, Suva LJ, Gaddy D. Inhibin A is an endocrine stimulator of bone mass and strength. Endocrinology 2007; 148:1654-65. [PMID: 17194739 DOI: 10.1210/en.2006-0848] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Gonadal function plays a major role in bone homeostasis. It is widely held that the skeletal consequences of hypogonadism are solely due to a loss of sex steroids; however, increases in bone turnover begin during perimenopause before decreases in serum estradiol levels. These data and our demonstration that inhibins acutely regulate bone cell differentiation in vitro led us to test whether inhibin A (InhA) regulates bone mass in vivo. Using a transgenic model of inducible human InhA expression, InhA increased total body bone mineral density, increased bone volume, and improved biomechanical properties at the proximal tibia in intact mice and also prevented the loss of BMD and bone volume and strength associated with gonadectomy at both the spine and proximal tibia. In addition, InhA increased mineral apposition rate, double-labeled surface, and serum osteocalcin levels in vivo and osteoblastogenesis ex vivo without affecting osteoclast number or activity. Together these results demonstrate novel stimulatory effects of InhA on the skeleton in vivo. These studies provide in vivo evidence demonstrating that gonadal factors other than sex steroids play an important role in regulating bone mass and strength and, combined with our previous clinical data, suggest that gonadal InhA may be a component of the normal endocrine repertoire that regulates bone quality in both the axial and appendicular skeleton.
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Affiliation(s)
- Daniel S Perrien
- Department of Physiology and Biophysics, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 505, Little Rock, Arkansas 72205, USA
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21
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Prior JC. FSH and bone--important physiology or not? Trends Mol Med 2006; 13:1-3. [PMID: 17141571 DOI: 10.1016/j.molmed.2006.11.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2006] [Revised: 11/03/2006] [Accepted: 11/20/2006] [Indexed: 11/17/2022]
Abstract
For many years, osteoporosis in women was equated with estrogen deficiency. The recent articles by Zaidi and colleagues offer a new challenge to the estrogen-deficiency-osteoporosis hypothesis by showing that follicle-stimulating hormone (FSH) stimulates osteoclastic bone resorption perhaps through tumor necrosis factor-alpha (TNF-alpha). These authors, however, neglected to mention bone abnormalities and high testosterone levels that were previously shown in FSH-receptor knockout and other modified mice. It is also possible that they have overemphasized potential relationships of these new data with human bone loss. Despite these fascinating data, the paradigm of FSH causing hypogonadal bone loss is not yet ready to displace the estrogen-deficiency-osteoporosis paradigm, although that model already faces considerable challenge.
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Affiliation(s)
- Jerilynn C Prior
- Endocrinology and Metabolism, Centre for Menstrual Cycle and Ovulation Research, University of British Columbia, Vancouver Coastal Health Research Institute, Vancouver V5Z 1M9, Canada.
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