Regulation of bone growth via ligand-specific activation of estrogen receptor alpha

Estrogens are well known for their capacity to promote bone maturation and at high doses to induce growth plate closure and thereby stop further growth. High-dose estrogen treatment has therefore been used to limit growth in extremely tall girls. However, recent data suggest that this treatment may have severe side effects, including increased risk of cancer and reduced fertility. We hypothesized that estrogenic effects in bone are mediated via ERα signaling. Twelve-week-old ovariectomized female C57BL/6 mice were subcutaneously injected for 4 weeks with E2 or selective ERα (PPT) or ERβ (DPN) agonists. After killing, tibia and femur lengths were measured, and growth plate morphology was analyzed. E2- and PPT-treated mice had shorter tibiae and femur bones when compared to vehicle-treated controls, whereas animals treated with DPN had similar bone lengths compared to controls. Growth plate height and hypertrophic zone height were reduced in animals treated with E2 or PPT but not in those treated with DPN, supporting that the effect was mediated via ERα. Moreover, PCNA staining revealed suppressed proliferation of chondrocytes in the tibia growth plate in PPT- or E2-treated mice compared to controls. Our data show that estrogenic effects on bone growth and growth plate maturation are mainly mediated via ERα. Our findings may have direct implications for the development of new and more selective treatment modalities of extreme tall stature using selective estrogen receptor modulators that may have low side effects than high-dose E2 treatment.

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The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00646.2011 ◽

2012 ◽

Vol 302 (11) ◽

pp. E1381-E1389 ◽

Cited By ~ 26

Author(s):

A. E. Börjesson ◽

S. H. Windahl ◽

E. Karimian ◽

E. E. Eriksson ◽

M. K. Lagerquist ◽

...

Keyword(s):

Estrogen Receptor ◽

Growth Plate ◽

Bone Growth ◽

High Dose ◽

Plate Height ◽

Chondrocyte Proliferation ◽

Growth Plates ◽

Longitudinal Bone Growth ◽

Female Mice

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)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα−/−) or ERαAF-1 (ERαAF-10) were evaluated. Old (16- to 19-mo-old) female ERα−/− 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 ERαAF-10 mice (tibia: −4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-10 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 ERα−/− 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 ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.

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Reduced Rate of Infectious Complications Following Bloodless Autologous Peripheral Blood Stem Cell Transplants (APBSCT).

Blood ◽

10.1182/blood.v108.11.5453.5453 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5453-5453 ◽

Cited By ~ 1

Author(s):

Patricia A. Ford ◽

Barbara A. Matthews ◽

Nicole M. Brown

Keyword(s):

Breast Cancer ◽

High Dose Chemotherapy ◽

Infectious Complications ◽

High Dose ◽

Blood Transfusions ◽

Risk Of Infection ◽

Infection Rates ◽

Autologous Transplants ◽

Increased Risk ◽

Risk Of Cancer

Abstract While blood transfusions can be life saving, the associated risk of transfusing allogeneic blood is significant. The most common patient fears are transfusion-transmitted diseases such as HIV, Hepatitis B and C and West Nile Virus; however, the known risk of transmitting these diseases is quite small. More common complications are due to immunosuppression which can cause an increased risk of cancer recurrence in the oncologic patient and a significantly increased risk of infection. In trauma patients, it has been shown that the risk of infection increases with each additional unit of blood transfused. Currently, about 2.2 units of platelets and 3.3 units of red blood cells are administered following high-dose chemotherapy and an APBSCT. At the Center for Bloodless Medicine and Surgery at Pennsylvania Hospital, many procedures are now being completed without the use of blood products. We have previously reported the ability to perform bloodless APBSCT (Ballen, et al. J Clin Oncol2004;22:4087-4094). Knowing that blood transfusions can increase the risk of infection, we wanted to evaluate this transfusion-free population to determine if there was a correlation between infection rates and blood transfusions in the high risk transplant population. We performed a retrospective chart review of 46 patients with multiple myeloma (22), lymphoma (22) and breast cancer (2) who underwent a bloodless APBSCT in our center. Prior to transplantation, all patients recieved standard transplant doses of cyclophosphamide, carmustine and etoposide (BCV) or Melphalan. A PubMed search was performed and the closest data set in terms of patient demographics was a study by Pereira, et al. who report the rate of infectious complications in 75 patients with myeloma (30), lymphoma (30) and breast cancer (15) who were transfused liberally following high-dose chemotherapy and APBSCT (Pereira, et al. Eur J Haematol2006;76:102-108). In our bloodless patients, 37% of the patients had at least one infection, compared to Pereira and colleagues’ rate of 68% (see table). Our results are also reported in the average number of infections per patient. This comparison demonstrates a substantial reduction in the rate of infection in the bloodless population. While immunosuppression and the resulting increased infection rates have been correlated to blood transfusions in other patients populations, to the best of our knowledge this is the first report that suggests decreased infection rates in transfusion-free transplant patients. This data provides further evidence to support the practice of blood management strategies in order to reduce or eliminate blood transfusions. Patients with at least one infection All infections per person Bacterial per person Viral per person Fungal per person Unknown per person Autologous Transplants (Pereira, et al.) 68% .64 .53 .01 .07 .03 Bloodless Autologous Transplants 37% .41 .39 0 0 .02

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Cancer After Spinal Fusion

Neurosurgery ◽

10.1227/neu.0000000000000018 ◽

2013 ◽

Vol 73 (3) ◽

pp. 440-449 ◽

Cited By ~ 48

Author(s):

Shivanand P. Lad ◽

Jacob H. Bagley ◽

Isaac O. Karikari ◽

Ranjith Babu ◽

Beatrice Ugiliweneza ◽

...

Keyword(s):

Propensity Score ◽

Benign Tumor ◽

Treated Group ◽

Benign Tumors ◽

High Dose ◽

Matched Cohort ◽

Covariate Balance ◽

Increased Risk ◽

Before And After ◽

Risk Of Cancer

Abstract BACKGROUND: Bone morphogenetic protein (BMP) is used in tens of thousands of spinal fusions each year. A trial evaluating a high-dose BMP formulation demonstrated that its use may be associated with an increased risk of cancer. OBJECTIVE: To evaluate whether BMP, as commonly used today, is associated with an increased risk of cancer or benign tumors. METHODS: We performed a retrospective study using the Thomson Reuter MarketScan database. We retained all patients who had no previous diagnosis of cancer or benign tumor and had at least 2 years of uninterrupted enrollment in the database before and after their operations. A propensity score--matched cohort was created to ensure greater covariate balance between treatment groups. RESULTS: Within the propensity score--matched cohort (n = 4698), BMP-exposed patients had a nonsignificant increase in the rate of cancer diagnosis (9.37% vs 7.92%; P = .08). After adjustment for covariates, BMP exposure was associated with a 31% increased risk of benign tumor diagnosis (odds ratio, 1.31; 95% confidence interval, 1.02-1.68; P < .05). When the benign tumor diagnoses were stratified by organ type, BMP patients had significantly more diagnoses of benign nervous system tumors (0.81% vs 0.34%; P = .03), and within this group, benign tumors of the spinal meninges were much more common in the BMP-treated group (0.13% vs 0.02%; P = .002). CONCLUSION: The results of this large, independent, propensity-matched study suggest that the use of BMP in lumbar fusions is associated with a significantly higher rate of benign neoplasms but not malignancies.

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DHEA Suppresses Longitudinal Bone Growth by Acting Directly at Growth Plate through Estrogen Receptors

Endocrinology ◽

10.1210/en.2010-0920 ◽

2011 ◽

Vol 152 (4) ◽

pp. 1423-1433 ◽

Cited By ~ 8

Author(s):

Hongzhi Sun ◽

Weijin Zang ◽

Bo Zhou ◽

Lin Xu ◽

Shufang Wu

Keyword(s):

Estrogen Receptor ◽

Growth Plate ◽

Bone Growth ◽

Nuclear Factor Κb ◽

Binding Activity ◽

Skeletal Maturation ◽

Chondrocyte Apoptosis ◽

Chondrocyte Proliferation ◽

Longitudinal Bone Growth ◽

Growth Plate Chondrocyte

Abstract Dehydroepiandrosterone (DHEA) is produced by the adrenal cortex and is the most abundant steroid in humans. Although in some physiological and pathological conditions the increased secretion of DHEA and its sulfated form is associated with accelerated growth rate and skeletal maturation, it is unclear whether DHEA can affect longitudinal bone growth and skeletal maturation by acting directly at the growth plate. In our study, DHEA suppressed metatarsal growth, growth plate chondrocyte proliferation, and hypertrophy/differentiation. In addition, DHEA increased the number of apoptotic chondrocytes in the growth plate. In cultured chondrocytes, DHEA reduced chondrocyte proliferation and induced apoptosis. The DHEA-induced inhibition of metatarsal growth and growth plate chondrocyte proliferation and hypertrophy/differentiation was nullified by culturing metatarsals with DHEA in the presence of ICI 182,780, an inhibitor of estrogen receptor, but not in the presence of Casodex, an inhibitor of androgen receptor. Lastly, nuclear factor-κB DNA binding activity was inhibited by the addition of DHEA in the medium of cultured chondrocyte. Our findings indicate that DHEA suppressed bone growth by acting directly at growth plate through estrogen receptor. Such growth inhibition is mediated by decreased chondrocyte proliferation and hypertrophy/differentiation and by increased chondrocyte apoptosis.

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The Association between Use of ICS and Psychiatric Symptoms in Patients with COPD—A Nationwide Cohort Study of 49,500 Patients

Biomedicines ◽

10.3390/biomedicines9101492 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1492

Author(s):

Alexander Jordan ◽

Pradeesh Sivapalan ◽

Josefin Eklöf ◽

Jakob B. Vestergaard ◽

Howraman Meteran ◽

...

Keyword(s):

Cohort Study ◽

Side Effects ◽

Psychiatric Symptoms ◽

Psychiatric Hospitals ◽

High Dose ◽

Moderate Increase ◽

High Exposure ◽

Increased Risk ◽

Antidepressant Use ◽

Psychiatric Side Effects

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified COPD, age ≥40 years, and no previous cancer. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder were assessed by Cox proportional hazards models. We observed a dose-dependent increase in the risk of antidepressant-use with ICS cumulated dose (HR 1.05, 95% CI 1.03–1.07, p = 0.0472 with low ICS exposure, HR 1.10, 95% CI 1.08–1.12, p < 0.0001 with medium exposure, HR 1.15, 95% CI 1.11–1.15, p < 0.0001 with high exposure) as compared to no ICS exposure. We found a discrete increased risk of admission to psychiatric hospitals in the medium and high dose group (HR 1.00, 95% CI 0.98–1.03, p = 0.77 with low ICS exposure, HR 1.07, 95% CI 1.05–1.10, p < 0.0001 with medium exposure, HR 1.13, 95% CI 1.10–1.15, p < 0.0001 with high exposure). The association persisted when stratifying for prior antidepressant use. Thus, exposure to ICS was associated with a small to moderate increase in antidepressant-use and psychiatric admissions.

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High dose antipsychotic treatment monitoring audit

BJPsych Open ◽

10.1192/bjo.2021.912 ◽

2021 ◽

Vol 7 (S1) ◽

pp. S348-S348

Author(s):

Jake Scott ◽

Jose Belda

Keyword(s):

Side Effects ◽

Physical Health ◽

Health Monitoring ◽

Clinical Benefit ◽

Health Assessment ◽

Antipsychotic Treatment ◽

High Dose ◽

Health Checks ◽

Increased Risk ◽

Multi Disciplinary Team

AimsTo quantify how many patients were prescribed high dose antipsychotic treatment (HDAT) and establish whether guidance for monitoring HDAT was being followed in an Assertive Outreach Team.BackgroundSevere mental health disorders are associated with significant premature mortality, predominantly due to physical health conditions. Antipsychotic medications are associated with side effects, including metabolic syndrome and QT prolongation, which increase the risk of serious physical illness. HDAT is defined as when the total dose of antipsychotics prescribed exceeds 100% of the maximum BNF dose, if each dose is expressed a percentage of its maximum dose. There is limited evidence of clinical benefit with HDAT but an increased risk of side effects. Patients prescribed HDAT should therefore be monitored for side effects and clinical benefit. Sussex Partnership NHS Foundation Trust developed a form specifically for this purpose, to be completed in addition to a physical health assessment.MethodAll patients on caseload were audited using the electronic notes. Current inpatients were excluded, as inpatient HDAT monitoring forms are attached to paper drug charts and therefore were not available for review.ResultA total of 61 patients were audited. Nine were excluded due to being inpatients. 16 were on community treatment orders and 26 were prescribed a long-acting antipsychotic injection. 10 were prescribed clozapine. The median number of medications prescribed was one. Four patients were prescribed HDAT ranging from 117-150% of the maximum BNF dose. Of these four, one had a HDAT form but this was out of date. 39 of 52 (75%) patients audited had had a physical health assessment in the past 12 months. Two of the 13 missing a physical health assessment were on HDAT.ConclusionPhysical health monitoring should be carried out for all patients on antipsychotics, but is particularly important for patients on HDAT. This audit identified a problem in both general physical health checks and HDAT monitoring. On discussion with the multi-disciplinary team a number of barriers to appropriate physical health monitoring were identified. There was a lack of awareness within the multi-disciplinary team that patients were receiving HDAT and regarding the implications for side effects. A reliable system to highlight the need for physical health checks was also missing and the team did not have sufficient equipment to perform the necessary checks. Identifying these barriers should enable improvements in physical health and HDAT monitoring which can be re-audited.

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Application of polymeric nanoparticles in oral delivery of recombinant human erythropoietin: A review

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v9i1-s.2336 ◽

2019 ◽

Vol 9 (1-s) ◽

pp. 403-407

Author(s):

Pankaj Rajendra Dhapake ◽

Jasmine G Avari

Keyword(s):

Side Effects ◽

Drug Release ◽

Oral Delivery ◽

Recombinant Human Erythropoietin ◽

Dosage Form ◽

The Body ◽

High Dose ◽

Risk Of Death ◽

Human Erythropoietin ◽

Increased Risk

Recombinant Human Erythropoietin drugs are known as erythropoietin stimulating agents which stimulate the bone marrow to produce more red blood cells in the body. It is used an antianemic in the treatment of renal anemia and chemotherapy induced anemia. It also use in treatment of HIV, cerebral malaria and neurological disease like schizophrenia. The recombinant human erythropoietin dosage form currently available in the market is parenteral dosage form that is ready for injection liquid vial (syringe), which is usually administered 2-3 times weekly. To achieve a therapeutic effect of parenterally administered EPO, cumulative doses are required that significantly exceed levels of endogenous EPO. These high serum levels result in prolonged circulation times of EPO and unspecific binding to non-targeted tissue, which may lead to severe undesired side effects i.e. growth of tumor and also increased risk of death. By using the nanotechnology, side effects and toxicity related to high dose of erythropoietin should be reduces and prolong drug release. this will achieve by reducing administration frequency and lowering dosage of erythropoietin. Keywords: Recombinant Human Erythropoietin, Nanoparticle, Prolong drug release, Anemia

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A Mixture of Humulus japonicus Increases Longitudinal Bone Growth Rate in Sprague Dawley Rats

Nutrients ◽

10.3390/nu12092625 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2625

Author(s):

Ok-Kyung Kim ◽

Jeong moon Yun ◽

Minhee Lee ◽

Soo-Jeung Park ◽

Dakyung Kim ◽

...

Keyword(s):

Growth Plate ◽

Bone Growth ◽

Tail Length ◽

Janus Kinase ◽

Sprague Dawley ◽

Plate Height ◽

Longitudinal Bone Growth ◽

Sd Rats ◽

Humulus Japonicus ◽

Igfbp 3

The aim of this study was to investigate the effects of administration of a mixture of Humulus japonicus (MH) on longitudinal bone growth in normal Sprague Dawley (SD) rats. We measured the femur and tibia length, growth plate area, proliferation of chondrocytes, and expression of insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3), and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) phosphorylation after dietary administration of MH in SD rats for four weeks. The nose–tail length gain and length of femur and tibia increased significantly in the group that received MH for a period of four weeks. We performed H&E staining and Bromodeoxyuridine/5-Bromo-2′-Deoxyuridine (BrdU) staining to examine the effect of dietary administration of MH on the growth plate and the proliferation of chondrocytes and found that MH stimulated the proliferation of chondrocytes and contributed to increased growth plate height during the process of longitudinal bone growth. In addition, serum levels of IGF-1 and IGFBP-3 and expression of IGF-1 and IGFBP-3 mRNAs in the liver and bone were increased, and phosphorylation of JAK2/STAT5 in the liver was increased in the MH groups. Based on these results, we suggest that the effect of MH on longitudinal bone growth is mediated by increased JAK2/STAT5-induced IGF-1 production.

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Analysis of Association between Morphometric Parameters of Growth Plate and Bone Growth of Tibia in Mice and Humans

Cartilage ◽

10.1177/1947603519900800 ◽

2020 ◽

pp. 194760351990080 ◽

Cited By ~ 1

Author(s):

Kimberly Wilson ◽

Yu Usami ◽

Danielle Hogarth ◽

Amanda L. Scheiber ◽

Hongying Tian ◽

...

Keyword(s):

Growth Rate ◽

Growth Plate ◽

Linear Correlation ◽

Bone Growth ◽

Plate Height ◽

Total Height ◽

Tibia Bone ◽

Proliferation Activity ◽

Tibia Length ◽

Plate Width

Objective The purposes of this study are to evaluate which growth plate parameters are associated with bone growth in mice and to compare the mouse results with those in humans. Design The sagittal sections of the proximal growth plate of the mouse tibia from neonate to young adult stages were subjected to histomorphometric and functional analyses. The radiographic images of tibias of human patients until puberty were analyzed to obtain the tibia length and the proximal growth plate height. It was found that a linear correlation best modeled the relationship between the growth plate variables with the tibia growth rate and length. Results In mice, total height, resting zone height, combined height of the proliferation and prehypertrophic zones, proliferation activity, and the total width of tibia growth plate showed high linear correlation with tibia bone length and bone growth rate, but the hypertrophic zone height and the growth plate area did not. In both mice and humans, the total growth plate width of tibia was found to have the strongest correlation with tibia length and growth rate. Conclusions The results validated that growth plate total height, the height of the resting zone and cell proliferation activity are appropriate parameters to evaluate the balance between growth plate activity and bone growth in mice, consistent with previous reports. The study also provided a new growth plate parameter candidate, growth plate width for growth plate activity evaluation in both mouse and human tibia bone.

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Visual Side Effects Linked to Sildenafil Consumption: An Update

Biomedicines ◽

10.3390/biomedicines9030291 ◽

2021 ◽

Vol 9 (3) ◽

pp. 291

Author(s):

Eva Ausó ◽

Violeta Gómez-Vicente ◽

Gema Esquiva

Keyword(s):

Clinical Trials ◽

Side Effects ◽

Medical Condition ◽

Case Reports ◽

Guanosine Monophosphate ◽

Cochrane Library ◽

High Dose ◽

Ischemic Optic Neuropathy ◽

Serous Macular Detachment ◽

Increased Risk

Phosphodiesterase type 5 (PDE5) inhibitors such as Viagra® (sildenafil citrate) have demonstrated efficacy in the treatment of erectile dysfunction (ED) by inducing cyclic guanosine monophosphate (cGMP) elevation followed by vasodilation and increased blood flow. It also exerts minor inhibitory action against PDE6, which is present exclusively in rod and cone photoreceptors. The effects of sildenafil on the visual system have been investigated in a wide variety of clinical and preclinical studies due to the fact that a high dose of sildenafil may cause mild and transient visual symptoms in some patients. A literature review was performed using PubMed, Cochrane Library and Clinical Trials databases from 1990 up to 2020, focusing on the pathophysiology of visual disorders induced by sildenafil. The aim of this review was not only to gather and summarize the information available on sildenafil clinical trials (CTs), but also to spot subpopulations with increased risk of developing undesirable visual side effects. This PDE inhibitor has been associated with transient and reversible ocular side effects, including changes in color vision and light perception, blurred vision, photophobia, conjunctival hyperemia and keratitis, and alterations in the electroretinogram (ERG). Sildenafil may induce a reversible increase in intraocular pressure (IOP) and a few case reports suggest it is involved in the development of nonarteritic ischemic optic neuropathy (NAION). Reversible idiopathic serous macular detachment, central serous retinopathy and ERG disturbances have been related to the significant impact of sildenafil on retinal perfusion. So far, sildenafil does not seem to cause permanent toxic effects on chorioretinal tissue and photoreceptors as long as the therapeutic dose is not exceeded and is taken under a physician’s direction to treat a medical condition. However, the recreational use of sildenafil can lead to harmful side effects, including vision changes.

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