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Zdrojowy-Wełna A, Stachowska B, Bolanowski M. Cushing's disease and bone. Pituitary 2024; 27:837-846. [PMID: 39008229 PMCID: PMC11631814 DOI: 10.1007/s11102-024-01427-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2024] [Indexed: 07/16/2024]
Abstract
Bone impairment associated with Cushing's disease (CD) is a complex disorder, mainly involving deterioration of bone quality and resulting in an increased fracture rate, often despite normal bone mineral density. Bone complications are common in patients with CD at the time of diagnosis but may persist even after successful treatment. There is currently no agreement on the optimal diagnostic methods, thresholds for anti-osteoporotic therapy and its timing in CD. In this review, we summarize the current data on the pathophysiology, diagnostic approach and management of bone complications in CD.
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Affiliation(s)
- Aleksandra Zdrojowy-Wełna
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland
| | - Barbara Stachowska
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland
| | - Marek Bolanowski
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland.
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Uygur MM, Menotti S, Santoro S, Giustina A. Modern approach to bone comorbidity in prolactinoma. Pituitary 2024; 27:802-812. [PMID: 39541075 DOI: 10.1007/s11102-024-01469-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
Prolactinomas account for more than half of pituitary adenomas, and besides their clinical impact on fertility and gonadal function, they lead to detrimental effects on bone. Patients with prolactinoma are prone to deterioration of bone structure caused not only by prolactin (PRL) induced hypogonadism but also by its direct actions on bone cells and calcium metabolism. However, clinical studies have shown inconsistent evidence regarding whether PRL could have a deleterious effect independently from gonadal insufficiency on skeletal integrity. Seminal studies from our group reported an increased prevalence of vertebral fractures (VFs) in both female and male patients with prolactinoma. Treatment of prolactinoma with dopamine agonists can restore gonadal function and improve bone mineral density. Since the presence of VFs may be related to more aggressive disease, bone comorbidities in prolactinoma should be managed by a multidisciplinary team in line with the recent concept of 'pituitary tumors centers of excellence'. The review aims to evaluate the mechanism of PRL actions on bone, as well as to provide practical indications for a modern approach to the management of skeletal complications of patients with prolactin-secreting adenoma considering different clinical characteristics and outcomes.
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Affiliation(s)
- Meliha Melin Uygur
- Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS Hospital, Via Olgettina 60, Milan, 20132, Italy.
- Department of Endocrinology and Metabolism Disease, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey.
| | - Sara Menotti
- Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS Hospital, Via Olgettina 60, Milan, 20132, Italy
| | - Simona Santoro
- Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS Hospital, Via Olgettina 60, Milan, 20132, Italy
| | - Andrea Giustina
- Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS Hospital, Via Olgettina 60, Milan, 20132, Italy
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Li M, Hasan AA, Chu C, Hocher JG, Liu Y, Zhang X, Chen X, Yard B, Krämer BK, Hocher B. Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin - evidence from in vitro and human studies. Pflugers Arch 2024; 476:889-899. [PMID: 38393416 PMCID: PMC11139748 DOI: 10.1007/s00424-024-02928-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/30/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024]
Abstract
Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.
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Affiliation(s)
- Mei Li
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Ahmed A Hasan
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Chang Chu
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Johann-Georg Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Yvonne Liu
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Xiaoli Zhang
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Xin Chen
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Benito Yard
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Bernhard K Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.
- Reproductive, Genetic Hospital of CITIC-Xiangya, Changsha, China.
- Institute of Medical Diagnostics, IMD Berlin-Potsdam, Berlin, Germany.
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China.
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Kuliczkowska-Płaksej J, Zdrojowy-Wełna A, Jawiarczyk-Przybyłowska A, Gojny Ł, Bolanowski M. Diagnosis and therapeutic approach to bone health in patients with hypopituitarism. Rev Endocr Metab Disord 2024; 25:513-539. [PMID: 38565758 DOI: 10.1007/s11154-024-09878-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2024] [Indexed: 04/04/2024]
Abstract
The results of many studies in recent years indicate a significant impact of pituitary function on bone health. The proper function of the pituitary gland has a significant impact on the growth of the skeleton and the appearance of sexual dimorphism. It is also responsible for achieving peak bone mass, which protects against the development of osteoporosis and fractures later in life. It is also liable for the proper remodeling of the skeleton, which is a physiological mechanism managing the proper mechanical resistance of bones and the possibility of its regeneration after injuries. Pituitary diseases causing hypofunction and deficiency of tropic hormones, and thus deficiency of key hormones of effector organs, have a negative impact on the skeleton, resulting in reduced bone mass and susceptibility to pathological fractures. The early appearance of pituitary dysfunction, i.e. in the pre-pubertal period, is responsible for failure to achieve peak bone mass, and thus the risk of developing osteoporosis in later years. This argues for the need for a thorough assessment of patients with hypopituitarism, not only in terms of metabolic disorders, but also in terms of bone disorders. Early and properly performed treatment may prevent patients from developing the bone complications that are so common in this pathology. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary disease.
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Affiliation(s)
- Justyna Kuliczkowska-Płaksej
- Department and Clinic of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wybrzeże Pasteura 4, Wrocław, 50-367, Poland
| | - Aleksandra Zdrojowy-Wełna
- Department and Clinic of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wybrzeże Pasteura 4, Wrocław, 50-367, Poland
| | - Aleksandra Jawiarczyk-Przybyłowska
- Department and Clinic of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wybrzeże Pasteura 4, Wrocław, 50-367, Poland.
| | - Łukasz Gojny
- Department and Clinic of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wybrzeże Pasteura 4, Wrocław, 50-367, Poland
| | - Marek Bolanowski
- Department and Clinic of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wybrzeże Pasteura 4, Wrocław, 50-367, Poland
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Li W, Wang W, Zhang M, Chen Q, Li F, Li S. Association of serum sclerostin levels with marrow adiposity in postmenopausal women with glucocorticoid-induced osteoporosis. BMC Endocr Disord 2024; 24:55. [PMID: 38679740 PMCID: PMC11056049 DOI: 10.1186/s12902-024-01591-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 04/24/2024] [Indexed: 05/01/2024] Open
Abstract
BACKGROUND Glucocorticoids and sclerostin act as inhibitors of the Wnt signaling pathway, thereby hindering bone formation. Given the pathway's intricate association with mesenchymal stem cells, the hypothesis suggests that heightened sclerostin levels may be intricately linked to an augmentation in marrow adiposity induced by glucocorticoids. This study endeavored to delve into the nuanced relationship between circulating sclerostin and bone marrow adipose tissue in postmenopausal women grappling with glucocorticoid-induced osteoporosis (GIO). METHODS In this cross-sectional study, 103 patients with autoimmune-associated diseases underwent glucocorticoid treatment, boasting an average age of 61.3 years (standard deviation 7.1 years). The investigation encompassed a thorough assessment, incorporating medical history, anthropometric data, biochemical analysis, and dual-energy X-ray absorptiometry measurements of lumbar and femoral bone mineral density (BMD). Osteoporosis criteria were established at a T-score of -2.5 or lower. Additionally, MR spectroscopy quantified the vertebral marrow fat fraction. RESULTS BMD at the femoral neck, total hip, and lumbar spine showcased an inverse correlation with marrow fat fraction (r = -0.511 to - 0.647, P < 0.001). Serum sclerostin levels exhibited a positive correlation with BMD at various skeletal sites (r = 0.476 to 0.589, P < 0.001). A noteworthy correlation emerged between circulating sclerostin and marrow fat fraction at the lumbar spine (r = -0.731, 95% CI, -0.810 to -0.627, P < 0.001). Multivariate analysis brought to light that vertebral marrow fat fraction significantly contributed to sclerostin serum concentrations (standardized regression coefficient ß = 0.462, P < 0.001). Even after adjusting for age, body mass index, physical activity, renal function, BMD, and the duration and doses of glucocorticoid treatment, serum sclerostin levels maintained a significant correlation with marrow fat fraction. CONCLUSIONS Circulating sclerostin levels exhibited a noteworthy association with marrow adiposity in postmenopausal women grappling with GIO.
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Affiliation(s)
- Wei Li
- Department of Radiology, Pudong New Area, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Shanghai, 201318, China
| | - Wei Wang
- Department of Radiology, Pudong New Area, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Shanghai, 201318, China
| | - Minlan Zhang
- Department of Laboratory Medicine, Pudong New Area, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China
| | - Qi Chen
- Department of Radiology, Pudong New Area, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Shanghai, 201318, China
| | - Fengyi Li
- Department of Radiology, Pudong New Area, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Shanghai, 201318, China
| | - Shaojun Li
- Department of Radiology, Pudong New Area, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Shanghai, 201318, China.
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Xu Z, Zheng L, Li S. Paclitaxel-induced inhibition of NSCLC invasion and migration via RBFOX3-mediated circIGF1R biogenesis. Sci Rep 2024; 14:774. [PMID: 38191906 PMCID: PMC10774373 DOI: 10.1038/s41598-024-51500-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 01/05/2024] [Indexed: 01/10/2024] Open
Abstract
We previously reported that circIGF1R is significantly downregulated in non-small cell lung cancer (NSCLC) cells and tissues. It inhibits cancer cell invasion and migration, although the underlying molecular mechanisms remain elusive. The invasion and migration of NSCLC cells was analyzed by routine in vivo and in vitro functional assays. Fluorescent in situ hybridization, luciferase reporter assay, RNA pull-down assay and RNA immunoprecipitation (RIP) assay were performed to explore the molecular mechanisms. Mechanism of action of paclitaxel-induced RBFOX3-mediated inhibition of NSCLC invasion and migration was investigated through in vitro and in vivo experiments.Our study reveals that circIGF1R acts as a Competing Endogenous RNA (ceRNA) for miR-1270, thereby regulating Van-Gogh-like 2 (VANGL2) expression and subsequently inhibiting NSCLC cell invasion and migration via the Wnt pathway. We also found that RNA binding protein fox-1 homolog 3 (RBFOX3) enhances circIGF1R biogenesis by binding to IGF1R pre-mRNA, which in turn suppresses migration and invasion in NSCLC cells. Additionally, the chemotherapeutic drug paclitaxel was shown to impede NSCLC invasion and migration by inducing RBFOX3-mediated circIGF1R biogenesis.RBFOX3 inhibits the invasion and migration of NSCLC cells through the circIGF1R/ miR-1270/VANGL2 axis, circIGF1R has the potential to serve as a biomarker and therapeutic target for NSCLC.
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Affiliation(s)
- Zhanyu Xu
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Liping Zheng
- Department of Anesthesia Catheter Room, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Shikang Li
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
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Tang Y, Sun Z, Wu S, Zhang C, Zhang Y, Cao Y. Jin-Fu-An decoction manipulation of macrophage polarization via β-catenin (CTNNB1) synergizes with cisplatin in lung cancer. Biomed Pharmacother 2023; 168:115828. [PMID: 37925939 DOI: 10.1016/j.biopha.2023.115828] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/20/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023] Open
Abstract
Previous studies have demonstrated that tumor-associated macrophages (TAMs) exhibiting an M2 phenotype contribute significantly to the pathogenesis of various cancer types, including lung cancer. Therapeutic approaches targeting TAMs have the potential to complement and synergize with conventional chemotherapy and immunotherapy. Through database analysis, it has become evident that the expression of CTNNB1 (β-catenin) is predominantly localized in macrophages, and its presence is associated with unfavorable outcomes in the absence of CD8+ cells. Jin-Fu-An decoction (JFAD) has been utilized as an adjunct to augment current clinical interventions. By conducting a network pharmacological analysis, we discovered that CTNNB1 is a significant target of JFAD. Experiments were conducted to examine the impact of JFAD on macrophage polarization both in vitro and in vivo. Furthermore, the study investigated the combined effect of JFAD and cisplatin (CDDP) on mitigating adverse reactions and prolonging survival in subcutaneously transplanted tumor models and orthotopic lung cancer models. The percentage of M1 and M2 macrophages in the tumor and spleen were measured using flow cytometry. Additionally, the levels of β-catenin, M1, and M2 macrophage markers were measured by Western blotting and qPCR, while CD8 and iNOS protein expression was analyzed via immunohistochemistry. Our research findings indicate that JFAD has the ability to modulate the transformation of M2 macrophages into M1 macrophages, augment the anticancer efficacy of CDDP, and diminish the expression of cell-related markers in M2 cells. This regulatory effect may potentially be associated with the downregulation of β-catenin expression.
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Affiliation(s)
- Yang Tang
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Department of Oncology, The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
| | - Zhe Sun
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
| | - Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
| | - Chengyu Zhang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China; Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - Yanling Zhang
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Department of Oncology, The Forth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China
| | - Yang Cao
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China.
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Radecka A, Lubkowska A. The Significance of Dual-Energy X-ray Absorptiometry (DXA) Examination in Cushing's Syndrome-A Systematic Review. Diagnostics (Basel) 2023; 13:diagnostics13091576. [PMID: 37174967 PMCID: PMC10178172 DOI: 10.3390/diagnostics13091576] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 04/13/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
In recent years, the usefulness of dual-energy X-ray absorptiometry (DXA) as a valuable complementary method of assessing the content and distribution of adipose and lean tissue as well as bone mineral density and estimating the risk of fractures has been increasingly confirmed. The diagnosis and treatment of Cushing's syndrome remain challenging, and monitoring the effects of treatment is often necessary. DXA tests offer a potential solution to many problems related to the availability of a quick, detailed, and reliable analysis of changes in the content and distribution of individual body composition components. The article discusses total body DXA scans (FMI, VAT, ALMI), lumbar spine scans (VFA, TBS), and osteoporosis scans (BMD, T-score, Z-score)-all are of potential interest in Cushing's syndrome. The article discusses the use of the most important indicators obtained from a DXA test (FMI, VAT, ALMI, BMD, T-score, Z-score, VFA, TBS) and their clinical significance in Cushing's syndrome was verified. The literature from the last decade was used for the study, available in MEDLINE, Web of Science, and ScienceDirect.
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Affiliation(s)
- Aleksandra Radecka
- Department of Functional Diagnostics and Physical Medicine, Pomeranian Medical University in Szczecin, Żołnierska 54, 71-210 Szczecin, Poland
| | - Anna Lubkowska
- Department of Functional Diagnostics and Physical Medicine, Pomeranian Medical University in Szczecin, Żołnierska 54, 71-210 Szczecin, Poland
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Uygur MM, Frara S, di Filippo L, Giustina A. New tools for bone health assessment in secreting pituitary adenomas. Trends Endocrinol Metab 2023; 34:231-242. [PMID: 36869001 DOI: 10.1016/j.tem.2023.01.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 03/05/2023]
Abstract
Pituitary hormones regulate skeletal physiology, and excess levels affect bone remodeling and alter bone microstructure. Vertebral fractures (VFs) are an early phenomenon of impaired bone health in secreting pituitary adenomas. However, they are not accurately predicted by areal bone mineral density (BMD). Emerging data demonstrate that a morphometric approach is essential for evaluating bone health in this clinical setting and is considered to be the gold standard method in acromegaly. Several novel tools have been proposed as alternative or additional methods for the prediction of fractures, particularly in pituitary-driven osteopathies. This review highlights the novel potential biomarkers and diagnostic methods for bone fragility, including their pathophysiological, clinical, radiological, and therapeutic implications in acromegaly, prolactinomas, and Cushing's disease.
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Affiliation(s)
- Meliha Melin Uygur
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale San Raffaele, Milan, Italy; Department of Endocrinology and Metabolism Disease, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey.
| | - Stefano Frara
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale San Raffaele, Milan, Italy
| | - Luigi di Filippo
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale San Raffaele, Milan, Italy
| | - Andrea Giustina
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale San Raffaele, Milan, Italy
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10
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Dincel AS, Jørgensen NR. New Emerging Biomarkers for Bone Disease: Sclerostin and Dickkopf-1 (DKK1). Calcif Tissue Int 2023; 112:243-257. [PMID: 36165920 DOI: 10.1007/s00223-022-01020-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/26/2022] [Indexed: 01/25/2023]
Abstract
A healthy skeleton depends on a continuous renewal and maintenance of the bone tissue. The process of bone remodeling is highly controlled and consists of a fine-tuned balance between bone formation and bone resorption. Biochemical markers of bone turnover are already in use for monitoring diseases and treatment involving the skeletal system, but novel biomarkers reflecting specific biological processes in bone and interacting tissues may prove useful for diagnostic, prognostic, and monitoring purposes. The Wnt-signaling pathway is one of the most important pathways controlling bone metabolism and consequently the action of inhibitors of the pathway such as sclerostin and Dickkopf-related protein 1 (DKK1) have crucial roles in controlling bone formation and resorption. Thus, they might be potential markers for clinical use as they reflect a number of physiological and pathophysiological events in bone and in the cross-talk with other tissues in the human body. This review focuses on the clinical utility of measurements of circulating sclerostin and DKK1 levels based on preanalytical and analytical considerations and on evidence obtained from published clinical studies. While accumulating evidence points to clear associations with a number of disease states for the two markers, and thus, the potential for especially sclerostin as a biochemical marker that may be used clinically, the lack of standardization or harmonization of the assays still hampers the clinical utility of the markers.
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Affiliation(s)
- Aylin Sepinci Dincel
- Department of Medical Biochemistry, Faculty of Medicine, Gazi University, Ankara, Turkey
- Department of Clinical Biochemistry, Rigshospitalet, Valdemar Hansens Vej 13 Glostrup, 2600, Copenhagen, Denmark
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niklas Rye Jørgensen
- Department of Medical Biochemistry, Faculty of Medicine, Gazi University, Ankara, Turkey.
- Department of Clinical Biochemistry, Rigshospitalet, Valdemar Hansens Vej 13 Glostrup, 2600, Copenhagen, Denmark.
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Franco CN, Noe MM, Albrecht LV. Metabolism and Endocrine Disorders: What Wnt Wrong? Front Endocrinol (Lausanne) 2022; 13:887037. [PMID: 35600583 PMCID: PMC9120667 DOI: 10.3389/fendo.2022.887037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/07/2022] [Indexed: 12/12/2022] Open
Abstract
A fundamental question in cell biology underlies how nutrients are regenerated to maintain and renew tissues. Physiologically, the canonical Wnt signaling is a vital pathway for cell growth, tissue remodeling, and organ formation; pathologically, Wnt signaling contributes to the development of myriad human diseases such as cancer. Despite being the focus of intense research, how Wnt intersects with the metabolic networks to promote tissue growth and remodeling has remained mysterious. Our understanding of metabolism has been revolutionized by technological advances in the fields of chemical biology, metabolomics, and live microscopy that have now made it possible to visualize and manipulate metabolism in living cells and tissues. The application of these toolsets to innovative model systems have propelled the Wnt field into new realms at the forefront answering the most pressing paradigms of cell metabolism in health and disease states. Elucidating the basis of Wnt signaling and metabolism in a cell-type and tissue-specific manner will provide a powerful base of knowledge for both basic biomedical fields and clinician scientists, and has the promise to generate new, transformative therapies in disease and even processes of aging.
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Affiliation(s)
- Carolina N. Franco
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California Irvine, Irvine, CA, United States
| | - May M. Noe
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California Irvine, Irvine, CA, United States
| | - Lauren V. Albrecht
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California Irvine, Irvine, CA, United States
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA, United States
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Zaheer S, Meyer K, Easly R, Bayomy O, Leung J, Koefoed AW, Heydarpour M, Freeman R, Adler GK. Effect of adrenocorticotropic hormone infusion on circulating sclerostin levels. Endocr Connect 2021; 10:1607-1614. [PMID: 34788228 PMCID: PMC8679878 DOI: 10.1530/ec-21-0263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022]
Abstract
Glucocorticoid use is the most common cause of secondary osteoporosis. Poor skeletal health related to glucocorticoid use is thought to involve inhibition of the Wnt/β-catenin signaling pathway, a key pathway in osteoblastogenesis. Sclerostin, a peptide produced primarily by osteocytes, is an antagonist of the Wnt/β-catenin signaling pathway, raising the possibility that sclerostin is involved in glucocorticoids' adverse effects on bone. The aim of this study was to determine whether an acute infusion of cosyntropin (i.e. ACTH(1-24)), which increases endogenous cortisol, increases serum sclerostin levels as compared to a placebo infusion. This study was performed using blood samples obtained from a previously published, double-blind, placebo-controlled, randomized, cross-over study among healthy men and women who received infusions of placebo or cosyntropin after being supine and fasted overnight (ClinicalTrials.gov NCT02339506). A total of 17 participants were analyzed. There was a strong correlation (R2 = 0.65, P < 0.0001) between the two baseline sclerostin measurements measured at the start of each visit, and men had a significantly higher average baseline sclerostin compared to women. As anticipated, cosyntropin significantly increased serum cortisol levels, whereas cortisol levels fell during placebo infusion, consistent with the diurnal variation in cortisol. There was no significant effect of cosyntropin as compared to placebo infusions on serum sclerostin over 6-24 h (P = 0.10). In conclusion, this randomized, placebo-controlled study was unable to detect a significant effect of a cosyntropin infusion on serum sclerostin levels in healthy men and women.
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Affiliation(s)
- Sarah Zaheer
- Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina, USA
| | - Kayla Meyer
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Rebecca Easly
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Omar Bayomy
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Janet Leung
- Section of Endocrinology, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Andrew W Koefoed
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Mahyar Heydarpour
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Roy Freeman
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Gail K Adler
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Correspondence should be addressed to G K Adler:
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Liao Y, Feng J, Sun W, Wu C, Li J, Jing T, Liang Y, Qian Y, Liu W, Wang H. CIRP promotes the progression of non-small cell lung cancer through activation of Wnt/β-catenin signaling via CTNNB1. J Exp Clin Cancer Res 2021; 40:275. [PMID: 34465343 PMCID: PMC8406911 DOI: 10.1186/s13046-021-02080-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 08/21/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cold-inducible RNA binding protein (CIRP) is a newly discovered proto-oncogene. In this study, we investigated the role of CIRP in the progression of non-small cell lung cancer (NSCLC) using patient tissue samples, cultured cell lines and animal lung cancer models. METHODS Tissue arrays, IHC and HE staining, immunoblotting, and qRT-PCR were used to detect the indicated gene expression; plasmid and siRNA transfections as well as viral infection were used to manipulate gene expression; cell proliferation assay, cell cycle analysis, cell migration and invasion analysis, soft agar colony formation assay, tail intravenous injection and subcutaneous inoculation of animal models were performed to study the role of CIRP in NSCLC cells; Gene expression microarray was used to select the underlying pathways; and RNA immunoprecipitation assay, biotin pull-down assay, immunopurification assay, mRNA decay analyses and luciferase reporter assay were performed to elucidate the mechanisms. The log-rank (Mantel-Cox) test, independent sample T-test, nonparametric Mann-Whitney test, Spearman rank test and two-tailed independent sample T-test were used accordingly in our study. RESULTS Our data showed that CIRP was highly expressed in NSCLC tissue, and its level was negatively correlated with the prognosis of NSCLC patients. By manipulating CIRP expression in A549, H460, H1299, and H1650 cell lines, we demonstrated that CIRP overexpression promoted the transition of G1/G0 phase to S phase and the formation of an enhanced malignant phenotype of NSCLC, reflected by increased proliferation, enhanced invasion/metastasis and greater tumorigenic capabilities both in vitro and in vivo. Transcriptome sequencing further demonstrated that CIRP acted on the cell cycle, DNA replication and Wnt signaling pathway to exert its pro-oncogenic action. Mechanistically, CIRP directly bound to the 3'- and 5'-UTRs of CTNNB1 mRNA, leading to enhanced stability and translation of CTNNB1 mRNA and promoting IRES-mediated protein synthesis, respectively. Eventually, the increased CTNNB1 protein levels mediated excessive activation of the Wnt/β-catenin signaling pathway and its downstream targets C-myc, COX-2, CCND1, MMP7, VEGFA and CD44. CONCLUSION Our results support CIRP as a candidate oncogene in NSCLC and a potential target for NSCLC therapy.
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Affiliation(s)
- Yi Liao
- The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China
- Department of Thoracic Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, P. R. China
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Province, Luzhou, 646099, Sichuan, China
| | - Weichao Sun
- The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China
| | - Chao Wu
- Department of Thoracic Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, P. R. China
| | - Jingyao Li
- The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China
| | - Tao Jing
- Department of Cardiology, Southwest Hospital, Army Medical University, Chongqing, 400038, P. R. China
| | - Yuteng Liang
- Department of Thoracic Surgery, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China
| | - Yonghui Qian
- Department of Thoracic Surgery, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China
| | - Wenlan Liu
- The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China.
- Department of Thoracic Surgery, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China.
| | - Haidong Wang
- Department of Thoracic Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, P. R. China.
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Corrado A, Rotondo C, Mele A, Cici D, Maruotti N, Sanpaolo E, Colia R, Cantatore FP. Influence of glucocorticoid treatment on trabecular bone score and bone remodeling regulators in early rheumatoid arthritis. Arthritis Res Ther 2021; 23:180. [PMID: 34229744 PMCID: PMC8261978 DOI: 10.1186/s13075-021-02562-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/23/2021] [Indexed: 11/17/2022] Open
Abstract
Background Glucocorticoids (GC) modulate several regulators involved in the pathogenesis of bone changes in rheumatoid arthritis (RA). Trabecular bone score (TBS) allows the indirect assessment of bone quality. The aim of this study was to investigate the effects of GC on TBS and serum levels of bone turnover regulators in patients with recent-onset RA. Materials and methods Forty-seven subjects with recent-onset RA (< 6 months) were classified in two groups, low (lGC) and high (hGC) glucocorticoids, according to glucocorticoid dose regimens. Bone mineral density (BMD), TBS, and circulating Dickkopf-1 (Dkk1), sclerostin, osteoprotegerin (OPG), and RANK-L were evaluated at baseline and 6 and 12 months. Results BMD significantly declined after 12 months with no significant difference between the lGC and hGC group, whereas TBS decreased in the hGC group only. Circulating OPG decreased during the follow-up period, the reduction being significantly greater in hGC group; conversely, sclerostin and RANK-L serum increased, in a significantly greater extent in the hGC group. TBS inversely correlated with sclerostin, RANK-L, and Dkk1 circulating levels whereas directly correlated with OPG circulating levels. GC cumulative dose showed an inverse relationship with BMD in both the hGC and lGC groups; TBS values showed an inverse relationship with GC cumulative dose in the hGC group only. GC cumulative dose was associated to higher sclerostin and lower OPG serum levels. TBS did not correlate with disease activity whereas BMD was inversely related to disease activity. Conclusions In early RA, GC exposure contributes to the reduction of BMD and affects bone quality depending on dose regimens. TBS could be a useful tool to evaluate the negative effect of GC on bone microarchitecture. Trial registration This study was ancillary to a parallel-group observational prospective study which was approved by the medical local ethics committee (protocol number DDG 334/19-06-2019).
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Affiliation(s)
- Addolorata Corrado
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy.
| | - Cinzia Rotondo
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy
| | - Angiola Mele
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy
| | - Daniela Cici
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy
| | - Nicola Maruotti
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy
| | - Eliana Sanpaolo
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy
| | - Ripalta Colia
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy
| | - Francesco Paolo Cantatore
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71100, Foggia, Italy
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Glucocorticoid therapy suppresses Wnt signaling by reducing the ratio of serum Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1. Clin Rheumatol 2021; 40:2947-2954. [PMID: 33420868 DOI: 10.1007/s10067-020-05554-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Our previous study suggested that suppression of Wnt/β-catenin signaling by increasing serum Wnt co-receptor inhibitors, sclerostin and Dickkopf-1, impairs bone formation in the first week after starting glucocorticoid therapy. The objective of this study was to investigate the involvement of the Wnt/β-catenin signaling pathway and its clinical significance in the subsequent suppression of bone formation. METHODS A total of 53 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg daily) were prospectively enrolled. We measured serum levels of Wnt3a and Wnt inhibitors, secreted Frizzled-related protein 1 (sFRP-1) and Wnt inhibitory factor 1 (Wif-1), before starting glucocorticoid therapy and every week for 4 weeks after its initiation. RESULTS Serum levels of sFRP-1 and Wif-1 slightly decreased compared with before glucocorticoid therapy from the second week. The serum Wnt3a level decreased from the first week. The ratios of Wnt3a to sFRP-1 and that of Wnt3a to Wif-1 both decreased from the first week onward. CONCLUSION The reduction of the ratio of Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1, suppresses Wnt signaling, which may result in impaired bone formation. Taken together with our previous studies, glucocorticoids may suppress Wnt signaling by inhibiting co-receptors of the Wnt/β-catenin signaling pathway in the early phase of glucocorticoid therapy and inhibiting its ligand in the subsequent weeks, which together impair bone formation. Key Points • The decrease in Wnt pathway-related molecules by glucocorticoids impairs bone formation. • Glucocorticoids inhibit co-receptors of Wnt signaling in the early phase of therapy. • Glucocorticoids inhibit ligands of Wnt signaling in the subsequent phase of therapy.
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Szulc P. Biochemical bone turnover markers in hormonal disorders in adults: a narrative review. J Endocrinol Invest 2020; 43:1409-1427. [PMID: 32335857 DOI: 10.1007/s40618-020-01269-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 04/18/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Hormonal disorders are often associated with abnormal levels of bone turnover markers (BTMs). N-terminal propeptide of type I procollagen (PINP) and serum C-terminal cross-linking telopeptide of type I collagen (CTX-I) are the reference markers of bone formation and bone resorption, respectively. METHODS A comprehensive literature search within the MEDLINE and Web of Science databases was performed. RESULTS Acromegaly is associated with higher BTM levels, which decrease during the remission after treatment. Adult-onset growth hormone deficiency is often associated with decreased BTM levels. Growth hormone replacement therapy stimulates bone turnover and increases BTM levels. Hypothyroidism is characterized by general slowing of bone metabolism which is reflected by lower BTM levels. The replacement thyroid hormone therapy increases the bone turnover rate and BTM levels increase. Patients with thyroid cancer receive a suppressive dose of thyroid hormones and may have slightly elevated BTM levels. Patients with overt hyperthyroidism had higher BTM levels and anti-thyroid therapy induces a rapid decrease in the BTM levels. Patients with overt primary hyperparathyroidism have higher BTM levels, whereas those with asymptomatic and normocalcemic hyperparathyroidism usually have normal BTM levels. Hypoparathyroidism is characterized by slightly decreased BTM levels. Cushing's syndrome is characterized consistently by markedly decreased osteocalcin concentration, whereas data on other BTMs are discordant. CONCLUSIONS BTMs help us to better understand mechanisms of the impact of hormonal disorders and their treatment on bone metabolism. However, it is unknown whether BTMs may be used to monitor the effect of their treatments on bone in the clinical practice.
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Affiliation(s)
- P Szulc
- INSERM UMR 1033, University of Lyon, Hôpital Edouard Herriot, Pavillon F, Place d'Arsonval, 69437, Lyon, France.
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Thiele S, Hannemann A, Winzer M, Baschant U, Weidner H, Nauck M, Thakker RV, Bornhäuser M, Hofbauer LC, Rauner M. Regulation of sclerostin in glucocorticoid-induced osteoporosis (GIO) in mice and humans. Endocr Connect 2019; 8:923-934. [PMID: 31234141 PMCID: PMC6612066 DOI: 10.1530/ec-19-0104] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 06/11/2019] [Indexed: 12/12/2022]
Abstract
Glucocorticoids (GC) are used for the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited, amongst others, by adverse effects on bone. The Wnt and bone formation inhibitor sclerostin was recently implicated in the pathogenesis of GC-induced osteoporosis. However, data are ambiguous. The aim of this study was to assess the regulation of sclerostin by GC using several mouse models with high GC levels and two independent cohorts of patients treated with GC. Male 24-week-old C57BL/6 and 18-week-old DBA/1 mice exposed to GC and 12-week-old mice with endogenous hypercortisolism displayed reduced bone formation as indicated by reduced levels of P1NP and increased serum sclerostin levels. The expression of sclerostin in femoral bone tissue and GC-treated bone marrow stromal cells, however, was not consistently altered. In contrast, GC dose- and time-dependently suppressed sclerostin at mRNA and protein levels in human mesenchymal stromal cells, and this effect was GC receptor dependent. In line with the human cell culture data, patients with rheumatoid arthritis (RA, n = 101) and polymyalgia rheumatica (PMR, n = 21) who were exposed to GC had lower serum levels of sclerostin than healthy age- and sex-matched controls (-40%, P < 0.01 and -26.5%, P < 0.001, respectively). In summary, sclerostin appears to be differentially regulated by GC in mice and humans as it is suppressed by GCs in humans but is not consistently altered in mice. Further studies are required to delineate the differences between GC regulation of sclerostin in mice and humans and assess whether sclerostin mediates GC-induced osteoporosis in humans.
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Affiliation(s)
- Sylvia Thiele
- Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Anke Hannemann
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Maria Winzer
- Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Ulrike Baschant
- Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Heike Weidner
- Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Rajesh V Thakker
- Academic Endocrine Unit, Radcliffe Department of Medicine University of Oxford, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford, UK
| | - Martin Bornhäuser
- Department of Medicine I, Technische Universität Dresden, Dresden, Germany
- DFG Research Center and Cluster of Excellence for Regenerative Therapies, Technical University, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
- DFG Research Center and Cluster of Excellence for Regenerative Therapies, Technical University, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:753-761. [PMID: 30664862 PMCID: PMC6445804 DOI: 10.1016/j.ajpath.2018.12.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/21/2018] [Accepted: 12/07/2018] [Indexed: 11/23/2022]
Abstract
Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signaling. Sclerostin, encoded by Sost gene, is the main negative regulator of the proformative and antiresorptive role of the Wnt signaling pathway in the skeleton. It was hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids, and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and nonconvulsive death. Detailed histopathologic analysis in a wide range of tissues identified peracute hemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials that explore the use of antisclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients who might otherwise benefit from antisclerostin antibody treatment.
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Tsoriev TT, Belaya ZE, Rozhinskaya LY, Mel’nichenko GA, Ilyin AV, Nikankina LV, Dedov II. New biomarkers of bone remodelling regulation in patients with acromegaly and endogenous hypercortisolism. ACTA ACUST UNITED AC 2018. [DOI: 10.14341/omet9447] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background: Bone tissue is a non-classical endocrine organ, which produces at least two hormones: fibroblast growth factor 23 (FGF-23) and decarboxylated osteocalcin (OC). In addition to this, recent studies demonstrate that specific proteins involved in the paracrine regulation of bone remodelling can be measured in peripheral serum samples and may serve as additional biomarkers of bone metabolism.
Aims: to evaluate the serum levels of biomarkers related to endocrine and paracrine function of bone tissue in patients with Cushings disease (CD) and acromegaly.
Materials and methods: The study was conducted according to the cross-sectional case-control type. Fasting serum samples were taken between 810 a.m. from patients with CD, acromegaly and age-, sex- and BMI-matched healthy volunteers and stored at -40 C. Commercially available kits for enzyme-linked immunosorbent assay (ELISA) were used to determine the serum levels of FGF-23, co-factor (co-receptor) Klotho, cathepsin K, sclerostin, P1NP. Insulin-like growth factor-1 (IGF-1) was measured by the immunochemiluminescence assay, late-night (11 p.m.) salivary cortisol (LNSC) was evaluated using the electrochemiluminescence method. Non-parametric tests (the Kruskal-Wallis test and the Mann-Whitney test) were used to assess the differences between the groups of patients.
Results: The study includes 78 patients, (37.6 years old, 95% CI 34.7540.46): 29 patients with CD (group 1), 22 with acromegaly (group 2), and 27 healthy individuals (group 3), matched by sex, age and BMI (p = 0.432, 0.373 and 0.725 between groups, respectively). LNSC in patients with CD and IGF-1 in patients with acromegaly were significantly higher compared to the control group (p = 0.004 and p 0.001, respectively). In patients with acromegaly, a statistically significant increase in FGF-23 (1.13 (0.78;1.49) vs 0.78 (0.54;1.09)) and phosphorus (1.38 (1.24;1.52) vs 1.16 (1.12;1.29)) (p = 0.01 and p 0.001, respectively) was observed along with increased levels of bone remodelling markers. In patients with CD, bone formation markers were suppressed, but differences in the levels of other biomarkers could not be identified.
Conclusions: Acromegaly leads to hyperphosphatemia and increase in FGF-23, which is most likely due to the development of resistance to FGF-23, and the intensification of bone remodelling. With CD, another bone hormone, osteocalcin, is suppressed along with the suppression of P1NP.
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20
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Belaya ZE, Grebennikova TA, Melnichenko GA, Nikitin AG, Solodovnikov AG, Brovkina OI, Grigoriev AU, Rozhinskaya LY, Dedov II. Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans. Osteoporos Int 2018; 29:211-221. [PMID: 28980049 DOI: 10.1007/s00198-017-4241-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 09/21/2017] [Indexed: 12/13/2022]
Abstract
UNLABELLED Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts. INTRODUCTION The purpose of this study was to evaluate the responses of bone to chronic glucocorticoid (GC) excess by measuring the levels of selected mRNA and microRNA (miR) in bone samples of patients with Cushing's disease (CD). METHODS Bone samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 16 patients with clinically and biochemically evident CD and 10 patients with clinically non-functioning pituitary adenomas (NFPA) matched by sex, age, and body mass index. Quantitative polymerase chain reactions (qPCR) were used to examine the expression of genes (mRNA and miRs) known to be involved in bone remodeling regulation based on studies in animals and cell culture. RESULTS Hypercortisolism was associated with the downregulation of genes involved in osteoblast function and maturation (ACP5, ALPL, BGLAP, COL1A1, COL1A2, BMP2, RUNX2, TWIST1). An excess of GC caused increased expression of Wnt-signaling antagonists (Dkk1, SOST) and changes in the levels of miRs that are known to suppress osteoblastogenesis (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) p < 0.05, q < 0.1. Interestingly, compensatory mechanisms were found in long-term hypercortisolism: upregulation of Wnt10b, LRP5, and LRP6; downregulation of SFRP4; changes in miRs involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p); and downregulation of genes associated with osteoclastogenesis. None of these changes prevented the suppression of bone formation. CONCLUSIONS An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis.
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Affiliation(s)
- Z E Belaya
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036.
| | - T A Grebennikova
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - G A Melnichenko
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - A G Nikitin
- Federal Research and Clinical Center FMBA of Russia, Moscow, Russia
| | | | - O I Brovkina
- Federal Research and Clinical Center FMBA of Russia, Moscow, Russia
| | - A U Grigoriev
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - L Y Rozhinskaya
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
| | - I I Dedov
- The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036
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Delaney MA, Wan YW, Kim GE, Creighton CJ, Taylor MG, Masand R, Park A, Valdes C, Gibbons W, Liu Z, Anderson ML. A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas. J Clin Endocrinol Metab 2017; 102. [PMID: 28637297 PMCID: PMC5587057 DOI: 10.1210/jc.2016-4014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
CONTEXT Despite progesterone's key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood. OBJECTIVE The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas. DESIGN Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro. METHODS Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein-protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines. RESULTS Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma. CONCLUSIONS Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone's ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis.
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Affiliation(s)
- Meaghan A. Delaney
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
| | - Ying-Wooi Wan
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
| | - Gyoung-Eun Kim
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
| | - Chad J. Creighton
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas 77030
| | - Margaret G. Taylor
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
| | - Ramya Masand
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030
| | - Andrew Park
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
| | - Cecilia Valdes
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
| | - William Gibbons
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
| | - Zhandong Liu
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas 77030
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030
| | - Matthew L. Anderson
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas 77030
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas 77030
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030
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Abstract
PURPOSE OF REVIEW The goal of this paper is to evaluate critically the literature published over the past 3 years regarding the Wnt signaling pathway. The Wnt pathway was found to be involved in bone biology in 2001-2002 with the discovery of a (G171V) mutation in the lipoprotein receptor-related protein 5 (LRP5) that resulted in high bone mass and another mutation that completely inactivated Lrp5 function and resulted in osteoporosis pseudoglioma syndrome (OPPG). The molecular biology has been complex, and very interesting. It has provided many opportunities for exploitation to develop new clinical treatments, particularly for osteoporosis. More clinical possibilities include: treatments for fracture healing, corticosteroid osteoporosis, osteogenesis imperfecta, and others. In addition, we wish to provide historical information coming from distant publications (~350 years ago) regarding bone biology that have been confirmed by study of Wnt signaling. RECENT FINDINGS A recent finding is the development of an antibody to sclerostin that is under study as a treatment for osteoporosis. Development of treatments for other forms of osteoporosis, such as corticosteroid osteoporosis, is also underway. The full range of the applications of the work is not yet been achieved.
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Affiliation(s)
- Mark L Johnson
- Department of Oral and Craniofacial Sciences, UMKC School of Dentistry, 650 East 25th Street, Kansas City, MO, 64108, USA
| | - Robert R Recker
- Creighton University, 601 N 30th St., Ste 4841, Omaha, NE, 68131, USA.
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Beier EE, Sheu TJ, Resseguie EA, Takahata M, Awad HA, Cory-Slechta DA, Puzas JE. Sclerostin activity plays a key role in the negative effect of glucocorticoid signaling on osteoblast function in mice. Bone Res 2017; 5:17013. [PMID: 28529816 PMCID: PMC5422922 DOI: 10.1038/boneres.2017.13] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 12/02/2016] [Accepted: 01/10/2017] [Indexed: 12/11/2022] Open
Abstract
Stress during prenatal development is correlated with detrimental cognitive and behavioral outcomes in offspring. However, the long-term impact of prenatal stress (PS) and disrupted glucocorticoid signaling on bone mass and strength is not understood. In contrast, the detrimental effect of lead (Pb) on skeletal health is well documented. As stress and Pb act on common biological targets via glucocorticoid signaling pathways and co-occur in the environment, this study first sought to assess the combined effect of stress and Pb on bone quality in association with alterations in glucocorticoid signaling. Bone parameters were evaluated using microCT, histomorphometry, and strength determination in 8-month-old male mouse offspring subjected to PS on gestational days 16 and 17, lifetime Pb exposure (100 p.p.m. Pb in drinking water), or to both. Pb reduced trabecular bone mass and, when combined with PS, Pb unmasked an exaggerated decrement in bone mass and tensile strength. Next, to characterize a mechanism of glucocorticoid effect on bone, prednisolone was implanted subcutaneously (controlled-release pellet, 5 mg·kg-1 per day) in 5-month-old mice that decreased osteoblastic activity and increased sclerostin and leptin levels. Furthermore, the synthetic glucocorticoid dexamethasone alters the anabolic Wnt signaling pathway. The Wnt pathway inhibitor sclerostin has several glucocorticoid response elements, and dexamethasone administration to osteoblastic cells induces sclerostin expression. Dexamethasone treatment of isolated bone marrow cells decreased bone nodule formation, whereas removal of sclerostin protected against this decrement in mineralization. Collectively, these findings suggest that bone loss associated with steroid-induced osteoporosis is a consequence of sclerostin-mediated restriction of Wnt signaling, which may mechanistically facilitate glucocorticoid toxicity in bone.
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Affiliation(s)
- Eric E Beier
- Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
- Department of Environmental and Occupational Medicine, Rutgers University, Piscataway, NJ, USA
| | - Tzong-Jen Sheu
- Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
| | - Emily A Resseguie
- Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
| | - Masahiko Takahata
- Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
| | - Hani A Awad
- Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
| | - Deborah A Cory-Slechta
- Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
| | - J Edward Puzas
- Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA
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sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss. Sci Rep 2016; 6:25198. [PMID: 27117872 PMCID: PMC4846872 DOI: 10.1038/srep25198] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 04/13/2016] [Indexed: 01/24/2023] Open
Abstract
sFRP4 is an extracellular Wnt antagonist that fine-tunes its signal activity by direct binding to Wnts. Bone fragility under oxidative stress by diabetes and aging is partly related to the suppression of the Wnt signal through upregulated sFRP4. Here, to explore the functions of sFRP4 as a balancer molecule in bone development and remodeling, we analyzed the sFRP4 knock-in mouse strain. X-gal and immunohistochemically stained signals in sFRP4-LacZ heterozygous mice were detectable in restricted areas, mostly in osteoblasts and osteoclasts, of the femoral diaphysis after neonatal and postnatal stages. Histological and μCT analyses showed increased trabecular bone mass with alteration of the Wnt signal and osteogenic activity in sFRP4 mutants; this augmented the effect of the buildup of trabecular bone during the ageing period. Our results indicate that sFRP4 plays a critical role in bone development and remodeling by regulating osteoblasts and osteoclasts, and that its functional loss prevents age-related bone loss in the trabecular bone area. These findings imply that sFRP4 functions as a key potential endogenous balancer of the Wnt signaling pathway by efficiently having direct influence on both bone formation and bone absorption during skeletal bone development and maintenance through remodeling.
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25
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Grebennikova TA, Belaya ZE, Rozhinskaya LY, Melnichenko GA. [The canonical Wnt/β-catenin pathway: From the history of its discovery to clinical application]. TERAPEVT ARKH 2016; 88:74-81. [PMID: 28635854 DOI: 10.17116/terarkh201688674-81] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
The Wnt/β signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/β-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.
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Affiliation(s)
- T A Grebennikova
- Endocrinology Research Center, Ministry of Health of Russia, Moscow, Russia
| | - Zh E Belaya
- Endocrinology Research Center, Ministry of Health of Russia, Moscow, Russia
| | - L Ya Rozhinskaya
- Endocrinology Research Center, Ministry of Health of Russia, Moscow, Russia
| | - G A Melnichenko
- Endocrinology Research Center, Ministry of Health of Russia, Moscow, Russia
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26
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Belaya ZE, Hans D, Rozhinskaya LY, Dragunova NV, Sasonova NI, Solodovnikov AG, Tsoriev TT, Dzeranova LK, Melnichenko GA, Dedov II. The risk factors for fractures and trabecular bone-score value in patients with endogenous Cushing's syndrome. Arch Osteoporos 2015; 10:44. [PMID: 26608406 DOI: 10.1007/s11657-015-0244-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/22/2015] [Indexed: 02/03/2023]
Abstract
UNLABELLED In a cohort study of 182 consecutive patients with active endogenous Cushing's syndrome, the only predictor of fracture occurrence after adjustment for age, gender bone mineral density (BMD) and trabecular bone score (TBS) was 24-h urinary free cortisol (24hUFC) levels with a threshold of 1472 nmol/24 h (odds ratio, 3.00 (95% confidence interval (CI), 1.52-5.92); p = 0.002). INTRODUCTION The aim was to estimate the risk factors for fracture in subjects with endogenous Cushing's syndrome (CS) and to evaluate the value of the TBS in these patients. METHODS All enrolled patients with CS (n = 182) were interviewed in relation to low-traumatic fractures and underwent lateral X-ray imaging from T4 to L5. BMD measurements were performed using a DXA Prodigy device (GEHC Lunar, Madison, Wisconsin, USA). The TBS was derived retrospectively from existing BMD scans, blinded to clinical outcome, using TBS iNsight software v2.1 (Medimaps, Merignac, France). Urinary free cortisol (24hUFC) was measured by immunochemiluminescence assay (reference range, 60-413 nmol/24 h). RESULTS Among enrolled patients with CS (149 females; 33 males; mean age, 37.8 years (95% confidence interval, 34.2-39.1); 24hUFC, 2370 nmol/24 h (2087-2632), fractures were confirmed in 81 (44.5%) patients, with 70 suffering from vertebral fractures, which were multiple in 53 cases; 24 patients reported non-vertebral fractures. The mean spine TBS was 1.207 (1.187-1.228), and TBS Z-score was -1.86 (-2.07 to -1.65); area under the curve (AUC) was used to predict fracture (mean spine TBS) = 0.548 (95% CI, 0.454-0.641)). In the final regression model, the only predictor of fracture occurrence was 24hUFC levels (p = 0.001), with an increase of 1.041 (95% CI, 1.019-1.063), calculated for every 100 nmol/24-h cortisol elevation (AUC (24hUFC) = 0.705 (95% CI, 0.629-0.782)). CONCLUSIONS Young patients with CS have a low TBS. However, the only predictor of low traumatic fracture is the severity of the disease itself, indicated by high 24hUFC levels.
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Affiliation(s)
- Zhanna E Belaya
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia.
| | - Didier Hans
- Center of Bone Diseases, Lausanne University Hospital, Lausanne, Switzerland
| | - Liudmila Y Rozhinskaya
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Natalia V Dragunova
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Natalia I Sasonova
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | | | - Timur T Tsoriev
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Larisa K Dzeranova
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Galina A Melnichenko
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
| | - Ivan I Dedov
- The National Research Center for Endocrinology, 11, Dmitria Uljanova Str., Moscow, 117036, Russia
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27
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Abstract
INTRODUCTION Cushing's syndrome is associated with a number of clinical manifestations and co-morbidities which may not resolve even after long-term remission leading to excessive mortality. MATERIALS AND METHODS This review summarizes the main manifestations of Cushing's syndrome (active or in remission) with particular focus on data from recently published literature. CONCLUSION Obesity and metabolic alterations, hypertension and cardio/cerebrovascular complications, hypercoagulability/thromboembolism, neuropsychiatric, muscle/skeletal and immune consequences remain the most challenging. Cardiovascular consequences and immunosuppression determine the main causes of death in Cushing's syndrome necessitating early intervention when possible.
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Affiliation(s)
- Georgia Ntali
- Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Rd, Headington, Oxford, OX3 7LJ, UK
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28
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Abstract
PURPOSE OF REVIEW Discovery of the Wnt signaling pathway and understanding the central role of osteocyte in skeletal homeostasis have been the major advances in skeletal biology over the past decade. Sclerostin, secreted mainly (but not exclusively) by osteocytes, has emerged as a key player in skeletal homeostasis. This review highlights the most relevant recent advances. RECENT FINDINGS Sclerostin by inhibiting Wnt signaling pathway decreases bone formation and osteoblast differentiation and promotes osteoblast apoptosis. Ability to measure serum sclerostin levels better clarified the role of sclerostin in various physiologic and pathologic states. Early clinical trials with antibodies to sclerostin have produced robust increases in bone mineral density, and fracture prevention trials are underway. SUMMARY Since the discovery of Wnt signaling pathway and sclerostin's association with high bone mass, there has been a remarkable progress. Clinical trials with fracture endpoints, already underway, should expand osteoanabolic therapeutic horizon in the very near future. Measurement of sclerostin levels in a number of conditions has advanced our knowledge about pathophysiology of skeletal and nonskeletal disorders in an altogether new light.
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Affiliation(s)
- Mahalakshmi Honasoge
- aDivision of Endocrinology, Diabetes, and Bone & Mineral Disorders, Henry Ford Hospital, Detroit, Michigan bSection of Endocrinology, Diabetes and Metabolism, Temple University School of Medicine, Philadelphia, Pennslyvania cBone and Mineral Research Laboratory, Henry Ford Hospital, Detroit, Michigan, USA
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29
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Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol 2014; 4:739-69. [PMID: 24715566 DOI: 10.1002/cphy.c130035] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control.
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Affiliation(s)
- Hershel Raff
- Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Aurora Research Institute and Departments of Medicine, Surgery, and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Bonani M, Rodriguez D, Fehr T, Mohebbi N, Brockmann J, Blum M, Graf N, Frey D, Wüthrich RP. Sclerostin Blood Levels Before and After Kidney Transplantation. Kidney Blood Press Res 2014; 39:230-9. [DOI: 10.1159/000355781] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2014] [Indexed: 11/19/2022] Open
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Guañabens N, Gifre L, Peris P. The role of Wnt signaling and sclerostin in the pathogenesis of glucocorticoid-induced osteoporosis. Curr Osteoporos Rep 2014; 12:90-7. [PMID: 24488619 DOI: 10.1007/s11914-014-0197-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Bone formation is suppressed in glucocorticoid-induced osteoporosis. One of the mechanisms by which glucocorticoids depress bone formation is through their effects on the Wnt/β-catenin signaling pathway, a critical regulator of osteoblastogenesis. Thus, Wnt signaling induces the differentiation of osteoblast precursors toward mature osteoblasts and prevents osteoblast and osteocyte apoptosis. Glucocorticoids increase the expression of Wnt signaling antagonists (sclerostin and Dkk-1) in experimental studies in rodents and cell cultures. However, the scarce data of their effects in humans are somewhat contradictory, probably due to the dose and duration of treatment as well as the characteristics of the patients. A progressive decrease in Dkk-1 serum levels and an increase in circulating sclerostin levels at long-term follow-up have recently been reported in patients treated with high doses of glucocorticoids. This review describes the most recent data on the effects of glucocorticoids on the Wnt signaling pathway, especially on their antagonists, sclerostin and Dkk-1.
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Affiliation(s)
- Núria Guañabens
- Department of Rheumatology, Hospital Clínic, C/Villarroel 170, Barcelona, 08036, Spain,
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Gifre L, Ruiz-Gaspà S, Monegal A, Nomdedeu B, Filella X, Guañabens N, Peris P. Effect of glucocorticoid treatment on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. Bone 2013; 57:272-6. [PMID: 23981659 DOI: 10.1016/j.bone.2013.08.016] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 08/09/2013] [Accepted: 08/13/2013] [Indexed: 02/07/2023]
Abstract
The aim of this study was to analyse the effect of glucocorticoid therapy (GCCT) on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. 25 patients (8 M/17 F, aged 48±19yrs) recently initiating GCCT (≥7.5mg/day, ≤6months) were prospectively included. Bone turnover markers (bone formation: P1NP, osteocalcin [OC], bone ALP; bone resorption: sCTx) and Wnt antagonists (serum sclerostin and Dkk-1) were assessed in all patients (short-term and 12months after initiating GCCT). Bone mineral density (BMD) was performed to assess osteoporosis. The results were compared with 60 healthy controls. At short-term patients on GCCT showed a significant decrease in bone formation markers versus controls (P1NP: 19±9 vs. 43±16ng/mL, p<0.001; OC: 7.4±2.4 vs. 18.4±5.2ng/mL, p=0.001) and in Dkk-1 levels (24.5±20.1 vs. 36.8±13.7pmol/L, p=0.008) with similar sclerostin values (41.8±21.8 vs. 42.1±13.9pmol/L, p=0.950). Sclerostin correlated positively with GCCT doses (r=0.449, p=0.024) and lumbar BMD (r=0.424, p=0.035), and negatively with bone ALP (r=-0.398, p=0.049). A progressive decrease in Dkk-1 levels was observed at 12months, (19.1±14.9, p=0.001), whereas sclerostin increased compared to controls (48.9±11.6, p=0.045). In conclusion, the effect of GCCT on the serum levels of the Wnt signalling parameters differs depending on the antagonist evaluated. Whereas sclerostin values increased and showed a relationship with the dose and bone AP, Dkk-1 levels decreased throughout the study suggesting a counter-regulatory mechanism of this factor thereby reducing the deleterious effect of GCCT in the bone.
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Affiliation(s)
- L Gifre
- Rheumatology Department, Metabolic Bone Diseases Unit, Hospital Clínic of Barcelona, Spain.
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33
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Clinical utility of serum sclerostin measurements. BONEKEY REPORTS 2013; 2:361. [PMID: 24578825 DOI: 10.1038/bonekey.2013.95] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 05/16/2013] [Indexed: 01/16/2023]
Abstract
Sclerostin is an osteocyte-secreted soluble antagonist of the Wnt/β-catenin signaling pathway requisite for osteoblast development and activity. Efforts over the past several years have focused on unraveling the role of sclerostin in both normal physiological and pathological conditions. Sclerostin levels are undetectable in the serum of patients with sclerosteosis. In normal individuals, serum sclerostin levels are higher in males and increase in both sexes across the adult lifespan. Some, but not other, studies have demonstrated that higher serum sclerostin levels are associated with increased fracture risk, particularly when paired with lower bone mineral density. Levels of circulating sclerostin are highly correlated with bone marrow sclerostin levels. Sclerostin levels are inversely related to parathyroid hormone levels. Clinical conditions in which serum sclerostin levels have been measured include ankylosing spondylitis, chronic kidney disease, diabetes, fractures, hypercortisolism, multiple myeloma and spinal cord injury. Even within clearly defined clinical conditions, however, consistent changes in serum sclerostin levels have not always been seen. This may reflect differences in currently available commercial assays or sample sources (serum versus plasma), and suggests further study is needed before sclerostin measurements are introduced into routine clinical practice. Until such issues are resolved, measurement of sclerostin levels appears to be most useful for understanding the mechanisms by which osteocytes regulate bone turnover through the integration of hormonal, physical and pharmacological stimuli, rather than to guide clinical-care decisions.
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