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Huang F, Fan X, Xu H, Lv Z, Zou Y, Lian J, Ding F, Sun Y. Computational insights into the aggregation mechanism of human calcitonin. Int J Biol Macromol 2025; 294:139520. [PMID: 39761900 DOI: 10.1016/j.ijbiomac.2025.139520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025]
Abstract
Human calcitonin (hCT) is a peptide hormone that regulates calcium homeostasis, but its abnormal aggregation can disrupt physiological functions and increase the risk of medullary thyroid carcinoma. To elucidate the mechanisms underlying hCT aggregation, we investigated the self-assembly dynamics of hCT segments (hCT1-14, hCT15-25, and hCT26-32) and the folding and dimerization of full-length hCT1-32 through microsecond atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that hCT1-14 and hCT26-32 predominantly existed as isolated monomers with transient small-sized oligomers, indicating weak aggregation tendencies. In contrast, hCT15-25 exhibited robust aggregation capability, forming stable β-sheet aggregates independently. Full-length hCT1-32 monomers displayed dynamic helical structures, with dimerization decreasing helix content and enhancing β-sheet formation. The transition to β-sheets in full-length hCT1-32 correlated with the loss of helical structure in the hCT15-25 region. Conformations with high helical content in hCT15-25 corresponded to significantly reduced β-sheet structures across the peptide, underscoring the importance of helical stability in preventing β-sheet conversion. Thus, the development of amyloid-resistant hCT analogues should focus on enhancing helical stability in this crucial region. Overall, our study not only elucidates the aggregation mechanism of hCT but also identifies a critical target for designing drug inhibitors to prevent hCT aggregation.
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Affiliation(s)
- Fengjuan Huang
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo 315211, China
| | - Xinjie Fan
- School of Physical Science and Technology, Ningbo University, Ningbo 315211, China
| | - Huan Xu
- School of Physical Science and Technology, Ningbo University, Ningbo 315211, China
| | - Zhongyue Lv
- Department of Neurology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China
| | - Yu Zou
- Department of Sport and Exercise Science, Zhejiang University, Hangzhou 310058, China
| | - Jiangfang Lian
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo 315211, China.
| | - Feng Ding
- Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States.
| | - Yunxiang Sun
- School of Physical Science and Technology, Ningbo University, Ningbo 315211, China; Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States.
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Huang F, Huang J, Yan J, Liu Y, Lian J, Sun Q, Ding F, Sun Y. Molecular Insights into the Effects of F16L and F19L Substitutions on the Conformation and Aggregation Dynamics of Human Calcitonin. J Chem Inf Model 2024; 64:4500-4510. [PMID: 38745385 PMCID: PMC11349047 DOI: 10.1021/acs.jcim.4c00553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Human calcitonin (hCT) regulates calcium-phosphorus metabolism, but its amyloid aggregation disrupts physiological activity, increases thyroid carcinoma risk, and hampers its clinical use for bone-related diseases like osteoporosis and Paget's disease. Improving hCT with targeted modifications to mitigate amyloid formation while maintaining its function holds promise as a strategy. Understanding how each residue in hCT's amyloidogenic core affects its structure and aggregation dynamics is crucial for designing effective analogues. Mutants F16L-hCT and F19L-hCT, where Phe residues in the core are replaced with Leu as in nonamyloidogenic salmon calcitonin, showed different aggregation kinetics. However, the molecular effects of these substitutions in hCT are still unclear. Here, we systematically investigated the folding and self-assembly conformational dynamics of hCT, F16L-hCT, and F19L-hCT through multiple long-time scale independent atomistic discrete molecular dynamics (DMD) simulations. Our results indicated that the hCT monomer primarily assumed unstructured conformations with dynamic helices around residues 4-12 and 14-21. During self-assembly, the amyloidogenic core of hCT14-21 converted from dynamic helices to β-sheets. However, substituting F16L did not induce significant conformational changes, as F16L-hCT exhibited characteristics similar to those of wild-type hCT in both monomeric and oligomeric states. In contrast, F19L-hCT exhibited substantially more helices and fewer β-sheets than did hCT, irrespective of their monomers or oligomers. The substitution of F19L significantly enhanced the stability of the helical conformation for hCT14-21, thereby suppressing the helix-to-β-sheet conformational conversion. Overall, our findings elucidate the molecular mechanisms underlying hCT aggregation and the effects of F16L and F19L substitutions on the conformational dynamics of hCT, highlighting the critical role of F19 as an important target in the design of amyloid-resistant hCT analogs for future clinical applications.
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Affiliation(s)
- Fengjuan Huang
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Lihuili Hospital Affiliated to Ningbo University, Ningbo University, Ningbo 315211, China
- School of Medicine, Ningbo University, Ningbo 315211, China
| | - Jiahui Huang
- School of Physical Science and Technology, Ningbo University, Ningbo 315211, China
| | - Jiajia Yan
- School of Physical Science and Technology, Ningbo University, Ningbo 315211, China
| | - Yuying Liu
- School of Physical Science and Technology, Ningbo University, Ningbo 315211, China
| | - Jiangfang Lian
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Lihuili Hospital Affiliated to Ningbo University, Ningbo University, Ningbo 315211, China
| | - Qinxue Sun
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Lihuili Hospital Affiliated to Ningbo University, Ningbo University, Ningbo 315211, China
| | - Feng Ding
- Department of Physics and Astronomy, Clemson University, Clemson, South Carolina 29634, United States
| | - Yunxiang Sun
- School of Physical Science and Technology, Ningbo University, Ningbo 315211, China
- Department of Physics and Astronomy, Clemson University, Clemson, South Carolina 29634, United States
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Alatabi HSH, Tobji S, Haouas Z. Effects of Calcitonin Administration on the Amount of Bone Formation After Sutural Expansion Using Micro-CT. J Craniofac Surg 2023; 34:2556-2559. [PMID: 38011270 DOI: 10.1097/scs.0000000000009575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/14/2023] [Indexed: 11/29/2023] Open
Abstract
OBJECTIVE Calcitonin injections were used in this investigation to see whether they influenced the quantity of bone formation after a rabbit model was subjected to micro-computed tomography expansion. MATERIALS AND METHODS Research was conducted on a total of 16 white male rabbits. Randomly, 4 groups of 4 rabbits each had their bone-borne expanders triggered by the Hyrax appliances as follows: In the first group (the control), the expansion was (0.5) mm per day for 12 days. In the second group, the same expansion protocol was used with 3 subcutaneous injections of calcitonin). In the third group, the expansion was (2.5) mm per day for 7 days followed by (0.5) mm per day for 7 days. In the fourth group, the same expansion protocol was used with 3 subcutaneous injections of calcitonin. As a result, all groups had their Hyrax devices expanded by 6 mm in total. Sutural separation and new bone growth were examined by micro-computed tomography after 6 weeks of retention. To end the experiment, the rabbits were given a high dosage of phenobarbitone (90 mg/kg). RESULTS In the calcitonin-receiving group, there was a significant increase in anterior and posterior sutural separation, when compared with non-calcitonin-receiving groups. In the (2.5) mm instant expansion protocol, there was a significant increase in anterior and posterior sutural separation, when compared with the (0.5) mm instant expansion protocol. CONCLUSION Calcitonin and the instant expansion protocol enhance new bone formation in rabbits.
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Affiliation(s)
| | - Samir Tobji
- Faculty of Dental Medicine, University of Monastir, Laboratory of Oral Health and Orofacial Rehabilitation
| | - Zohra Haouas
- Research Unit of Genetic, Laboratory of Histology and Cytogenetic, Faculty of Medicine, Avenue Avicenne, Monastir, Tunisia
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Surowiec RK, Saldivar R, Rai RK, Metzger CE, Jacobson AM, Allen MR, Wallace JM. Ex vivo exposure to calcitonin or raloxifene improves mechanical properties of diseased bone through non-cell mediated mechanisms. Bone 2023; 173:116805. [PMID: 37196853 PMCID: PMC10330631 DOI: 10.1016/j.bone.2023.116805] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/01/2023] [Accepted: 05/12/2023] [Indexed: 05/19/2023]
Abstract
Raloxifene (RAL) reduces clinical fracture risk despite modest effects on bone mass and density. This reduction in fracture risk may be due to improved material level-mechanical properties through a non-cell mediated increase in bone hydration. Synthetic salmon calcitonin (CAL) has also demonstrated efficacy in reducing fracture risk with only modest bone mass and density improvements. This study aimed to determine if CAL could modify healthy and diseased bone through cell-independent mechanisms that alter hydration similar to RAL. 26-week-old male C57BL/6 mice induced with chronic kidney disease (CKD) beginning at 16 weeks of age via 0.2 % adenine-laced casein-based (0.9 % P, 0.6 % C) chow, and their non-CKD control littermates (Con), were utilized. Upon sacrifice, right femora were randomly assigned to the following ex vivo experimental groups: RAL (2 μM, n = 10 CKD, n = 10 Con), CAL (100 nM, n = 10 CKD, n = 10 Con), or Vehicle (VEH; n = 9 CKD, n = 9 Con). Bones were incubated in PBS + drug solution at 37 °C for 14 days using an established ex vivo soaking methodology. Cortical geometry (μCT) was used to confirm a CKD bone phenotype, including porosity and cortical thinning, at sacrifice. Femora were assessed for mechanical properties (3-point bending) and bone hydration (via solid state nuclear magnetic resonance spectroscopy with magic angle spinning (ssNMR)). Data were analyzed by two-tailed t-tests (μCT) or 2-way ANOVA for main effects of disease, treatment, and their interaction. Tukey's post hoc analyses followed a significant main effect of treatment to determine the source of the effect. Imaging confirmed a cortical phenotype reflective of CKD, including lower cortical thickness (p < 0.0001) and increased cortical porosity (p = 0.02) compared to Con. In addition, CKD resulted in weaker, less deformable bones. In CKD bones, ex vivo exposure to RAL or CAL improved total work (+120 % and +107 %, respectively; p < 0.05), post-yield work (+143 % and +133 %), total displacement (+197 % and +229 %), total strain (+225 % and +243 %), and toughness (+158 % and +119 %) vs. CKD VEH soaked bones. Ex vivo exposure to RAL or CAL did not impact any mechanical properties in Con bone. Matrix-bound water by ssNMR showed CAL treated bones had significantly higher bound water compared to VEH treated bones in both CKD and Con cohorts (p = 0.001 and p = 0.01, respectively). RAL positively modulated bound water in CKD bone compared to VEH (p = 0.002) but not in Con bone. There were no significant differences between bones soaked with CAL vs. RAL for any outcomes measured. RAL and CAL improve important post-yield properties and toughness in a non-cell mediated manner in CKD bone but not in Con bones. While RAL treated CKD bones had higher matrix-bound water content in line with previous reports, both Con and CKD bones exposed to CAL had higher matrix-bound water. Therapeutic modulation of water, specifically the bound water fraction, represents a novel approach to improving mechanical properties and potentially reducing fracture risk.
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Affiliation(s)
- Rachel K Surowiec
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Rosario Saldivar
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Epidemiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ratan K Rai
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Corinne E Metzger
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Andrea M Jacobson
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
| | - Matthew R Allen
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
| | - Joseph M Wallace
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
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Liu Y, Wang Y, Zhang Y, Zou Y, Wei G, Ding F, Sun Y. Structural Perturbation of Monomers Determines the Amyloid Aggregation Propensity of Calcitonin Variants. J Chem Inf Model 2023; 63:308-320. [PMID: 36456917 PMCID: PMC9839651 DOI: 10.1021/acs.jcim.2c01202] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Human calcitonin (hCT) is a polypeptide hormone that participates in calcium-phosphorus metabolism. Irreversible aggregation of 32-amino acid hCT into β-sheet-rich amyloid fibrils impairs physiological activity and increases the risk of medullary carcinoma of the thyroid. Amyloid-resistant hCT derivatives substituting critical amyloidogenic residues are of particular interest for clinical applications as therapeutic drugs against bone-related diseases. Uncovering the aggregation mechanism of hCT at the molecular level, therefore, is important for the design of amyloid-resistant hCT analogues. Here, we investigated the aggregation dynamics of hCT, non-amyloidogenic salmon calcitonin (sCT), and two hCT analogues with reduced aggregation tendency─TL-hCT and phCT─using long timescale discrete molecular dynamics simulations. Our results showed that hCT monomers mainly adopted unstructured conformations with dynamically formed helices around the central region. hCT self-assembled into helix-rich oligomers first, followed by a conformational conversion into β-sheet-rich oligomers with β-sheets formed by residues 10-30 and stabilized by aromatic and hydrophobic interactions. Our simulations confirmed that TL-hCT and phCT oligomers featured more helices and fewer β-sheets than hCT. Substitution of central aromatic residues with leucine in TL-hCT and replacing C-terminal hydrophobic residue with hydrophilic amino acid in phCT only locally suppressed β-sheet propensities in the central region and C-terminus, respectively. Having mutations in both central and C-terminal regions, sCT monomers and dynamically formed oligomers predominantly adopted helices, confirming that both central aromatic and C-terminal hydrophobic residues played important roles in the fibrillization of hCT. We also observed the formation of β-barrel intermediates, postulated as the toxic oligomers in amyloidosis, for hCT but not for sCT. Our computational study depicts a complete picture of the aggregation dynamics of hCT and the effects of mutations. The design of next-generation amyloid-resistant hCT analogues should consider the impact on both amyloidogenic regions and also take into account the amplification of transient β-sheet population in monomers upon aggregation.
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Affiliation(s)
- Yuying Liu
- Department of Physics, Ningbo University, Ningbo 315211, China
- State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433, P. R. China
| | - Ying Wang
- Department of Physics, Ningbo University, Ningbo 315211, China
| | - Yu Zhang
- Department of Physics, Ningbo University, Ningbo 315211, China
| | - Yu Zou
- Department of Sport and Exercise Science, Zhejiang University, Hangzhou 310058, China
| | - Guanghong Wei
- State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433, P. R. China
| | - Feng Ding
- Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA
| | - Yunxiang Sun
- Department of Physics, Ningbo University, Ningbo 315211, China
- State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433, P. R. China
- Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA
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Kang J, Liu Y, Zhang Y, Yan W, Wu Y, Su R. The Influence of the Prolactins on the Development of the Uterus in Neonatal Mice. Front Vet Sci 2022; 9:818827. [PMID: 35252420 PMCID: PMC8891943 DOI: 10.3389/fvets.2022.818827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 01/20/2022] [Indexed: 11/13/2022] Open
Abstract
The endometrial gland is one of the most important components of the mammalian uterus. However, few studies have been conducted on the regulatory mechanisms of adenogenesis during the development of endometrium. In the present study, we detected the genes expression of 35 different prolactin family members (PRLs) together with the prolactin receptor (PRL-R) in the endometrium of neonatal mice along with the adenogenesis process, to address which prolactin-like genes play a key role during gland development in mice. We found that: (1) The expression of Prl1a1, Prl3d1, Prl5a1, Prl7a1, Prl7a2, Prl7d1, Prl8a6, Prl8a8, and Prl8a9 genes were significantly increased along with the development of uterine glands. Prl7c1 and Prl8a1 were observably up-regulated on Postnatal day 5 (PND5) when the uterine glandular bud invagination begins. Prl3a1, Prl3b1, and Prl7b1 suddenly increased significantly on PND9. But, Prl3c1 and Prl8a2 were markedly down-regulated on PND5 and the expression of Prl6a1 and Prlr were stable extremely. (2) After continuous injection of Progesterone (P4), a well-known method to suppress the endometrial adenogenesis, the expression of Prl1a1, Prl3d1, Prl5a1, Prl7a1, Prl7a2, Prl7d1, Prl8a6, Prl8a8, Prl8a9, and Prlr were suppressed on PND7. And on PND9, Prl1a1, Prl3d1, Prl8a6, Prl8a8, and Prl8a9 were significantly inhibited. (3) Further analysis of the epithelial and stroma showed that these PRLs were mainly expressed in the endometrial stroma of neonatal mice. Our results indicate that multiple PRLs are involved in uterine development and endometrial adenogenesis. Continued progesterone therapy may alter the expression pattern of these PRLs in endometrial stromal cells, thereby altering the interaction and communication between stroma and epithelium, and ultimately leading to complete suppression of endometrial adenogenesis.
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Kang ML, Goo JTT, Lee DJK. CHOP protocol: streamlining access to definitive intervention for major trauma victims. Singapore Med J 2021; 62:620-622. [PMID: 32728086 PMCID: PMC8804424 DOI: 10.11622/smedj.2020113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Min Li Kang
- Department of Surgery, Khoo Teck Puat Hospital, Singapore
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Kaneb A, Berardino K, Hanukaai JS, Rooney K, Kaye AD. Calcitonin (FORTICAL, MIACALCIN) for the treatment of vertebral compression fractures. Orthop Rev (Pavia) 2021; 13:24976. [PMID: 34745472 DOI: 10.52965/001c.24976] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 06/18/2021] [Indexed: 12/28/2022] Open
Abstract
Purpose of Review Osteoporosis is a common condition affecting the musculoskeletal system. It carries with it increased risks of fracture in many areas of the body, leading to reduced quality of life, limited mobility, and other long-term implications such as chronic pain. Vertebral compression fractures are a common development in patients with osteoporosis. Current treatment options focus on reducing pain; preventative methods are somewhat limited and focus on minimizing risk factors for the development of osteoporosis. In this review, we explore the use of calcitonin (FORTICAL, MIACALCIN) to treat vertebral compression fractures (VCFs). Recent Findings Osteoporosis had a prevalence of more than 10% in the United States in 2010. The CDC estimates that nearly 25% of women over age 65 have findings of osteoporosis, which include low spinal bone mass. The condition is highly prevalent and, in an aging U.S. population, quite clinically relevant. Risk factors for development include advanced age, cigarette smoking, medications, reduced physical activity, and low calcium and vitamin D intake. Family history may also play a role. Diagnosis is made based on bone mineral density.Standard therapy for VCFs in osteoporosis includes analgesic medications, such as NSAIDs and biphosphonates, and surgical intervention. NSAIDs address the chronic pain that is a common long-term effect of VCFs. Biphosphonates have recently been used to attempt to halt the progression and provide prevention. Surgical interventions such as balloon kyphoplasty and vertebroplasty are typically reserved for patients who have failed other methods.Calcitonin is a peptide naturally produced by the human body, released from the parathyroid gland. It binds to osteoclasts, inhibiting them from inducing bone resorption. By relatively unknown mechanisms, it also appears to cause endorphin release and mitigate pain. Clinical data has shown safety and efficacy for exogenous calcitonin in reducing bone turnover and reducing VCF-induced pain. Summary Osteoporosis is a common condition that can lead to complications such as vertebral compression fractures. It can significantly impact the quality of life in many elderly Americans. There is currently no singular treatment, but calcitonin has recently been explored as a possible option for minimizing pain and reducing disease progression. Further studies are needed to understand its preventative benefits fully.
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Affiliation(s)
- Alicia Kaneb
- Georgetown University School of Medicine, Washington D.C
| | | | | | - Kelsey Rooney
- Louisiana State University Health Science Center, Shreveport, LA
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Zoe N, Antigoni S, Christodoulos L, Albaghal Y, Zervides C, Ilana K. Cherubism treated with intranasal calcitonin: A case report and literature review. ORAL AND MAXILLOFACIAL SURGERY CASES 2021. [DOI: 10.1016/j.omsc.2021.100225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Kornel A, Den Hartogh DJ, Klentrou P, Tsiani E. Role of the Myokine Irisin on Bone Homeostasis: Review of the Current Evidence. Int J Mol Sci 2021; 22:9136. [PMID: 34502045 PMCID: PMC8430535 DOI: 10.3390/ijms22179136] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/16/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Bone is a highly dynamic tissue that is constantly adapting to micro-changes to facilitate movement. When the balance between bone building and resorption shifts more towards bone resorption, the result is reduced bone density and mineralization, as seen in osteoporosis or osteopenia. Current treatment strategies aimed to improve bone homeostasis and turnover are lacking in efficacy, resulting in the search for new preventative and nutraceutical treatment options. The myokine irisin, since its discovery in 2012, has been shown to play an important role in many tissues including muscle, adipose, and bone. Evidence indicate that irisin is associated with increased bone formation and decreased bone resorption, leading to reduced risk of osteoporosis in post-menopausal women. In addition, low serum irisin levels have been found in individuals with osteoporosis and osteopenia. Irisin targets key signaling proteins, promoting osteoblastogenesis and reducing osteoclastogenesis. The present review summarizes the existing evidence regarding the effects of irisin on bone homeostasis.
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Affiliation(s)
- Amanda Kornel
- Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (A.K.); (D.J.D.H.)
| | - Danja J. Den Hartogh
- Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (A.K.); (D.J.D.H.)
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada;
| | - Panagiota Klentrou
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada;
- Department of Kinesiology, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (A.K.); (D.J.D.H.)
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada;
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Lantz R, Busbee B, Wojcikiewicz EP, Du D. Flavonoids with Vicinal Hydroxyl Groups Inhibit Human Calcitonin Amyloid Formation. Chemistry 2020; 26:13063-13071. [PMID: 32458489 DOI: 10.1002/chem.202002027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/20/2020] [Indexed: 12/14/2022]
Abstract
Human calcitonin (hCT) is a 32-residue peptide hormone that can aggregate into amyloid fibrils and cause cellular toxicity. In this study, we investigated the inhibition effects of a group of polyphenolic molecules on hCT amyloid formation. Our results suggest that the gallate moiety in epigallocatechin-3-gallate (EGCG), a well-recognized amyloid inhibitor, is not critical for its inhibition function in the hCT amyloid formation. Our results demonstrate that flavonoid compounds, such as myricetin, quercetin, and baicalein, that contain vicinal hydroxyl groups on the phenyl ring effectively prevent hCT fibrillization. This structural feature may also be applied to non-flavonoid polyphenolic inhibitors. Moreover, our results indicate a plausible mechanistic role of these vicinal hydroxyl groups which might include the oxidation to form a quinone and the subsequent covalent linkage with amino acid residues such as lysine or histidine in hCT. This may further disrupt the crucial electrostatic and aromatic interactions involved in the process of hCT amyloid fibril formation. The inhibition activity of the polyphenolic compounds against hCT fibril formation may likely be attributed to a combination of factors such as covalent linkage formation, aromatic stacking, and hydrogen bonding interactions.
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Affiliation(s)
- Richard Lantz
- Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Brian Busbee
- Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Ewa P Wojcikiewicz
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Deguo Du
- Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL, 33431, USA
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Kim SM, Taneja C, Perez-Pena H, Ryu V, Gumerova A, Li W, Ahmad N, Zhu LL, Liu P, Mathew M, Korkmaz F, Gera S, Sant D, Hadelia E, Ievleva K, Kuo TC, Miyashita H, Liu L, Tourkova I, Stanley S, Lizneva D, Iqbal J, Sun L, Tamler R, Blair HC, New MI, Haider S, Yuen T, Zaidi M. Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass. Proc Natl Acad Sci U S A 2020; 117:14386-14394. [PMID: 32513693 PMCID: PMC7321982 DOI: 10.1073/pnas.2000950117] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine β-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.
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Affiliation(s)
- Se-Min Kim
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Charit Taneja
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Helena Perez-Pena
- Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, WC1N 1AX London, United Kingdom
| | - Vitaly Ryu
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Anisa Gumerova
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Wenliang Li
- Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, WC1N 1AX London, United Kingdom
| | - Naseer Ahmad
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Ling-Ling Zhu
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Peng Liu
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Mehr Mathew
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Funda Korkmaz
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Sakshi Gera
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Damini Sant
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Elina Hadelia
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Kseniia Ievleva
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Reproductive Health, Scientific Center for Family Health and Human Reproduction Problems, 664003 Irkutsk, Russian Federation
| | - Tan-Chun Kuo
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Hirotaka Miyashita
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Li Liu
- Department of Pathology, Pittsburgh Veterans Affairs Healthcare System, Pittsburgh, PA 15240
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
| | - Irina Tourkova
- Department of Pathology, Pittsburgh Veterans Affairs Healthcare System, Pittsburgh, PA 15240
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
| | - Sarah Stanley
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Daria Lizneva
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Jameel Iqbal
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Li Sun
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Ronald Tamler
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Harry C Blair
- Department of Pathology, Pittsburgh Veterans Affairs Healthcare System, Pittsburgh, PA 15240
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
| | - Maria I New
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Shozeb Haider
- Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, WC1N 1AX London, United Kingdom
| | - Tony Yuen
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Mone Zaidi
- The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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13
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Anselmino N, Starbuck M, Labanca E, Cotignola J, Navone N, Gueron G, Zenclussen AC, Vazquez E. Heme Oxygenase-1 Is a Pivotal Modulator of Bone Turnover and Remodeling: Molecular Implications for Prostate Cancer Bone Metastasis. Antioxid Redox Signal 2020; 32:1243-1258. [PMID: 31861963 PMCID: PMC7232646 DOI: 10.1089/ars.2019.7879] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 12/10/2019] [Accepted: 12/18/2019] [Indexed: 01/28/2023]
Abstract
Aims: Bone is the most frequent site of prostate cancer (PCa) metastasis. Tumor cells interact with the bone microenvironment interrupting tissue balance. Heme oxygenase-1 (HO-1; encoded by Hmox1) appears as a potential target in PCa maintaining the cellular homeostasis. Our hypothesis is that HO-1 is implicated in bone physiology and modulates the communication with PCa cells. Here we aimed at (i) assessing the physiological impact of Hmox1 gene knockout (KO) on bone metabolism in vivo and (ii) determining the alterations of the transcriptional landscape associated with tumorigenesis and bone remodeling in cells growing in coculture (PCa cells with primary mouse osteoblasts [PMOs] from BALB/c Hmox1+/+, Hmox1+/-, and Hmox1-/- mice). Results: Histomorphometric analysis of Hmox1-/- mice bones exhibited significantly decreased bone density with reduced remodeling parameters. A positive correlation between Hmox1 expression and Runx2, Col1a1, Csf1, and Opg genes was observed in PMOs. Flow cytometry studies revealed two populations of PMOs with different reactive oxygen species (ROS) levels. The high ROS population was increased in PMOs Hmox1+/- compared with Hmox1+/+, but was significantly reduced in PMOs Hmox1-/-, suggesting restrained ROS tolerance in KO cells. Gene expression was altered in PMOs upon coculture with PCa cells, showing a pro-osteoclastic profile. Moreover, HO-1 induction in PCa cells growing in coculture with PMOs resulted in a significant modulation of key bone markers such as PTHrP and OPG. Innovation and Conclusion: We here demonstrate the direct implications of HO-1 expression in bone remodeling and how it participates in the alterations in the communication between bone and prostate tumor cells.
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Affiliation(s)
- Nicolás Anselmino
- Laboratorio de inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Michael Starbuck
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Estefania Labanca
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Javier Cotignola
- Laboratorio de inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Nora Navone
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Geraldine Gueron
- Laboratorio de inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ana C. Zenclussen
- Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Elba Vazquez
- Laboratorio de inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
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14
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Yang R, Deng H, Hou J, Li W, Zhang C, Yu M, Tang Y, Li Q, Li F, Song B, Zhang Z, Jiang C, Shen H. Investigation of salmon calcitonin in regulating fibrosis-related molecule production and cell-substrate adhesion in frozen shoulder synovial/capsular fibroblasts. J Orthop Res 2020; 38:1375-1385. [PMID: 31854470 DOI: 10.1002/jor.24571] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/08/2019] [Accepted: 12/12/2019] [Indexed: 02/04/2023]
Abstract
The purpose of this study was to evaluate the effect of salmon calcitonin (sCT) on improving fibrosis-related indicators in frozen shoulder synovial/capsular fibroblasts (SCFs) and detect the potential downstream pathway. Quantitative real-time polymerase chain reaction and cell-substrate adhesion assays were used to measure alterations in fibrosis-related molecule expression and the cell adhesion ability of frozen shoulder SCFs after treatment with range concentrations of sCT. The presence of calcitonin receptors (CTRs) in shoulder joint synovial/capsular tissue samples was detected by immunohistochemistry (IHC). The downstream pathways of sCT in SCFs were further explored by utilizing three classical pathway inhibitors. With the addition of sCT to the culture medium of frozen shoulder SCFs, the messenger RNA (mRNA) expression of collagen type I (COL1A1), COL3A1, fibronectin 1, laminin 1, transforming growth factor-β1 (TGF-β1), and interleukin-1α (IL-1α) showed a descending trend as the sCT concentration increased. Treatment with sCT increased the expression of vascular endothelial growth factor and IL-6 in a dose-dependent manner. The enhanced adhesion ability of frozen shoulder SCFs gradually diminished with increasing concentrations of sCT. By using IHC, the CTR was detected extensively in the frozen shoulder joint synovium and capsule. Blocking the protein kinase C (PKC) pathway reversed the sCT-mediated suppression of COL1A1 production. Blocking the PKC or protein kinase A (PKA) pathway eliminated the sCT-induced inhibition of TGF-β1 production. This study demonstrated that sCT effectively improved the mRNA expression of fibrosis-related molecules and decreased the enhanced cell-substrate adhesion ability of frozen shoulder SCFs. sCT might achieve these effects by interacting with the CTR that is expressed on the SCF surface and by activating the downstream PKC or PKA pathway.
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Affiliation(s)
- Rui Yang
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haiquan Deng
- Department of Orthopaedic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jingyi Hou
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiping Li
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Congda Zhang
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Menglei Yu
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yiyong Tang
- Department of Orthopaedic Surgery, The Eighth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China
| | - Qingyue Li
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fangqi Li
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Song
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhengzheng Zhang
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chuan Jiang
- Department of Orthopaedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huiyong Shen
- Department of Orthopaedic Surgery, The Eighth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China
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15
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Omi M, Mishina Y. Role of osteoclasts in oral homeostasis and jawbone diseases. ACTA ACUST UNITED AC 2020; 18:14-27. [PMID: 34220275 DOI: 10.1002/osi2.1078] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The jawbone is a unique structure as it serves multiple functions in mastication. Given the fact that the jawbone is remodeled faster than other skeletal bones, bone cells in the jawbone may respond differently to local and systemic cues to regulate bone remodeling and adaptation. Osteoclasts are bone cells responsible for removing old bone, playing an essential role in bone remodeling. Although bone resorption by osteoclasts is required for dental tissue development, homeostasis and repair, excessive osteoclast activity is associated with oral skeletal diseases such as periodontitis. In addition, antiresorptive medications used to prevent bone homeostasis of tumors can cause osteonecrosis of the jaws that is a major concern to the dentist. Therefore, understanding of the role of osteoclasts in oral homeostasis under physiological and pathological conditions leads to better targeted therapeutic options for skeletal diseases to maintain patients' oral health. Here, we highlight the unique features of the jawbone compared to the long bone and the involvement of osteoclasts in the jawbone-specific diseases.
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Affiliation(s)
- Maiko Omi
- Department of Biologic and Materials Sciences & Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Yuji Mishina
- Department of Biologic and Materials Sciences & Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
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16
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Xie J, Guo J, Kanwal Z, Wu M, Lv X, Ibrahim NA, Li P, Buabeid MA, Arafa ESA, Sun Q. Calcitonin and Bone Physiology: In Vitro, In Vivo, and Clinical Investigations. Int J Endocrinol 2020; 2020:3236828. [PMID: 32963524 PMCID: PMC7501564 DOI: 10.1155/2020/3236828] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/18/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022] Open
Abstract
Calcitonin was discovered as a peptide hormone that was known to reduce the calcium levels in the systemic circulation. This hypocalcemic effect is produced due to multiple reasons such as inhibition of bone resorption or suppression of calcium release from the bone. Thus, calcitonin was said as a primary regulator of the bone resorption process. This is the reason why calcitonin has been used widely in clinics for the treatment of bone disorders such as osteoporosis, hypercalcemia, and Paget's disease. However, presently calcitonin usage is declined due to the development of efficacious formulations of new drugs. Calcitonin gene-related peptides and several other peptides such as intermedin, amylin, and adrenomedullin (ADM) are categorized in calcitonin family. These peptides are known for the structural similarity with calcitonin. Aside from having a similar structure, these peptides have few overlapping biological activities and signal transduction action through related receptors. However, several other activities are also present that are peptide specific. In vitro and in vivo studies documented the posttreatment effects of calcitonin peptides, i.e., positive effect on bone osteoblasts and their formation and negative effect on osteoclasts and their resorption. The recent research studies carried out on genetically modified mice showed the inhibition of osteoclast activity by amylin, while astonishingly calcitonin plays its role by suppressing osteoblast and bone turnover. This article describes the review of the bone, the activity of the calcitonin family of peptides, and the link between them.
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Affiliation(s)
- Jingbo Xie
- Department of Orthopedics, Fengcheng People's Hospital, Fengcheng, Jiangxi 331100, China
| | - Jian Guo
- Department of the Second Orthopedics, Hongdu Hospital of Traditional Chinese Medicine Affiliated to Jiangxi University of Traditional Chinese Medicine, Nanchang Hongdu Traditional Chinese Medicine Hospital, Nanchang, Jiangxi 330008, China
| | | | - Mingzheng Wu
- Department of Orthopaedics, Pu'ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Xiangyang Lv
- Department of Orthopaedics, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, China
| | | | - Ping Li
- Department of Orthopaedics, Ya'an People's Hospital, Ya'an, Sichuan 625000, China
| | | | | | - Qingshan Sun
- Department of Orthopedics, The Third Hospital of Shandong Province, Jinan, Shandong 250031, China
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17
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Lantz R, Busbee B, Wojcikiewicz EP, Du D. Effects of disulfide bond and cholesterol derivatives on human calcitonin amyloid formation. Biopolymers 2019; 111:e23343. [PMID: 31804717 DOI: 10.1002/bip.23343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/13/2019] [Accepted: 11/20/2019] [Indexed: 12/13/2022]
Abstract
Human calcitonin (hCT) is a 32-residue peptide that aggregates to form amyloid fibrils under appropriate conditions. In this study, we investigated the effect of the intramolecular disulfide bond formed at the N-terminal region of the peptide in the aggregation kinetics of hCT. Our results indicate that the presence of the disulfide bond in hCT plays a crucial role in forming the critical nucleus needed for fibril formation, facilitating the rate of hCT amyloidogenesis. Furthermore, we reported for the first time the effects of cholesterol, cholesterol sulfate, and 3β-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC-cholesterol) on the amyloid formation of oxidized hCT. Our results show that while cholesterol does not affect amyloidogenesis of oxidized hCT, high concentrations of cholesterol sulfate exhibits a moderate inhibiting activity on hCT amyloid formation. In particular, our results show that DC-cholesterol strongly inhibits amyloidogenesis of oxidized hCT in a dose-dependent manner. Further studies at different pH conditions imply the crucial impact of electrostatic and hydrogen bonding interactions in mediating the interplay of hCT and the surface of DC-cholesterol vesicles and the inhibiting function of DC-cholesterol on hCT fibrillization.
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Affiliation(s)
- Richard Lantz
- Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL, 33431, U.S.A
| | - Brian Busbee
- Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL, 33431, U.S.A
| | - Ewa P Wojcikiewicz
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, U.S.A
| | - Deguo Du
- Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL, 33431, U.S.A
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18
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Batty BS, Bionaz M. Graduate Student Literature Review: The milk behind the mustache: A review of milk and bone biology. J Dairy Sci 2019; 102:7608-7617. [DOI: 10.3168/jds.2019-16421] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 04/19/2019] [Indexed: 12/11/2022]
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19
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High Concentrations of Polyelectrolyte Complex Nanoparticles Decrease Activity of Osteoclasts. Molecules 2019; 24:molecules24122346. [PMID: 31242715 PMCID: PMC6630339 DOI: 10.3390/molecules24122346] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/18/2019] [Accepted: 06/24/2019] [Indexed: 11/24/2022] Open
Abstract
Fracture treatment in osteoporotic patients is still challenging. Osteoporosis emerges when there is an imbalance between bone formation and resorption in favor of resorption by osteoclasts. Thus, new implant materials for osteoporotic fracture treatment should promote bone formation and reduce bone resorption. Nanoparticles can serve as drug delivery systems for growth factors like Brain-Derived Neurotrophic Factor (BDNF), which stimulated osteoblast differentiation. Therefore, polyelectrolyte complex nanoparticles (PEC-NPs) consisting of poly(l-lysine) (PLL) and cellulose sulfate (CS), with or without addition of BDNF, were used to analyze their effect on osteoclasts in vitro. Live cell images showed that osteoclast numbers decreased after application of high PLL/CS PEC-NPs concentrations independent of whether BDNF was added or not. Real-time RT-PCR revealed that relative mRNA expression of cathepsin K and calcitonin receptor significantly declined after incubation of osteoclasts with high concentrations of PLL/CS PEC-NPs. Furthermore, Enzyme-Linked Immunosorbent Assay indicated that tartrate-resistant acidic phosphatase 5b activity was significantly reduced in the presence of high PLL/CS PEC-NPs concentrations. Consistent with these results, the pit formation analysis showed that less hydroxyapatite was resorbed by osteoclasts after incubation with high concentrations of PLL/CS PEC-NPs. BDNF had no influence on osteoclasts. We conclude that highly concentrated PLL/CS PEC-NPs dosages decreased osteoclastogenesis and osteoclasts activity. Moreover, BDNF might be a promising growth factor for osteoporotic fracture treatment since it did not increase osteoclast activity.
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20
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Lerner UH, Kindstedt E, Lundberg P. The critical interplay between bone resorbing and bone forming cells. J Clin Periodontol 2019; 46 Suppl 21:33-51. [DOI: 10.1111/jcpe.13051] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 11/05/2018] [Accepted: 12/01/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Ulf H. Lerner
- Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition; Institute of Medicine; Sahlgrenska Academy; University of Gothenburg; Gothenburg Sweden
- Department of Odontology; Division of Molecular Periodontology; Umeå University; Umeå Sweden
| | - Elin Kindstedt
- Department of Odontology; Division of Molecular Periodontology; Umeå University; Umeå Sweden
| | - Pernilla Lundberg
- Department of Odontology; Division of Molecular Periodontology; Umeå University; Umeå Sweden
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21
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Adeyemi WJ, Olayaki LA. Effects of salmon calcitonin and omega – 3 fatty acids on selected biomarkers in experimental diabetic – osteoarthritic rats. ACTA ACUST UNITED AC 2019. [DOI: 10.1016/j.synres.2018.100045] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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22
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Ye H, Zhou J, Li H, Gao Z. Heme prevents highly amyloidogenic human calcitonin (hCT) aggregation: A potential new strategy for the clinical reuse of hCT. J Inorg Biochem 2019; 196:110686. [PMID: 31003065 DOI: 10.1016/j.jinorgbio.2019.03.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/20/2019] [Accepted: 03/31/2019] [Indexed: 11/26/2022]
Abstract
Irreversible aggregation can extremely limit the bioavailability and therapeutic activity of peptide-based drugs. Thus, peptide fibrillation is an excellent challenge for biotechnological drug development. Human calcitonin (hCT) is such a peptide hormone known for its hypocalcaemic effect but has limited pharmaceutical potential due to a high tendency to aggregate. hCT is therefore not widely used preparation in clinical practice. Nonetheless, hCT seems to be still an ideal target for clinical therapy when fibrillation is effectively inhibited, because the alternatives of hCT can stimulate undesirable immune responses in patients and cause side effects. Interestingly, heme is an essential component for many livings and has been shown a strong inhibitory effect on some amyloidogenic peptides aggregation. Here we demonstrate that it may be a most suitable, safe, biocompatible small molecule inhibitor on hCT aggregation, and thereby improving its activity when guiding the drug peptide in clinical therapeutics. In this work, we found that heme was able to reversibly bind with hCT to form a heme-hCT complex with a moderate binding constant (9.17 × 106 M-1) and significantly suppress the aggregation of hCT probably accomplished by heme binding to it, blocking the β-sheet structure assembly which is essential in hCT fibril aggregation. Meanwhile, the heme-hCT complexes showed enhanced bioactivity compared to hCT itself after a 24 h incubation time in reducing blood calcium levels in mice. This study may develop a new strategy to reuse the wild-type hCT in clinical therapeutics.
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Affiliation(s)
- Huixian Ye
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of chemistry and chemical Engineering, Huazhong university of Science and Technology, Wuhan 430074, People's Republic of China
| | - Jun Zhou
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of chemistry and chemical Engineering, Huazhong university of Science and Technology, Wuhan 430074, People's Republic of China
| | - Hailing Li
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of chemistry and chemical Engineering, Huazhong university of Science and Technology, Wuhan 430074, People's Republic of China.
| | - Zhonghong Gao
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of chemistry and chemical Engineering, Huazhong university of Science and Technology, Wuhan 430074, People's Republic of China.
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Naot D, Musson DS, Cornish J. The Activity of Peptides of the Calcitonin Family in Bone. Physiol Rev 2019; 99:781-805. [PMID: 30540227 DOI: 10.1152/physrev.00066.2017] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Calcitonin was discovered over 50 yr ago as a new hormone that rapidly lowers circulating calcium levels. This effect is caused by the inhibition of calcium efflux from bone, as calcitonin is a potent inhibitor of bone resorption. Calcitonin has been in clinical use for conditions of accelerated bone turnover, including Paget's disease and osteoporosis; although in recent years, with the development of drugs that are more potent inhibitors of bone resorption, its use has declined. A number of peptides that are structurally similar to calcitonin form the calcitonin family, which currently includes calcitonin gene-related peptides (αCGRP and βCGRP), amylin, adrenomedullin, and intermedin. Apart from being structurally similar, the peptides signal through related receptors and have some overlapping biological activities, although other activities are peptide specific. In bone, in vitro studies and administration of the peptides to animals generally found inhibitory effects on osteoclasts and bone resorption and positive effects on osteoblasts and bone formation. Surprisingly, studies in genetically modified mice have demonstrated that the physiological role of calcitonin appears to be the inhibition of osteoblast activity and bone turnover, whereas amylin inhibits osteoclast activity. The review article focuses on the activities of peptides of the calcitonin family in bone and the challenges in understanding the relationship between the pharmacological effects and the physiological roles of these peptides.
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Affiliation(s)
- Dorit Naot
- Department of Medicine, University of Auckland , Auckland , New Zealand
| | - David S Musson
- Department of Medicine, University of Auckland , Auckland , New Zealand
| | - Jillian Cornish
- Department of Medicine, University of Auckland , Auckland , New Zealand
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24
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Schwartz J, Réalis-Doyelle E, Dubos MP, Lefranc B, Leprince J, Favrel P. Characterization of an evolutionarily conserved calcitonin signaling system in a lophotrochozoan, the Pacific oyster (Crassostrea gigas). J Exp Biol 2019; 222:jeb.201319. [DOI: 10.1242/jeb.201319] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 06/14/2019] [Indexed: 12/19/2022]
Abstract
In Protostoma, the diuretic hormone 31 (DH31) signaling system was long considered as the orthologue of the chordate calcitonin (CT) signaling system. Using the Pacific oyster (Crassostrea gigas) transcriptomic database GigaTON (http://ngspipelines-sigenae.toulouse.inra.fr/), we characterized seven G-protein-coupled receptors (GPCRs) named Cragi-CTR1/7 and phylogenetically related to chordate CT receptors (CTRs) and to protostome DH31 receptors. Two CT Precursors (Cragi-CTP1 and Cragi-CTP2) containing two CT-type peptides and encoded by two distinct genes with a similar organization were also characterized. These oyster neuropeptides (Cragi-CT1/2) exhibit the two N-terminal paired cysteine residues and except CTP2 derived peptide (Cragi-CTP2dp) the C-terminal proline-amide motif typical of deuterostome CT-type peptides. All mature Cragi-CTs but Cragi-CTP2dp were detected in visceral ganglion (VG) extracts using mass spectrometry. Cell-based assays revealed that the formerly characterized oyster receptors Cg-CTR and Cragi-CTR2 were specifically activated by Cragi-CT1b and Cragi-CT2, respectively. This activation does not require the co-expression of receptor activity-modifying proteins (RAMPs). Thus, the oyster CT signaling appears functionally more closely related to the vertebrate CT/CTR signaling than to the (Calcitonin Gene Related Peptide) CGRP/CLR signaling. Gene expression profiles in different adult tissues and in oysters acclimated to brackish water suggest the potential implication of both Cg-CT-R/Cragi-CT1b and Cragi-CTR2/Cragi-CT2 in water and ionic regulations, though with apparently opposite effects. The present study represents the first comprehensive characterization of a functional CT-type signaling system in a protostome and provides evidence for its evolutionarily ancient origin and its early role in osmotic homeostasis.
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Affiliation(s)
- Julie Schwartz
- Normandie Université, UNICAEN, Sorbonne Universités, MNHN, UPMC, UA, CNRS 7208, IRD 207, Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), CS14032, 14032 CAEN, Cedex 5, France
| | - Emilie Réalis-Doyelle
- Normandie Université, UNICAEN, Sorbonne Universités, MNHN, UPMC, UA, CNRS 7208, IRD 207, Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), CS14032, 14032 CAEN, Cedex 5, France
| | - Marie-Pierre Dubos
- Normandie Université, UNICAEN, Sorbonne Universités, MNHN, UPMC, UA, CNRS 7208, IRD 207, Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), CS14032, 14032 CAEN, Cedex 5, France
| | - Benjamin Lefranc
- Normandie Université, UNIROUEN, INSERM, U1239, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, Institut de Recherche et d'Innovation Biomédicale de Normandie, F-76000 Rouen, France
| | - Jérôme Leprince
- Normandie Université, UNIROUEN, INSERM, U1239, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, Institut de Recherche et d'Innovation Biomédicale de Normandie, F-76000 Rouen, France
| | - Pascal Favrel
- Normandie Université, UNICAEN, Sorbonne Universités, MNHN, UPMC, UA, CNRS 7208, IRD 207, Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), CS14032, 14032 CAEN, Cedex 5, France
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25
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Shang H, Zhou A, Jiang J, Liu Y, Xie J, Li S, Chen Y, Zhu X, Tan H, Li J. Inhibition of the fibrillation of highly amyloidogenic human calcitonin by cucurbit[7]uril with improved bioactivity. Acta Biomater 2018; 78:178-188. [PMID: 30076991 DOI: 10.1016/j.actbio.2018.07.045] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 07/20/2018] [Accepted: 07/25/2018] [Indexed: 02/08/2023]
Abstract
Protein/peptide fibrillation is an important challenge for biotechnological drug development. Salmon calcitonin (sCT) is currently used in the clinical treatment of bone-related diseases such as osteoporosis and hypercalcemia, but it still has the risk of immune responses. Although human calcitonin (hCT) would be a better choice in terms of immunogenicity, it has a strong tendency to irreversibly aggregate in aqueous solutions and form long amyloid fibrils, which significantly reduces its bioavailability and therapeutic potency. Here, we demonstrate that cucurbit[7]uril (CB[7]) can inhibit hCT fibrillation by supramolecular interaction with its aromatic groups (affinity: Phe16 > Tyr12 > Phe19 > Phe22). The hCT-CB[7] complex exhibits low cytotoxicity, even promotes osteoblast proliferation and osteogenic capacity of MC3T3 cells. Meanwhile the hCT-CB[7] complexes shows higher bioactivity compared to hCT in reducing blood calcium levels in rats, and also decreases the immunogenicity of hCT. These results suggest that CB[7] has the potential to improve the therapeutic potency of amyloidogenic protein/peptide drugs such as hCT.
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Affiliation(s)
- Hui Shang
- Department of Biomedical Polymers and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Anna Zhou
- Department of Biomedical Polymers and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Jian Jiang
- College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Yanpeng Liu
- Department of Biomedical Polymers and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Jing Xie
- Department of Biomedical Polymers and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610065, China
| | - Yantao Chen
- Shenzhen Key Laboratory of Functional Polymer, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060, China.
| | - Xiaofeng Zhu
- College of Life Sciences, Sichuan University, Chengdu 610065, China.
| | - Hong Tan
- Department of Biomedical Polymers and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Jianshu Li
- Department of Biomedical Polymers and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China; State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China.
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26
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Durgia H, Sahoo J, Kamalanathan S, Palui R, Sridharan K, Raj H. Role of bisphosphonates in the management of acute Charcot foot. World J Diabetes 2018; 9:115-126. [PMID: 30079147 PMCID: PMC6068741 DOI: 10.4239/wjd.v9.i7.115] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 04/26/2018] [Accepted: 06/13/2018] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is the most common cause of Charcot neuropathy affecting foot and ankle. Acute Charcot foot (CF) presents with a red and swollen foot in contrast to the painless deformed one of chronic CF. Enhanced osteoclastogenesis plays a central role in the pathogenesis of acute CF. Many studies have shown elevated levels of bone turnover markers in patients with acute CF confirming it. These findings have led clinicians to use anti-resorptive agents [bisphosphonates (BP), calcitonin, and denosumab] along with immobilization and offloading in acute CF patients. The maximum evidence among all anti-resorptive agents is available for BPs, although its quality is low. Pamidronate has been shown to reduce the markers of activity of CF like raised skin temperature, pain, edema, and bone turnover markers in the majority of studies. Intravenous BPs are known to cause acute phase reactions leading to flu-like illness following their first infusion, which can be ameliorated by oral acetaminophen. Alendronate is the only oral BP used in these patients. It needs to be taken on an empty stomach with a full glass of water to avoid esophagitis. The side-effects and contraindications to BPs should be kept in mind while treating acute CF patients with them.
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Affiliation(s)
- Harsh Durgia
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Rajan Palui
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Kalyani Sridharan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Henith Raj
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Abstract
The bone remodelling cycle replaces old and damaged bone and is a highly regulated, lifelong process essential for preserving bone integrity and maintaining mineral homeostasis. During the bone remodelling cycle, osteoclastic resorption is tightly coupled to osteoblastic bone formation. The remodelling cycle occurs within the basic multicellular unit and comprises five co-ordinated steps; activation, resorption, reversal, formation and termination. These steps occur simultaneously but asynchronously at multiple different locations within the skeleton. Study of rare human bone disease and animal models have helped to elucidate the cellular and molecular mechanisms that regulate the bone remodelling cycle. The key signalling pathways controlling osteoclastic bone resorption and osteoblastic bone formation are receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin and canonical Wnt signalling. Cytokines, growth factors and prostaglandins act as paracrine regulators of the cycle, whereas endocrine regulators include parathyroid hormone, vitamin D, calcitonin, growth hormone, glucocorticoids, sex hormones, and thyroid hormone. Disruption of the bone remodelling cycle and any resulting imbalance between bone resorption and formation leads to metabolic bone disease, most commonly osteoporosis. The advances in understanding the cellular and molecular mechanisms underlying bone remodelling have also provided targets for pharmacological interventions which include antiresorptive and anabolic therapies. This review will describe the remodelling process and its regulation, discuss osteoporosis and summarize the commonest pharmacological interventions used in its management.
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Affiliation(s)
- J S Kenkre
- 1 Section of Investigative Medicine, Imperial College London, London, UK
| | - Jhd Bassett
- 2 Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK
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Moghani-Ghoroghi F, Moshkdanian G, Sehat M, Nematollahi-Mahani SN, Ragerdi-Kashani I, Pasbakhsh P. Melatonin Pretreated Blastocysts along with Calcitonin Administration Improved Implantation by Upregulation of Heparin Binding-Epidermal Growth Factor Expression in Murine Endometrium. CELL JOURNAL 2017; 19:599-606. [PMID: 29105394 PMCID: PMC5672098 DOI: 10.22074/cellj.2018.4737] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 12/02/2016] [Indexed: 12/20/2022]
Abstract
Objective Implantation failure is an obstacle in assisted reproduction techniques (ART). Calcitonin is a molecules
involved in uterine receptivity and embryo implantation. Melatonin can promote embryo quality and improve
implantation. This study examines the effect of pretreatment of blastocysts with melatonin and calcitonin on heparin
binding-epidermal growth factor (HB-EGF) expression in murine endometrium.
Materials and Methods In this experimental study, we collected 2-cell embryos from the oviducts of 1.5 day pregnant
NMRI mice. Embryos were cultured to the blastocyst in GTM medium with or without 10-9 M melatonin. Pregnant and
pseudo-pregnant mice received intraperitoneal (IP) injections of 2 IU calcitonin. After 24 hours, we transferred the
cultured blastocysts into the uteri of pseudo-pregnant mice. Two days later, implantation sites were counted and we
assessed the levels of HB-EGF mRNA and protein in the uteri of naturally pregnant and pseudo-pregnant mice by
quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Statistical analysis was performed with
one-way ANOVA followed by the Tukey post hoc test. P<0.05 was considered statistically significant.
Results Melatonin pretreatment of blastocysts along with calcitonin administration significantly increased HB-EGF
mRNA and protein (P<0.001) in the endometrium of pseudo-pregnant mice. Administration of calcitonin in naturally
pregnant mice significantly increased HB-EGF mRNA and protein levels (P<0.001). Compared with the control group
(2.6 ± 0.5), the average number of implantation sites in the melatonin group (4.6 ± 0.5, P<0.05) and calcitonin group (7
± 1, P<0.001) significantly increased. There was a significant increase in implantation sites in the combined melatonin
and calcitonin group (8.6 ± 0.5, P<0.001). Calcitonin significantly enhanced calcitonin receptor mRNA (P<0.001) and
protein (P<0.05) in the uteri of naturally pregnant and pseudo-pregnant mice.
Conclusion Melatonin pretreated blastocysts along with calcitonin increased HB-EGF expression in the uteri of pseudo-
pregnant mice. Calcitonin administration upregulated HB-EGF in uteri of naturally pregnant mice.
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Affiliation(s)
| | - Ghazaleh Moshkdanian
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Anatomical Science Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Mojtaba Sehat
- Department of Social Medicine, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Iraj Ragerdi-Kashani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parichehr Pasbakhsh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Kamgar-Parsi K, Hong L, Naito A, Brooks CL, Ramamoorthy A. Growth-incompetent monomers of human calcitonin lead to a noncanonical direct relationship between peptide concentration and aggregation lag time. J Biol Chem 2017; 292:14963-14976. [PMID: 28739873 PMCID: PMC5592673 DOI: 10.1074/jbc.m117.791236] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 07/19/2017] [Indexed: 11/06/2022] Open
Abstract
The role of the peptide hormone calcitonin in skeletal protection has led to its use as a therapeutic for osteoporosis. However, calcitonin aggregation into amyloid fibrils limits its therapeutic efficacy, necessitating a modification of calcitonin's aggregation kinetics. Here, we report a direct relationship between human calcitonin (hCT) concentration and aggregation lag time. This kinetic trend was contrary to the conventional understanding of amyloid aggregation and persisted over a range of aggregation conditions, as confirmed by thioflavin-T kinetics assays, CD spectroscopy, and transmission EM. Dynamic light scattering, 1H NMR experiments, and seeded thioflavin-T assay results indicated that differences in initial peptide species contribute to this trend more than variations in the primary nucleus formation rate. On the basis of kinetics modeling results, we propose a mechanism whereby a structural conversion of hCT monomers is needed before incorporation into the fibril. Our kinetic mechanism recapitulates the experimentally observed relationship between peptide concentration and lag time and represents a novel mechanism in amyloid aggregation. Interestingly, hCT at low pH and salmon calcitonin (sCT) exhibited the canonical inverse relationship between concentration and lag time. Comparative studies of hCT and sCT with molecular dynamics simulations and CD indicated an increased α-helical structure in sCT and low-pH hCT monomers compared with neutral-pH hCT, suggesting that α-helical monomers represent a growth-competent species, whereas unstructured random coil monomers represent a growth-incompetent species. Our finding that initial monomer concentration is positively correlated with lag time in hCT aggregation could help inform future efforts for improving therapeutic applications of CT.
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Affiliation(s)
- Kian Kamgar-Parsi
- From the Applied Physics Program, University of Michigan, Ann Arbor, Michigan 48109
| | - Liu Hong
- Zhou Pei-Yuan Center for Applied Mathematics, Tsinghua University, Beijing 100084, China
| | - Akira Naito
- Graduate School of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan, and
| | - Charles L Brooks
- Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, Michigan 48109-1055
| | - Ayyalusamy Ramamoorthy
- Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, Michigan 48109-1055
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Yamashita T, Udagawa N, Thirukonda GJ, Uehara S, Yamauchi H, Suzuki N, Li F, Kobayashi Y, Takahashi N. Platypus and opossum calcitonins exhibit strong activities, even though they belong to mammals. Gen Comp Endocrinol 2017; 246:270-278. [PMID: 28062306 DOI: 10.1016/j.ygcen.2017.01.001] [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] [Received: 06/29/2016] [Revised: 01/01/2017] [Accepted: 01/02/2017] [Indexed: 10/20/2022]
Abstract
In mammalian assay systems, calcitonin peptides of non-mammalian species exhibit stronger activity than those of mammals. Recently, comparative analyses of a wide-range of species revealed that platypus and opossum, which diverged early from other mammals, possess calcitonins that are more similar in amino acid sequence to those of non-mammals than mammals. We herein determined whether platypus and opossum calcitonins exhibit similar biological activities to those of non-mammalian calcitonins using an assay of actin ring formation in mouse osteoclasts. We also compared the dose-dependent effects of each calcitonin on cAMP production in osteoclasts. Consistent with the strong similarities in their primary amino acid sequences, platypus and opossum calcitonins disrupted actin rings with similar efficacies to that of salmon calcitonin. Human calcitonin exhibited the weakest inhibitory potency and required a 100-fold higher concentration (EC50=3×10-11M) than that of salmon calcitonin (EC50=2×10-13M). Platypus and opossum calcitonins also induced cAMP production in osteoclast cultures with the same efficacies as that of salmon calcitonin. Thus, platypus and opossum calcitonins exhibited strong biological activities, similar to those of the salmon. In addition, phylogenetic analysis revealed that platypus and opossum calcitonins clustered with the salmon-type group but not human- or porcine-type group. These results suggest that platypus and opossum calcitonins are classified into the salmon-type group, in terms of the biological activities and amino acid sequences.
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Affiliation(s)
- Teruhito Yamashita
- Institute for Oral Science, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan.
| | - Nobuyuki Udagawa
- Department of Oral Biochemistry, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan
| | | | - Shunsuke Uehara
- Department of Oral Biochemistry, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan
| | - Hirose Yamauchi
- Institute for Oral Science, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan; Japan Osteoporosis Foundation, 11-2 Nihonbashi-kobunacho, Chuo-ku, Tokyo 103-0024, Japan
| | - Nobuo Suzuki
- Noto Marine Laboratory, Institute of Nature and Environment Technology, Kanazawa University, 4-1 Ogi, Noto-cho, Ishikawa 927-0553, Japan
| | - Feng Li
- Institute of Nature Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Yasuhiro Kobayashi
- Institute for Oral Science, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan
| | - Naoyuki Takahashi
- Institute for Oral Science, Matsumoto Dental University, 1780 Hirooka-Gobara, Shiojiri, Nagano 399-0781, Japan
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31
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Zhang LB, Man ZT, Li W, Zhang W, Wang XQ, Sun S. Calcitonin protects chondrocytes from lipopolysaccharide-induced apoptosis and inflammatory response through MAPK/Wnt/NF-κB pathways. Mol Immunol 2017; 87:249-257. [PMID: 28514714 DOI: 10.1016/j.molimm.2017.05.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 04/28/2017] [Accepted: 05/01/2017] [Indexed: 10/19/2022]
Abstract
Calcitonin (CT) is an anti-absorbent, which has long been used for treatment of osteoporosis. However, little information is available about the effects of CT on osteoarthritis (OA). This study was mainly aimed to explore the effects of CT on the treatment of OA, as well as the underlying mechanisms. Chondrocytes were isolated from immature mice and then were incubated with lipopolysaccharide (LPS), CT, small interfering (si) RNA against bone morphogenetic protein (BMP)-2, and/or the inhibitors of MAPK/Wnt/NF-κB pathway. Thereafter, cell viability, apoptosis, nitric oxide (NO) and inflammatory factors productions, and expression levels of cartilage synthesis protein key factors, cartilage-derived morphogenetic protein (CDMP) 1, SRY (sex-determining region Y)-box 9 protein (SOX9), and MAPK/Wnt/NF-κB pathways key factors were determined. CT significantly reversed LPS-induced cell viability decrease, apoptosis increase, the inflammatory factors and NO secretion, the abnormally expression of cartilage synthesis proteins and the activation of MAPK/Wnt/NF-κB pathways (P<0.05). In addition, we observed that administration of the inhibitors of MAPK/Wnt/NF-κB pathways statistically further increased the levels of CDMP1 and SOX9 (P<0.05). Suppression of BMP-2 decreased the levels of CDMP1 and SOX9 and activated MAPK/Wnt/NF-κB pathways, and could partially abolish CT-modulated the expression changes in CDMP1 and SOX9, and MAPK/Wnt/NF-κB pathways key factors (P<0.05). The results showed that CT protects chondrocytes from LPS-induced apoptosis and inflammatory response by regulating BMP-2 and thus blocking MAPK/Wnt/NF-κB pathways.
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Affiliation(s)
- Lai-Bo Zhang
- Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Zhen-Tao Man
- Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Wei Li
- Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Wei Zhang
- Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Xian-Quan Wang
- Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Shui Sun
- Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
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32
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Kamgar-Parsi K, Tolchard J, Habenstein B, Loquet A, Naito A, Ramamoorthy A. Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation. Isr J Chem 2016. [DOI: 10.1002/ijch.201600096] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Kian Kamgar-Parsi
- Applied Physics Program; University of Michigan; Ann Arbor MI 48109-1040 USA
| | - James Tolchard
- Institute of Chemistry and Biology of Membranes and Nanoobjects, CNRS, CBMN, UMR 5248; University of Bordeaux; 33600 Pessac France
| | - Birgit Habenstein
- Institute of Chemistry and Biology of Membranes and Nanoobjects, CNRS, CBMN, UMR 5248; University of Bordeaux; 33600 Pessac France
| | - Antoine Loquet
- Institute of Chemistry and Biology of Membranes and Nanoobjects, CNRS, CBMN, UMR 5248; University of Bordeaux; 33600 Pessac France
| | - Akira Naito
- Graduate School of Engineering; Yokohama National University; 79-5 Tokiwadai Hodogaya-ku Yokohama 240-8501 Japan
| | - Ayyalusamy Ramamoorthy
- Department of Chemistry and Biophysics Program; University of Michigan; 930 North University Avenue Ann Arbor MI 48109-1055 USA
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Wen ZH, Tang CC, Chang YC, Huang SY, Lin YY, Hsieh SP, Lee HP, Lin SC, Chen WF, Jean YH. Calcitonin attenuates cartilage degeneration and nociception in an experimental rat model of osteoarthritis: role of TGF-β in chondrocytes. Sci Rep 2016; 6:28862. [PMID: 27345362 PMCID: PMC4921823 DOI: 10.1038/srep28862] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 06/06/2016] [Indexed: 12/19/2022] Open
Abstract
We investigated the role of the calcitonin (Miacalcin) in the progression of osteoarthritis (OA) and in nociceptive behavior in an experimental rat model of OA and osteoporosis. OA was induced by anterior cruciate ligament transection (ACLT) of the right knee and by bilateral ovariectomy (OVX) in Wistar rats. Nociceptive behaviors (secondary mechanical allodynia and weight-bearing distribution of the hind paws) were analyzed prior to surgery and every week, beginning at 12 weeks after surgery, up to 20 weeks. At 20 weeks, histopathological studies were performed on the cartilage of the knee joints. Immunohistochemical analysis was performed to examine the effect of calcitonin on transforming growth factor (TGF)-β1 expression in articular cartilage chondrocytes. Rats subjected to ACLT + OVX surgery showed obvious OA changes in the joints. Animals subjected to ACLT + OVX and treated with calcitonin showed significantly less cartilage degeneration and improved nociceptive tests compared with animals subjected to ACLT + OVX surgeries alone. Moreover, calcitonin increased TGF-β1 expression in chondrocytes in ACLT + OVX-affected cartilage. Subcutaneous injection of calcitonin (1) attenuated the development of OA, (2) concomitantly reduced nociception, and (3) modulated chondrocyte metabolism, possibly by increasing cellular TGF-β1 expression.
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Affiliation(s)
- Zhi-Hong Wen
- Department of Marine Biotechnology &Resources, and Center for Translational Biopharmaceuticals, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chi-Chieh Tang
- Department of Early Childhood Education, National Pintung University, Taiwan
| | - Yi-Chen Chang
- Department of Marine Biotechnology &Resources, and Center for Translational Biopharmaceuticals, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Shi-Ying Huang
- Department of Marine Biotechnology &Resources, and Center for Translational Biopharmaceuticals, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Yen-You Lin
- Department of Marine Biotechnology &Resources, and Center for Translational Biopharmaceuticals, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Shih-Peng Hsieh
- Section of Pathology, Pingtung Christian Hospital, Pingtung, Taiwan
| | - Hsin-Pai Lee
- Section of Pathology, Pingtung Christian Hospital, Pingtung, Taiwan.,Department of Orthopedic Surgery, Pingtung Christian Hospital, Pingtung, Taiwan
| | - Sung-Chun Lin
- Section of Pathology, Pingtung Christian Hospital, Pingtung, Taiwan.,Department of Orthopedic Surgery, Pingtung Christian Hospital, Pingtung, Taiwan
| | - Wu-Fu Chen
- Department of Orthopedic Surgery, Pingtung Christian Hospital, Pingtung, Taiwan.,Department of Neurosurgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan
| | - Yen-Hsuan Jean
- Department of Orthopedic Surgery, Pingtung Christian Hospital, Pingtung, Taiwan
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Inhibitory effects of magnolol and honokiol on human calcitonin aggregation. Sci Rep 2015; 5:13556. [PMID: 26324190 PMCID: PMC4555095 DOI: 10.1038/srep13556] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 07/30/2015] [Indexed: 02/07/2023] Open
Abstract
Amyloid formation is associated with multiple amyloidosis diseases. Human calcitonin (hCT) is a typical amyloidogenic peptide, its aggregation is associated with medullary carcinoma of the thyroid (MTC), and also limits its clinical application. Magnolia officinalis is a traditional Chinese herbal medicine; its two major polyphenol components, magnolol (Mag) and honokiol (Hon), have displayed multiple functions. Polyphenols like flavonoids and their derivatives have been extensively studied as amyloid inhibitors. However, the anti-amyloidogenic property of a biphenyl backbone containing polyphenols such as Mag and Hon has not been reported. In this study, these two compounds were tested for their effects on hCT aggregation. We found that Mag and Hon both inhibited the amyloid formation of hCT, whereas Mag showed a stronger inhibitory effect; moreover, they both dose-dependently disassembled preformed hCT aggregates. Further immuno-dot blot and dynamic light scattering studies suggested Mag and Hon suppressed the aggregation of hCT both at the oligomerization and the fibrillation stages, while MTT-based and dye-leakage assays demonstrated that Mag and Hon effectively reduced cytotoxicity caused by hCT aggregates. Furthermore, isothermal titration calorimetry indicated Mag and Hon both interact with hCT. Together, our study suggested a potential anti-amyloidogenic property of these two compounds and their structure related derivatives.
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Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. BIOMED RESEARCH INTERNATIONAL 2015; 2015:421746. [PMID: 26247020 PMCID: PMC4515490 DOI: 10.1155/2015/421746] [Citation(s) in RCA: 1054] [Impact Index Per Article: 105.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 04/30/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023]
Abstract
Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling.
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Filipović B, Šošić-Jurjević B, Ajdžanović V, Živanović J, Isenović E, Popovska-Perčinić F, Milošević V. Tamoxifen stimulates calcitonin-producing thyroid C-cells and prevents trabecular bone loss in a rat model of androgen deficiency. J Anat 2015; 226:489-96. [PMID: 25851663 DOI: 10.1111/joa.12298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2015] [Indexed: 11/30/2022] Open
Abstract
Thyroid C-cells produce calcitonin (CT), a hypocalcemic hormone, that acts as an inhibitor of bone resorption. In this study, we investigated the effects of tamoxifen (TAM) as a selective estrogen receptor modulator on thyroid C-cells, trabecular bone and biochemical markers of bone metabolism in an animal model of androgen deficiency, represented by middle-aged orchidectomized (Orx) rats. Fifteen-month-old male Wistar rats were divided into: Orx and sham-operated (SO) groups. Rats from one Orx group were injected subcutaneously with TAM citrate (Orx + TAM; 0.3 mg kg(-1) b.w.), while the rats from SO and a second Orx group received vehicle alone, once a day for 3 weeks. The peroxidase-antiperoxidase method was applied for localization of CT in C-cells. Thyroid C-cells were morphometrically and ultrastructurally analyzed. An ImageJ image-processing program was used to measure bone histomorphometric parameters. Blood serum samples were analyzed for CT, osteocalcin (OC), calcium (Ca2+ ) and phosphorus (P). Urinary Ca2+ concentrations were measured. TAM treatment significantly increased thyroid C-cell volume (Vc ) and serum CT when compared with vehicle-treated Orx rats. Analysis of trabecular microarchitecture of the tibia showed that administration of TAM significantly increased cancellous bone area, trabecular thickness and trabecular number, whereas trabecular separation was significantly decreased compared with vehicle-treated Orx rats. Serum OC and urinary Ca2+ concentrations were significantly lower in comparison with the control Orx group. These results indicate that in our rat model of androgen deficiency, TAM stimulated calcitonin-producing thyroid C-cells and increased trabecular bone mass.
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Affiliation(s)
- Branko Filipović
- Institute for Biological Research ″Siniša Stanković″, University of Belgrade, Belgrade, Serbia
| | - Branka Šošić-Jurjević
- Institute for Biological Research ″Siniša Stanković″, University of Belgrade, Belgrade, Serbia
| | - Vladimir Ajdžanović
- Institute for Biological Research ″Siniša Stanković″, University of Belgrade, Belgrade, Serbia
| | - Jasmina Živanović
- Institute for Biological Research ″Siniša Stanković″, University of Belgrade, Belgrade, Serbia
| | - Esma Isenović
- Vinca Institute of Nuclear Science, Laboratory for Molecular Genetics and Radiobiology, University of Belgrade, Belgrade, Serbia
| | - Florina Popovska-Perčinić
- Faculty of Veterinary Medicine, ″Ss Cyril and Methodius″ University of Skopje, Skopje, FYR of Macedonia
| | - Verica Milošević
- Institute for Biological Research ″Siniša Stanković″, University of Belgrade, Belgrade, Serbia
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Ishtiaq S, Fogelman I, Hampson G. Treatment of post-menopausal osteoporosis: beyond bisphosphonates. J Endocrinol Invest 2015; 38:13-29. [PMID: 25194424 DOI: 10.1007/s40618-014-0152-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 08/02/2014] [Indexed: 12/26/2022]
Abstract
Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/1.73 m(2). Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.
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Affiliation(s)
- S Ishtiaq
- Osteoporosis Screening Unit, Guy's Hospital, London, UK
- Department of Chemical Pathology, St Thomas' Hospital, 5th Floor, North Wing, Lambeth Palace Road, London, SE1 7EH, UK
| | - I Fogelman
- Osteoporosis Screening Unit, Guy's Hospital, London, UK
- Department of Nuclear Medicine, Guy's Hospital, London, UK
| | - G Hampson
- Osteoporosis Screening Unit, Guy's Hospital, London, UK.
- Department of Chemical Pathology, St Thomas' Hospital, 5th Floor, North Wing, Lambeth Palace Road, London, SE1 7EH, UK.
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Abstract
Diabetes mellitus is a leading global metabolic disorder accompanied by the overwhelming burden of its associated complications. Hyperglycaemia-induced endothelial damage or endothelial dysfunction serves as the primary instigator for the development of microvascular disease. Diabetic neuropathy represents the majority of microvascular sequelae and is the renowned perpetrator of a variety of foot complications, namely the Charcot foot (CF). CF is a debilitating medical emergency which is often mismanaged either due to a delayed diagnosis or lack of clinical expertise in the management of CF. Often, misdiagnosis during the acute stages of CF leads to irreversible and persistent joint destruction which may be refractory to medical or surgical treatment. Timely intervention with offloading measures is crucial during acute CF in ceasing active bone resorption. Current anti-resorptive agents may be considered as adjunctive therapy in combination with offloading. Novel agents are underway that will enable bone formation and suppress bone resorption.
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Affiliation(s)
- Janice V Mascarenhas
- Diabetes and Endocrinology, Tameside Hospital NHS Foundation Trust, Fountain Street, Ashton-Under-Lyne, Lancashire, OL6 9RW, UK,
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Liu L, Wang H, Liu N, Yang Q, Luo E. Osteoporosis in the jawbones: a correlative factor of primary trigeminal neuralgia? Med Sci Monit 2014; 20:1481-5. [PMID: 25141822 PMCID: PMC4148358 DOI: 10.12659/msm.890935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Trigeminal neuralgia (TN), a neuropathic disorder of one or both of the trigeminal nerves, occurs most often in people over age 50. Extreme, sporadic, sudden burning or shock-like face pain in common activities greatly lowers quality of life. The precise cause of primary TN remains unknown, but it may be caused by vascular pressing on the trigeminal nerve in its root entry zone (REZ), demyelinization of trigeminal sensory fibers, or jawbone cavity. Accordingly, many treatments carry risks of adverse effects, recurrence, and complications. TN and osteoporosis have similar high-risk populations and a common influential factor – emotional stress – is also closed related to primary TN for calcitonin gene-related peptide and calcitonin. Jawbone cavity, which is a possible pathogenesis of TN, may be another form of jawbone osteoporosis. Therefore, we hypothesized that osteoporosis in jaws could be a correlative factor of primary TN. If this hypothesis is verified, it may suggest specific new ideas for the early preventive treatment of primary TN.
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Affiliation(s)
- Li Liu
- Department of Oral Radiology, State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China (mainland)
| | - Hu Wang
- Department of Oral Radiology, State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China (mainland)
| | - Na Liu
- Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China (mainland)
| | - Qianmei Yang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China (mainland)
| | - En Luo
- Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China (mainland)
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Andreassen KV, Hjuler ST, Furness SG, Sexton PM, Christopoulos A, Nosjean O, Karsdal MA, Henriksen K. Prolonged calcitonin receptor signaling by salmon, but not human calcitonin, reveals ligand bias. PLoS One 2014; 9:e92042. [PMID: 24643196 PMCID: PMC3958426 DOI: 10.1371/journal.pone.0092042] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 02/19/2014] [Indexed: 11/23/2022] Open
Abstract
Salmon calcitonin (sCT) and human calcitonin (hCT) are pharmacologically distinct. However, the reason for the differences is unclear. Here we analyze the differences between sCT and hCT on the human calcitonin receptor (CT(a)R) with respect to activation of cAMP signaling, β-arrestin recruitment, ligand binding kinetics and internalization. The study was conducted using mammalian cell lines heterologously expressing the human CT(a) receptor. CT(a)R downstream signaling was investigated with dose response profiles for cAMP production and β-arrestin recruitment for sCT and hCT during short term (<2 hours) and prolonged (up to 72 hours) stimulation. CT(a)R kinetics and internalization was investigated with radio-labeled sCT and hCT ligands on cultured cells and isolated membrane preparations from the same cell line. We found that sCT and hCT are equipotent during short-term stimulations with differences manifesting themselves only during long-term stimulation with sCT inducing a prolonged activation up to 72 hours, while hCT loses activity markedly earlier. The prolonged sCT stimulation of both cAMP accumulation and β-arrestin recruitment was attenuated, but not abrogated by acid wash, suggesting a role for sCT activated internalized receptors. We have demonstrated a novel phenomenon, namely that two distinct CT(a)R downstream signaling activation patterns are activated by two related ligands, thereby highlighting qualitatively different signaling responses in vitro that could have implications for sCT use in vivo.
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Affiliation(s)
| | | | - Sebastian G. Furness
- Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia
| | - Patrick M. Sexton
- Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia
| | - Arthur Christopoulos
- Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia
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Goff J, Liesegang A, Horst R. Diet-induced pseudohypoparathyroidism: A hypocalcemia and milk fever risk factor. J Dairy Sci 2014; 97:1520-8. [DOI: 10.3168/jds.2013-7467] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Accepted: 11/18/2013] [Indexed: 11/19/2022]
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Prolonged hypocalcemic effect by pulmonary delivery of calcitonin loaded poly(methyl vinyl ether maleic acid) bioadhesive nanoparticles. BIOMED RESEARCH INTERNATIONAL 2014; 2014:932615. [PMID: 24701588 PMCID: PMC3950494 DOI: 10.1155/2014/932615] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 12/08/2013] [Accepted: 01/12/2014] [Indexed: 11/17/2022]
Abstract
The purpose of the present study was to design a pulmonary controlled release system of salmon calcitonin (sCT). Therefore, poly(methyl vinyl ether maleic acid) [P(MVEMA)] nanoparticles were prepared by ionic cross-linking method using Fe2+ and Zn2+ ions. Physicochemical properties of nanoparticles were studied in vitro. The stability of sCT in the optimized nanoparticles was studied by electrophoretic gel method. Plasma calcium levels until 48 h were determined in rats as pulmonary-free sCT solution or nanoparticles (25 μg·kg−1), iv solution of sCT (5 μg·kg−1), and pulmonary blank nanoparticles. The drug remained stable during fabrication and tests on nanoparticles. The optimized nanoparticles showed proper physicochemical properties. Normalized reduction of plasma calcium levels was at least 2.76 times higher in pulmonary sCT nanoparticles compared to free solution. The duration of hypocalcemic effect of pulmonary sCT nanoparticles was 24 h, while it was just 1 h for the iv solution. There was not any significant difference between normalized blood calcium levels reduction in pulmonary drug solution and iv injection. Pharmacological activity of nanoparticles after pulmonary delivery was 65% of the iv route. Pulmonary delivery of P(MVEMA) nanoparticles of sCT enhanced and prolonged the hypocalcemic effect of the drug significantly.
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Abstract
The Charcot foot is a problematic clinical entity that worsens in the absence of timely intervention. As of now, based on the ADA consensus report, offloading with TCC continues to remain the mainstay of therapy for CN.1 A standardized approach to the management of CN is depicted in Fig. 1. Furthermore, ongoing inflammatory activity can be controlled with antiresorptive agents, like BPPs and calcitonin; however, data acquired from larger trials with these agents are awaited. Newer agents that target the inflammatory cascade have been identified and applied in limited clinical trials in non-Charcot conditions. Their potential role in the future management of CN has yet to be established.
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Affiliation(s)
- Janice V Mascarenhas
- Department of Endocrinology, St. John's National Academy of Health Sciences, Bangalore 560034, Karnataka, India
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Clinckspoor I, Verlinden L, Mathieu C, Bouillon R, Verstuyf A, Decallonne B. Vitamin D in thyroid tumorigenesis and development. ACTA ACUST UNITED AC 2013; 48:65-98. [PMID: 23890557 DOI: 10.1016/j.proghi.2013.07.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Besides its classical role in bone and calcium homeostasis, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has many non-classical effects; antiproliferative, anti-apoptotic and prodifferentiating effects of 1,25(OH)2D3 have been described in several tumour types in preclinical models. This review focuses on the insights gained in the elucidation of the role of 1,25(OH)2D3 in the normal thyroid and in the pathogenesis, progression and treatment of thyroid cancer, the most common endocrine malignancy. An increasing amount of observations points towards a role for impaired 1,25(OH)2D3-VDR signalling in the occurrence and progression of thyroid cancer, and a potential for structural analogues in the multimodal treatment of dedifferentiated iodine-resistant thyroid cancer. A role for vitamin D in thyroid-related autoimmunity is less convincing and needs further study. Altered 1,25(OH)2D3-VDR signalling does not influence normal thyroid development nor thyrocyte function, but does affect C-cell function, at least in rodents. If these findings also apply to humans deserves further study.
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Affiliation(s)
- Isabelle Clinckspoor
- Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Bus 902, Herestraat 49, 3000 Leuven, Belgium
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Rawat A, Kumar D. NMR investigations of structural and dynamics features of natively unstructured drug peptide - salmon calcitonin: implication to rational design of potent sCT analogs. J Pept Sci 2012. [DOI: 10.1002/psc.2471] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Atul Rawat
- Centre of Biomedical Magnetic Resonance; Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raibareli Road; Lucknow-; 226014; India
| | - Dinesh Kumar
- Centre of Biomedical Magnetic Resonance; Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raibareli Road; Lucknow-; 226014; India
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46
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Granholm S, Henning P, Lerner UH. Comparisons between the effects of calcitonin receptor-stimulating peptide and intermedin and other peptides in the calcitonin family on bone resorption and osteoclastogenesis. J Cell Biochem 2012; 112:3300-12. [PMID: 21748786 DOI: 10.1002/jcb.23256] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Calcitonin receptor-stimulating peptide (CRSP) and intermedin (IMD) are two recently discovered peptides in the calcitonin (CT) family of peptides. CRSP and IMD, similar to CT, calcitonin gene-related peptide (CGRP), and amylin (AMY), but in contrast to adrenomedullin (ADM), inhibited bone resorption in mouse calvarial bones. CRSP and IMD, similar to CT, CGRP, AMY, but in contrast to ADM, decreased formation of osteoclasts and number of pits in bone marrow macrophage cultures stimulated by M-CSF and RANKL, with no effect on the expression of a number of genes associated with osteoclast progenitor cell differentiation. CRSP and IMD inhibited osteoclastogenesis at a late stage but had no effect on DC-STAMP mRNA. IMD, similar to CGRP, AMY, and ADM stimulated cyclic AMP formation in M-CSF expanded osteoclast progenitor cells lacking CT receptors (CTRs). RANKL induced CTRs and a cyclic AMP response also to CT and CRSP, and increased the cyclic AMP response to CGRP, AMY, and IMD but decreased the response to ADM. Our data demonstrates that CRSP and IMD share several functional properties of peptides in the CT family of peptides, including inhibition of bone resorption and osteoclast formation. The data also show that the reason why ADM does not inhibit osteoclast activity or formation is related to the fact that RANKL decreases ADM receptor signaling through the adenylate cyclase-cyclic AMP pathway. Finally, the findings indicate that activation by CGRP, AMY, and IMD may include activation of both CT and CT receptor-like receptors.
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Affiliation(s)
- Susanne Granholm
- Department of Molecular Periodontology, Umeå University, S-901 87 Umeå, Sweden
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Huang R, Vivekanandan S, Brender JR, Abe Y, Naito A, Ramamoorthy A. NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG. J Mol Biol 2011; 416:108-20. [PMID: 22200484 DOI: 10.1016/j.jmb.2011.12.023] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Revised: 12/05/2011] [Accepted: 12/10/2011] [Indexed: 11/17/2022]
Abstract
Calcitonin is a 32-residue peptide hormone known for its hypocalcemic effect and its inhibition of bone resorption. While calcitonin has been used in therapy for osteoporosis and Paget's disease for decades, human calcitonin (hCT) forms fibrils in aqueous solution that limit its therapeutic application. The molecular mechanism of fiber formation by calcitonin is not well understood. Here, high-resolution structures of hCT at concentrations of 0.3 mM and 1 mM have been investigated using NMR spectroscopy. Comparing the structures of hCT at different concentrations, we discovered that the peptide undergoes a conformational transition from an extended to a β-hairpin structure in the process of molecular association. This conformational transition locates the aromatic side chains of Tyr12 and Phe16 in a favorable way for intermolecular π-π stacking, which is proposed to be a crucial interaction for peptide association and fibrillation. One-dimensional (1)H NMR experiments confirm that oligomerization of hCT accompanies the conformational transition at 1 mM concentration. The effect of the polyphenol epigallocatechin 3-gallate (EGCG) on hCT fibrillation was also investigated by NMR and electron microscopy, which show that EGCG efficiently inhibits fibril formation of hCT by preventing the initial association of hCT before fiber formation. The NMR experiments also indicate that the interaction between aromatic rings of EGCG and the aromatic side chains of the peptide may play an important role in inhibiting fibril formation of hCT.
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Affiliation(s)
- Rui Huang
- Biophysics and Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA
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48
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Crockett JC, Rogers MJ, Coxon FP, Hocking LJ, Helfrich MH. Bone remodelling at a glance. J Cell Sci 2011; 124:991-8. [PMID: 21402872 DOI: 10.1242/jcs.063032] [Citation(s) in RCA: 330] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Julie C Crockett
- Musculoskeletal Research Programme, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
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Abstract
OBJECTIVE Pancreatic endocrine tumors (PETs) are characterized by the presence of hormone syndromes. Reports focusing on calcitonin-secreting PET (CTsPETs) are very rare. This study aimed to define a CTsPET-associated syndrome in regard to chemical, anatomical, and developmental aspects. METHODS A computerized MEDLINE search was conducted under the search items: "pancreatic endocrine tumor," "calcitonin," "neuroendocrine pancreatic tumor," and "pancreas." Results of clinical, histopathological, immunohistochemical, and biochemical assessments of all patients identified with CTsPET were registered and statistically analyzed. RESULTS Thirty-seven patients with CTsPET were identified. Mean serum calcitonin was elevated to the 89.2-fold of the upper reference value. Main symptoms were watery diarrhea (51.4%) and abdominal pain (35.1%). Most patients (59.5%) presented with metastatic spread at the time of diagnosis. Of all patients, 66.7% were alive after a mean follow-up of 28.9 months. Survival was higher in patients who underwent more aggressive surgical therapies independent from tumor sizes and in those with no metastases at the time of diagnosis. CONCLUSIONS High calcitonin levels should always raise suspicion of medullary thyroid carcinomas. However, when thyroid examination remains without pathological findings, a CTsPET should be excluded. An aggressive surgical approach even in cases with large primary tumor sizes may lead to a longer survival.
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Kratzsch J, Petzold A, Raue F, Reinhardt W, Bröcker-Preuβ M, Görges R, Mann K, Karges W, Morgenthaler N, Luster M, Reiners C, Thiery J, Dralle H, Fuhrer D. Basal and Stimulated Calcitonin and Procalcitonin by Various Assays in Patients with and without Medullary Thyroid Cancer. Clin Chem 2011; 57:467-74. [DOI: 10.1373/clinchem.2010.151688] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND
Calcitonin (CT) is a sensitive marker for evaluation of medullary thyroid cancer (MTC). However, CT measurement can vary with assay- and nonassay-dependent factors, and procalcitonin (PCT) measurement has been proposed for evaluating questionable increases in CT.
METHODS
We tested 2 fully automated CT assays (Immulite [IL] and Liaison [LIA]) and 1 nonautomated CT assay (IRMA, Medipan) and compared these results with PCT (Brahms Kryptor). We evaluated preanalytical conditions and PCT cross-reactivity in sera of 437 patients with clinical conditions associated with hypercalcitoninemia. Additionally, we determined the true “nil” CT concentration in 60 thyroidectomized patients and defined CT cutoff concentrations for pentagastrin stimulation testing in 13 chronic kidney disease (CKD) patients and 10 MTC patients.
RESULTS
Markedly decreased CT concentrations were found after storage of sera for >2 h at room temperature and >6 h at 4 °C. Cutoff concentrations for basal and stimulated CT were disease and assay dependent. Proton pump inhibitor therapy was the most frequent reason for increased CT. PCT concentrations were higher in patients with MTC than in patients with CKD without infections (P < 0.001). Whereas IL and LIA demonstrated comparable analytical quality, the IRMA gave increased CT concentrations in nil sera and showed cross-reactivity with PCT in patients with concomitant bacterial infection.
CONCLUSIONS
IL, LIA, and IRMA detected increased CT concentrations in non-MTC patients and discriminated MTC from CKD patients in pentagastrin tests. PCT assessment may be helpful in the diagnostic work-up of increased CT concentrations in questionable clinical circumstances.
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Affiliation(s)
- Jürgen Kratzsch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics; and
| | - Anne Petzold
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics; and
- Department of Internal Medicine, Neurology and Dermatology, Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany
| | | | | | | | - Rainer Görges
- Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
| | | | - Wolfram Karges
- Department of Internal Medicine III, RWTH Aachen University, Aachen, Germany
| | - Nils Morgenthaler
- Department of Research, Brahms Aktiengesellschaft, Henningsdorf, Germany
| | - Markus Luster
- Department of Nuclear Medicine, University of Ulm, Ulm, Germany
| | - Christoph Reiners
- Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany
| | - Joachim Thiery
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics; and
| | - Henning Dralle
- Department of General, Visceral and Vascular Surgery, University Halle-Wittenberg, Halle, Germany
| | - Dagmar Fuhrer
- Department of Internal Medicine, Neurology and Dermatology, Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany
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