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Li Z, Li Z, Wang J, Liao L, Li X, Zhang Z, Yang X, Yu X, Fan B, Li B, Hai J, Zhang B. Binary Doping of Strontium-Magnesium to Bioactive Glasses to Enhance Antibacterial and Osteogenic Effects. ACS OMEGA 2025; 10:215-229. [PMID: 39829480 PMCID: PMC11739949 DOI: 10.1021/acsomega.4c04898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 11/24/2024] [Accepted: 12/09/2024] [Indexed: 01/22/2025]
Abstract
Bone defects that exceed the critical defect value, resulting from fractures and diseases, are often difficult to heal. Although bone tissue engineering is a promising treatment for extensive osseous defects, orthopedic-implant-related infections increase the likelihood of failure. Bioactive glass (BG) has been widely used in the manufacture of artificial bone scaffolds, owing to its excellent biocompatibility and osteoinductivity. Nevertheless, considering that infection conditions and trauma can affect the osteogenic capacity of bioactive glass, this study combined BG with magnesium and strontium to promote osteogenesis and confer significant antimicrobial activity. Novel bioactive glass doped with magnesium-strontium (BGMSN) with good biocompatibility, excellent antibacterial properties, and promising osteogenic induction ability was constructed from 45S5, Mg, and Sr carbonates via a melt-quenching approach. The results of an in vitro cell biocompatibility study indicated that the BGMSN exhibited good cellular compatibility. Furthermore, osteogenic alkaline phosphatase, osteocalcin, and osteopontin genes were upregulated upon BGMSN/MC3T3-E1 coculture. BGMSN exhibited potent in vitro antibacterial effects against Staphylococcus aureus, Escherichia coli, and Streptococcus mutans. Animal experiments further demonstrated the exceptional bone-inducing ability of BGMSN. Accordingly, owing to their excellent antimicrobial properties, BGMSN can be used for bone regeneration, particularly under infected conditions.
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Affiliation(s)
- Zhige Li
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Ziyuan Li
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Jiao Wang
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Lingzi Liao
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Xinjie Li
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Zhidong Zhang
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Xin Yang
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Xiangxue Yu
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Baoquan Fan
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Bo Li
- State
Key Laboratory of Military Stomatology, Department of Oral Implants,
School of Stomatology, The Fourth Military
Medical University, Xi’an 710032, China
| | - Jun Hai
- CAS
Key Laboratory of Chemistry of Northwestern Plant Resources and Key
Laboratory of Natural Medicine of Gansu Province, Lanzhou Institute
of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, China
| | - Baoping Zhang
- School
of Stomatology, Lanzhou University, Lanzhou 730000, China
- Key
Laboratory of Mechanics on Disaster and Environment in Western China,
Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Institute
of Biomechanics and Medical Engineering, Lanzhou University, Lanzhou 730000, China
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Semenova PI, Panova AV, Sopova JV, Krasnova OA, Turilova VI, Yakovleva TK, Kulikova KS, Petrova DA, Kiselev SL, Neganova IE. Generation of CRISPR/Cas9 modified human iPSC line with correction of heterozygous mutation in exon 6 of the CaSR gene. Hum Cell 2024; 38:6. [PMID: 39446198 DOI: 10.1007/s13577-024-01135-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/28/2024] [Indexed: 10/25/2024]
Abstract
The calcium-sensing receptor (CaSR) gene encodes a cell membrane G protein-coupled receptor (GPCR) which has a key role in maintaining the extracellular Ca2+ homeostasis. We aimed at correcting the compound heterozygous mutation in the 6th [c.1656delA, p.I554SfsX73] and 7th [c.2217 T > A, p.C739X] exons of the CASR gene which the original patient-derived iPSC line had. The mutation is associated with neonatal severe primary hyperparathyroidism of the patient. We generated and characterized a CRISP/Cas9-edited hiPSC line with the restored sequence in the sixth exon of the CASR gene, bearing only heterozygous mutation in the 7th exon. The results showed that the new genetically modified cell line has karyotype without abnormalities, typical hiPSCs morphology, characteristic expression of pluripotency markers, and ability to develop into three germ layers, and differentiates in chondrogenic, adipogenic, osteogenic directions. This new cell line will complement the existing pool of CaSR-mutated cell lines, a valuable resource for in-depth understanding of neonatal severe primary hyperparathyroidism. This will allow further exploration of the application of pharmacological drugs in the context of personalized medicine to correct Ca-homeostasis disorders.
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Affiliation(s)
- P I Semenova
- The Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia
| | - A V Panova
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 117971, Russia
| | - J V Sopova
- The Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia
- St. Petersburg Branch of the Vavilov Institute of General Genetics, Saint-Petersburg, 199034, Russia
| | - O A Krasnova
- The Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia
| | - V I Turilova
- The Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia
| | - T K Yakovleva
- The Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia
| | - K S Kulikova
- Research Centre for Medical Genetics, Moscow, 115478, Russia
- Endocrinology Research Centre, Moscow, 115478, Russia
| | - D A Petrova
- Endocrinology Research Centre, Moscow, 115478, Russia
| | - S L Kiselev
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 117971, Russia
| | - I E Neganova
- The Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia.
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Saetang J, Issuriya A, Suyapoh W, Sornying P, Nilsuwan K, Benjakul S. Bio-Calcium from Skipjack Tuna Frame Attenuates Bone Loss in Ovariectomy-Induced Osteoporosis Rats. Mar Drugs 2024; 22:472. [PMID: 39452880 PMCID: PMC11509285 DOI: 10.3390/md22100472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024] Open
Abstract
Bio-calcium derived from fish frames may offer several advantages for osteoporosis prevention. This study aimed to evaluate the effects of bio-calcium derived from skipjack tuna frames on bone loss in ovariectomized rats. Tuna bio-calcium was prepared through enzymatic hydrolysis, defatting, bleaching, and grinding processes. The bioavailability of calcium was tested using the Caco-2 cell monolayer model, showing that 13% of tuna bio-calcium was absorbed, compared to 10% for calcium carbonate. Rats were divided into the five following groups: (1) OVX, (2) sham-operated, (3), OVX + estrogen-treated (4) OVX + calcium carbonate-treated, and (5) OVX + tuna bio-calcium-treated. All groups were raised for eight weeks. Tuna bio-calcium was able to increase BV/TV by 26% in the femur and 29% in the tibia, compared to 13% and 17% in the OVX group, respectively. Trabecular thickness in the femur upsurged to 360 µm in the tuna group, while a thickness of 290 µm was observed in the control. Additionally, osteoclast numbers were reduced to 5 N.Oc/mm in the femur and 6 N.Oc/mm in the tibia in the tuna group, compared to 35 and 45 N.Oc/mm in the control. Overall, tuna bio-calcium effectively prevented bone loss and can serve as a promising natural alternative for managing osteoporosis.
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Affiliation(s)
- Jirakrit Saetang
- International Center of Excellence in Seafood Science and Innovation, Faculty of Agro-Industry, Prince of Songkla University, Hat Yai 90110, Thailand; (J.S.); (K.N.)
| | - Acharaporn Issuriya
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai 90110, Thailand;
| | - Watcharapol Suyapoh
- Faculty of Veterinary Science, Prince of Songkla University, Hat Yai 90110, Thailand; (W.S.); (P.S.)
| | - Peerapon Sornying
- Faculty of Veterinary Science, Prince of Songkla University, Hat Yai 90110, Thailand; (W.S.); (P.S.)
| | - Krisana Nilsuwan
- International Center of Excellence in Seafood Science and Innovation, Faculty of Agro-Industry, Prince of Songkla University, Hat Yai 90110, Thailand; (J.S.); (K.N.)
| | - Soottawat Benjakul
- International Center of Excellence in Seafood Science and Innovation, Faculty of Agro-Industry, Prince of Songkla University, Hat Yai 90110, Thailand; (J.S.); (K.N.)
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Anish RJ, Nair A. Osteoporosis management-current and future perspectives - A systemic review. J Orthop 2024; 53:101-113. [PMID: 38495575 PMCID: PMC10940894 DOI: 10.1016/j.jor.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 02/23/2024] [Accepted: 03/01/2024] [Indexed: 03/19/2024] Open
Abstract
Introduction Osteoporosis is a geriatric metabolic ailment distinguished by low bone mineral density (BMD) and strength with enhanced micro-architectural retrogression of the extracellular matrix, further increasing bone fragility risk. Osteoporotic fractures and associated complications become common in women and men after 55 and 65 years, respectively. The loss in BMD markedly enhances the risk of fracture, non-skeletal injury, and subsequent pain, adversely affecting the quality of life. Methods Data summarised in this review were sourced and summarised, including contributions from 2008 to 2023, online from scientific search engines, based on scientific inclusion and exclusion criteria. Results Biochemical serum markers such as BALP, collagen, osteocalcin, and cathepsin-K levels can reveal the osteoporotic status. DEXA scan techniques evaluate the whole body's BMD and bone mineral content (BMC), crucial in osteoporosis management. Anabolic and anti-osteoporotic agents are commonly used to enhance bone formation, minimize bone resorption, and regulate remodelling. The challenges and side effects of drug therapy can be overcome by combining the various drug moieties. Conclusion The current review discusses the management protocol for osteoporosis, ranging from lifestyle modification, including physical exercise, pharmaceutical approaches, drug delivery applications, and advanced therapeutic possibilities of AI and machine learning techniques to reduce osteoporosis complications and fracture risk.
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Affiliation(s)
- Rajamohanan Jalaja Anish
- Department of Biochemistry, University of Kerala, Kariyavattom Campus, Trivandrum, 695581, India
| | - Aswathy Nair
- Department of Biochemistry, University of Kerala, Kariyavattom Campus, Trivandrum, 695581, India
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Baheti W, Chen X, La M, He H. Biomimetic HA-GO implant coating for enhanced osseointegration via macrophage M2 polarization-induced osteo-immunomodulation. J Appl Biomater Funct Mater 2024; 22:22808000241266665. [PMID: 39129373 DOI: 10.1177/22808000241266665] [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] [Indexed: 08/13/2024] Open
Abstract
The pro-inflammatory/anti-inflammatory polarized phenotypes of macrophages (M1/M2) can be used to predict the success of implant integration. Hence, activating and inducing the transformation of immunocytes that promote tissue repair appears to be a highly promising strategy for facilitating osteo-anagenesis. In a previous study, titanium implants were coated with a graphene oxide-hydroxyapatite (GO-HA) nanocomposite via electrophoretic deposition, and the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) was found to be significantly enhanced when the GO content was 2wt%. However, the effectiveness of the GO-HA nanocomposite coating in modifying the in vivo immune microenvironment still remains unclear. In this study, the effects of GO-HA coatings on osteogenesis were investigated based on the GO-HA-mediated immune regulation of macrophages. The HA-2wt%GO nanocomposite coatings exhibited good biocompatibility and favored M2 macrophage polarization. Meanwhile, they could also significantly upregulate IL-10 (anti-inflammatory factor) expression and downregulate TNF-α (pro-inflammatory factor) expression. Additionally, the microenvironment, which was established by M2 macrophages, favored the osteogenesis of BMSCs both in vivo and in vitro. These findings show that the GO-HA nanocomposite coating is a promising surface-modification material. Hence, this study provides a reference for the development of next-generation osteoimmunomodulatory biomaterials.
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Affiliation(s)
- Wufanbieke Baheti
- Department of Stomatology, People's Hospital of Xinjiang Autonomous Region, Urumqi, China
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaotao Chen
- Department of Stomatology, People's Hospital of Xinjiang Autonomous Region, Urumqi, China
| | - Mi La
- Department of Stomatology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Huiyu He
- Department of Stomatology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Mazmanian K, Grauffel C, Dudev T, Lim C. Protein Ca 2+-Sites Prone to Sr 2+ Substitution: Implications for Strontium Therapy. J Phys Chem B 2023. [PMID: 37327495 DOI: 10.1021/acs.jpcb.3c01637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Strontium (Sr), an alkali metal with properties similar to calcium, in the form of soluble salts is used to treat osteoporosis. Despite the information accumulated on the role of Sr2+ as a Ca2+ mimetic in biology and medicine, there is no systematic study of how the outcome of the competition between the two dications depends on the physicochemical properties of (i) the metal ions, (ii) the first- and second-shell ligands, and (iii) the protein matrix. Specifically, the key features of a Ca2+-binding protein that enable Sr2+ to displace Ca2+ remain unclear. To address this, we studied the competition between Ca2+ and Sr2+ in protein Ca2+-binding sites using density functional theory combined with the polarizable continuum model. Our findings indicate that Ca2+-sites with multiple strong charge-donating protein ligands, including one or more bidentately bound Asp-/Glu- that are relatively buried and rigid are protected against Sr2+ attack. On the other hand, Ca2+-sites crowded with multiple protein ligands may be prone to Sr2+ displacement if they are solvent-exposed and flexible enough so that an extra backbone ligand from the outer shell can bind to Sr2+. In addition, solvent-exposed Ca2+ sites with only a few weak charge-donating ligands that can rearrange to fit the strontium's coordination requirements are susceptible to Sr2+ displacement. We provide the physical basis of these results and discuss potential novel protein targets of therapeutic Sr2+.
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Affiliation(s)
- Karine Mazmanian
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Cédric Grauffel
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Todor Dudev
- Faculty of Chemistry and Pharmacy, Sofia University, Sofia 1164, Bulgaria
| | - Carmay Lim
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
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Qi L, Zhang H, Guo Y, Zhang C, Xu Y. A novel calcium-binding peptide from bovine bone collagen hydrolysate and chelation mechanism and calcium absorption activity of peptide-calcium chelate. Food Chem 2023; 410:135387. [PMID: 36621334 DOI: 10.1016/j.foodchem.2023.135387] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/11/2022] [Accepted: 01/02/2023] [Indexed: 01/05/2023]
Abstract
A novel calcium-binding peptide from bovine bone collagen hydrolysate was screened based on a new target-the calcium-sensing receptor (CaSR), and its chelation mechanism and calcium absorption activity were investigated. Glu-Tyr-Gly exhibited superior binding affinities to CaSR because of its interaction with the active sites of the CaSR Venus Flytrap (VFT) domain. Glu-Tyr-Gly-Ca may exist in five potential chelation modes and its potential chelation mechanism was that calcium ions were located in the center and surrounded by ionic bonds (carboxyl group) and coordination bonds (carbonyl, amino, and carboxyl group). Glu-Tyr-Gly-Ca was slightly damaged in the intestinal fluid and at different temperatures, whereas it was severely damaged in the gastric fluid and acidic conditions. The results of the calcium dialysis percentage and Caco-2 cells experiments showed that Glu-Tyr-Gly-Ca possessed good calcium transport activity and bioavailability. The findings provided theoretical basis for Glu-Tyr-Gly-Ca as potential calcium supplement to improve intestinal calcium absorption.
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Affiliation(s)
- Liwei Qi
- Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Hongru Zhang
- Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Biomass and Green Technologies, University of Liege-Gembloux Agro-Bio Tech, Passage des déportés 2, B-5030 Gembloux, Belgium
| | - Yujie Guo
- Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Chunhui Zhang
- Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Yang Xu
- Inner Mongolia Mengtai Biological Engineering Co., Ltd, Shengle Economic Park, Helinger County, Hohhot, Inner Mongolia 010000, China
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Kaur G, Bhadada SK, Sachdeva N, Saikia UN, Dahiya D, Seth S, Raik S, Behera A, Rao SD. Establishment and characterization of long-term human primary parathyroid tumor subclones derived from Indian PHPT. 3 Biotech 2023; 13:161. [PMID: 37152002 PMCID: PMC10160248 DOI: 10.1007/s13205-023-03540-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 03/28/2023] [Indexed: 05/09/2023] Open
Abstract
The continuous cell line of epithelial human parathyroid cells has been proven difficult. Previously, PTH-C1 cell line was only established rat parathyroid tissue cell line known to express the parathyroid hormone-related peptide (Pthrp) gene. The paucity of continuous cell line of human parathyroid cells secreting parathyroid hormone (PTH) has imposed hurdle in in vitro assessment of the mechanisms involved in the control of parathyroid cell function and proliferation. The primary cell cultures of human parathyroid cells were derived from parathyroid adenoma tissue biopsy (n = 5). The cells were subsequently subcultured to maintained primary subclones. Karyotyping analysis was performed to analyze the genotypic identity of derived subclones. The expression of calcium-sensing receptor (CaSR) and intact parathyroid hormone (iPTH) were analyzed using immunocytochemistry and immunofluorescence. In the present study, we have used a defined condition medium to generate the continuous culture of human parathyroid cells derived from patients with parathyroid adenoma due to primary hyperparathyroidism. The subcultured primary subclones were maintained epithelial and polygonal morphology, doubling time of approximately 25 h, displaying a diploid chromosome number, and secretion of PTH. This cell line produces PTH and expresses the calcium-sensing receptor (CaSR) known to be involved in parathyroid function. Altogether these findings indicate the uniqueness of the human parathyroid cell line as an in vitro model for cellular and molecular studies on parathyroid physiopathology.
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Affiliation(s)
- Gurjeet Kaur
- Department of Endocrinology, Research Block B, Postgraduate Institute of Medical Education and Research (PGIMER), Sector – 12, Chandigarh, 160012 India
| | - Sanjay Kumar Bhadada
- Department of Endocrinology, Research Block B, Postgraduate Institute of Medical Education and Research (PGIMER), Sector – 12, Chandigarh, 160012 India
| | - Naresh Sachdeva
- Department of Endocrinology, Research Block B, Postgraduate Institute of Medical Education and Research (PGIMER), Sector – 12, Chandigarh, 160012 India
| | - Uma Nahar Saikia
- Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Divya Dahiya
- Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Saurabh Seth
- Department of Genetics in Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Shalini Raik
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Arunanshu Behera
- Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Bernardor J, De Mul A, Bacchetta J, Schmitt CP. Impact of Cinacalcet and Etelcalcetide on Bone Mineral and Cardiovascular Disease in Dialysis Patients. Curr Osteoporos Rep 2023; 21:193-204. [PMID: 36848027 DOI: 10.1007/s11914-023-00782-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/15/2023] [Indexed: 03/01/2023]
Abstract
PURPOSES OF REVIEW With chronic kidney disease (CKD) progression, secondary hyperparathyroidism (sHPT) and mineral and bone metabolism disease (MBD) almost inevitably develop and result in renal osteodystrophy and cardiovascular disease (CVD). Together with active vitamin D, calcimimetics are the main therapy for sHPT in CKD. This review provides an overview of the therapeutic effects of oral cinacalcet and intravenous etelcalcetide on CKD-MBD and vascular disease, with a focus on pediatric dialysis patients. RECENT FINDINGS Randomized controlled trials in adults and children demonstrate efficient lowering of parathyroid hormone (PTH) by the calcimimetics together with a reduction in serum calcium and phosphate when combined with low-dose active vitamin D, while therapy with active vitamin D analogs alone increases serum calcium and phosphate. Cinacalcet and etelcalcetide both improve bone formation and correct adynamic bone, i.e., have a direct bone anabolic effect. They decrease serum calciprotein particles, which are involved in endothelial dysfunction, atherogenesis, and vascular calcification. Clinical trials in adults suggest a modest slowing of the progression of cardiovascular calcification with cinacalcet. Calcimimetic agents represent a major pharmacological tool for improved control of CKD-MBD, by efficiently counteracting sHPT and allowing for better control of calcium/phosphate and bone homeostasis. Albeit definite evidence is lacking, the beneficial effects of calcimimetics on CVD are promising. Routine use of cinacalcet has been suggested in children.
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Affiliation(s)
- Julie Bernardor
- UMR 1033, Faculté de Médecine Lyon Est, INSERM, Université Claude Bernard Lyon1, Lyon, France.
- Centre de Référence Des Maladies Rares du Calcium Et du Phosphate, Filière Maladies Rares OSCAR, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.
- Centre de Référence Des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Filières Maladies Rares ORKID Et ERK-Net, Bron, France.
- Faculté de Médecine, Université de Nice Côte d'Azur, Nice, France.
- Unité d'hémodialyse Pédiatrique, CHU de Nice, Archet 2, 06202, Nice, France.
| | - Aurélie De Mul
- Centre de Référence Des Maladies Rares du Calcium Et du Phosphate, Filière Maladies Rares OSCAR, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- Centre de Référence Des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Filières Maladies Rares ORKID Et ERK-Net, Bron, France
- Pediatric Nephrology Unit, Geneva University Hospital, Geneva, Switzerland
| | - Justine Bacchetta
- UMR 1033, Faculté de Médecine Lyon Est, INSERM, Université Claude Bernard Lyon1, Lyon, France
- Centre de Référence Des Maladies Rares du Calcium Et du Phosphate, Filière Maladies Rares OSCAR, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- Centre de Référence Des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Filières Maladies Rares ORKID Et ERK-Net, Bron, France
- Faculté de Médecine Lyon Est, Université Claude Bernard, Lyon 1, Lyon, France
| | - Claus Peter Schmitt
- Department of Pediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
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Werner LE, Wagner U. Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation. Front Physiol 2023; 13:1078569. [PMID: 36685206 PMCID: PMC9854345 DOI: 10.3389/fphys.2022.1078569] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 11/17/2022] [Indexed: 01/09/2023] Open
Abstract
The calcium-sensing receptor (CaSR) is expressed in many cell types - including immune cells and in particular circulating monocytes. Here, the receptor plays an important physiological role as a regulator of constitutive macropinocytosis. This review article provides an overview of the literature on the role of the calcium sensing receptor in the context of inflammatory processes. Special emphasis is laid upon the importance for monocytes in the context of rheumatoid arthritis. We have shown previously, that stimulation of the receptor by increased extracellular Ca2+ ([Ca2+]ex) triggers a pro-inflammatory response due to NLRP3 inflammasome assembly and interleukin (IL)-1β release. The underlying mechanism includes macropinocytosis of calciprotein particles (CPPs), which are taken up in a [Ca2+]ex-induced, CaSR dependent manner, and leads to strong IL-1β release. In rheumatoid arthritis (RA), this uptake and the resulting IL-1β release is significantly increased due to increased expression of the receptor. Moreover, increased [Ca2+]ex-induced CPP uptake and IL-1β release is associated with more active disease, while CaSR overexpression has been reported to be associated with cardiovascular complications of RA. Most importantly, however, in animal experiments with arthritic mice, increased local calcium concentrations are present, which in combination with release of fetuin-A from eroded bone could contribute to formation of CPPs. We propose, that increased [Ca2+]ex, CPPs and pro-inflammatory cytokines drive a vicious cycle of inflammation and bone destruction which in turn offers new potential therapeutic approaches.
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11
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Yang Q, Zhao Z, Zhao W, Chen Y, Chen Y, Shi J, Ni Q, Cao Y, Sun X, Wang H, Yuan H, Wang R, Sun W. A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR-mediated inhibition of osteoclastogenesis. FASEB J 2023; 37:e22673. [PMID: 36468692 DOI: 10.1096/fj.202200761rrr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 11/09/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022]
Abstract
Calcium modulates bone cell recruitment, differentiation, and function by binding to the calcium-sensing receptor (CaSR). However, the function of CaSR induced by high extracellular calcium (Ca2+ e ) in the regulation of osteoclast formation in rheumatoid arthritis (RA) remains unknown. Here, we used TNFα-transgenic (TNFTG ) RA mice and their wildtype (WT) littermates fed a normal or a rescue diet (high calcium, high phosphorus, and high lactose diet, termed rescue diet) to compare their joint bone phenotypes. In comparison to TNFTG mice fed the normal diet, articular bone volume and cartilage area are increased, whereas inflamed area, eroded surface, TRAP+ surface, and osteoclast-related genes expression are decreased in TNFTG mice fed the rescue diet. Besides, TNFTG mice fed the rescue diet were found to exhibit more CaSR+ area and less NFATc1+ /TRAP+ area. Furthermore, at normal Ca2+ e concentrations, osteoclast precursors (OCPs) from TNFTG mice formed more osteoclasts than OCPs from WT mice, but the number of osteoclasts gradually decreased when the Ca2+ e concentration increased. Meanwhile, the expression of CaSR increased responding to a high level of Ca2+ e , whereas the expression of NF-κB/NFATc1 signaling molecules decreased. At last, the knockdown of CaSR blocked the inhibition of osteoclast differentiation attributed to high Ca2+ e . Taken together, our findings indicate that high Ca2+ e inhibits osteoclast differentiation in RA mice partially through the CaSR/NF-κB/NFATc1 pathway.
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Affiliation(s)
- Qiudong Yang
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.,Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Ziwei Zhao
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.,Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Wenhua Zhao
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Yue Chen
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yuyi Chen
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Jiali Shi
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Qiaoqi Ni
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yanan Cao
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Xu Sun
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.,Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Hua Wang
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Hua Yuan
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Ruixia Wang
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Wen Sun
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
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12
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Eugen G, Claus M, Anna-Maria S, Niklas D, Philipp S, Andrea E, Andrea ML, Elke V. Degradation of 3D-printed magnesium phosphate ceramics in vitro and a prognosis on their bone regeneration potential. Bioact Mater 2023; 19:376-391. [PMID: 35574054 PMCID: PMC9062425 DOI: 10.1016/j.bioactmat.2022.04.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/30/2022] [Accepted: 04/17/2022] [Indexed: 12/13/2022] Open
Abstract
Regenerative bone implants promote new bone formation and ideally degrade simultaneously to osteogenesis. Although clinically established calcium phosphate bone grafts provide excellent osseointegration and osteoconductive efficacy, they are limited in terms of bioresorption. Magnesium phosphate (MP) based ceramics are a promising alternative, because they are biocompatible, mechanically extremely stable, and degrade much faster than calcium phosphates under physiological conditions. Bioresorption of an implant material can include both chemical dissolution as well as cellular resorption. We investigated the bioresorption of 3D powder printed struvite and newberyite based MP ceramics in vitro by a direct human osteoclast culture approach. The osteoclast response and cellular resorption was evaluated by means of fluorescence and TRAP staining, determination of osteoclast activities (CA II and TRAP), SEM imaging as well as by quantification of the ion release during cell culture. Furthermore, the bioactivity of the materials was investigated via SBF immersion, whereas hydroxyapatite precipitates were analyzed by SEM and EDX measurements. This bioactive coating was resorbed by osteoclasts. In contrast, only chemical dissolution contributed to bioresorption of MP, while no cellular resorption of the materials was observed. Based on our results, we expect an increased bone regeneration effect of MP compared to calcium phosphate based bone grafts and complete chemical degradation within a maximum of 1.5-3.1 years.
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Affiliation(s)
- Gefel Eugen
- Institute and Department for Functional Materials in Medicine and Dentistry, University Clinic Wuerzburg, Wuerzburg, Germany
| | - Moseke Claus
- Institute for Biomedical Engineering (IBMT), University of Applied Sciences Mittelhessen (THM), Wiesenstraße 14, Gießen, Germany
| | - Schmitt Anna-Maria
- Institute and Department for Functional Materials in Medicine and Dentistry, University Clinic Wuerzburg, Wuerzburg, Germany
| | - Dümmler Niklas
- Institute and Department for Functional Materials in Medicine and Dentistry, University Clinic Wuerzburg, Wuerzburg, Germany
| | - Stahlhut Philipp
- Institute and Department for Functional Materials in Medicine and Dentistry, University Clinic Wuerzburg, Wuerzburg, Germany
| | - Ewald Andrea
- Institute and Department for Functional Materials in Medicine and Dentistry, University Clinic Wuerzburg, Wuerzburg, Germany
| | - Meyer-Lindenberg Andrea
- Clinic for Small Animal Surgery and Reproduction, Ludwig-Maximilians-Universität, Munich, Germany
| | - Vorndran Elke
- Institute and Department for Functional Materials in Medicine and Dentistry, University Clinic Wuerzburg, Wuerzburg, Germany
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13
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How Theoretical Evaluations Can Generate Guidelines for Designing/Engineering Metalloproteins with Desired Metal Affinity and Selectivity. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010249. [PMID: 36615442 PMCID: PMC9822464 DOI: 10.3390/molecules28010249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022]
Abstract
Almost half of all known proteins contain metal co-factors. Crucial for the flawless performance of a metalloprotein is the selection with high fidelity of the cognate metal cation from the surrounding biological fluids. Therefore, elucidating the factors controlling the metal binding and selectivity in metalloproteins is of particular significance. The knowledge thus acquired not only contributes to better understanding of the intimate mechanism of these events but, also, significantly enriches the researcher's toolbox that could be used in designing/engineering novel metalloprotein structures with pre-programmed properties. A powerful tool in aid of deciphering the physical principles behind the processes of metal recognition and selectivity is theoretical modeling of metal-containing biological structures. This review summarizes recent findings in the field with an emphasis on elucidating the major factors governing these processes. The results from theoretical evaluations are discussed. It is the hope that the physical principles evaluated can serve as guidelines in designing/engineering of novel metalloproteins of interest to both science and industry.
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Sahm F, Freiin Grote V, Zimmermann J, Haack F, Uhrmacher AM, van Rienen U, Bader R, Detsch R, Jonitz-Heincke A. Long-term stimulation with alternating electric fields modulates the differentiation and mineralization of human pre-osteoblasts. Front Physiol 2022; 13:965181. [PMID: 36246121 PMCID: PMC9562827 DOI: 10.3389/fphys.2022.965181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
Biophysical stimulation by electric fields can promote bone formation in bone defects of critical size. Even though, long-term effects of alternating electric fields on the differentiation of osteoblasts are not fully understood. Human pre-osteoblasts were stimulated over 31 days to gain more information about these cellular processes. An alternating electric field with 0.7 Vrms and 20 Hz at two distances was applied and viability, mineralization, gene expression, and protein release of differentiation factors were analyzed. The viability was enhanced during the first days of stimulation. A higher electric field resulted in upregulation of typical osteogenic markers like osteoprotegerin, osteopontin, and interleukin-6, but no significant changes in mineralization. Upregulation of the osteogenic markers could be detected with a lower electric field after the first days of stimulation. As a significant increase in the mineralized matrix was identified, an enhanced osteogenesis due to low alternating electric fields can be assumed.
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Affiliation(s)
- Franziska Sahm
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
- *Correspondence: Franziska Sahm, ; Anika Jonitz-Heincke,
| | - Vivica Freiin Grote
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
| | - Julius Zimmermann
- Chair of Theoretical Electrical Engineering, Institute for General Electrical Engineering, University of Rostock, Rostock, Germany
| | - Fiete Haack
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| | - Adelinde M. Uhrmacher
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| | - Ursula van Rienen
- Chair of Theoretical Electrical Engineering, Institute for General Electrical Engineering, University of Rostock, Rostock, Germany
- Department Life, Light and Matter, University of Rostock, Rostock, Germany
- Department Ageing of Individuals and Society, University of Rostock, Rostock, Germany
| | - Rainer Bader
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
| | - Rainer Detsch
- Department of Materials Science and Engineering, Institute of Biomaterials, Friedrich Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Anika Jonitz-Heincke
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
- *Correspondence: Franziska Sahm, ; Anika Jonitz-Heincke,
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15
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Okagu IU, Ezeorba TPC, Aguchem RN, Ohanenye IC, Aham EC, Okafor SN, Bollati C, Lammi C. A Review on the Molecular Mechanisms of Action of Natural Products in Preventing Bone Diseases. Int J Mol Sci 2022; 23:ijms23158468. [PMID: 35955603 PMCID: PMC9368769 DOI: 10.3390/ijms23158468] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 12/10/2022] Open
Abstract
The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs’ adoption. This review discusses the pathological development of some BDs, the NP-targeted components, and the actions exerted on bone remodeling signaling pathways (e.g., Receptor Activator of Nuclear Factor κ B-ligand (RANKL)/monocyte/macrophage colony-stimulating factor (M-CSF)/osteoprotegerin (OPG), mitogen-activated protein kinase (MAPK)s/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2–related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1), Bone Morphogenetic Protein 2 (BMP2)-Wnt/β-catenin, PhosphatidylInositol 3-Kinase (PI3K)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 Beta (GSK3β), and other signaling pathways). Although majority of the studies on the osteoprotective properties of NPs against BDs were conducted ex vivo and mostly on animals, the use of NPs for treating human BDs and the prospects for future development remain promising.
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Affiliation(s)
- Innocent U. Okagu
- Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka 410001, Nigeria; (I.U.O.); (T.P.C.E.); (R.N.A.); (E.C.A.)
| | - Timothy P. C. Ezeorba
- Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka 410001, Nigeria; (I.U.O.); (T.P.C.E.); (R.N.A.); (E.C.A.)
| | - Rita N. Aguchem
- Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka 410001, Nigeria; (I.U.O.); (T.P.C.E.); (R.N.A.); (E.C.A.)
| | - Ikenna C. Ohanenye
- School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Emmanuel C. Aham
- Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka 410001, Nigeria; (I.U.O.); (T.P.C.E.); (R.N.A.); (E.C.A.)
- Natural Science Unit, School of General Studies, University of Nigeria, Nsukka 410001, Nigeria
- School of Environment and Safety Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Sunday N. Okafor
- Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka 410001, Nigeria;
| | - Carlotta Bollati
- Department of Pharmaceutical Sciences, University of Milan, via Mangiagalli 25, 20133 Milano, Italy;
| | - Carmen Lammi
- Department of Pharmaceutical Sciences, University of Milan, via Mangiagalli 25, 20133 Milano, Italy;
- Correspondence: ; Tel.: +39-02-5031-9372
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Bohner M, Maazouz Y, Ginebra MP, Habibovic P, Schoenecker JG, Seeherman H, van den Beucken JJ, Witte F. Sustained local ionic homeostatic imbalance caused by calcification modulates inflammation to trigger heterotopic ossification. Acta Biomater 2022; 145:1-24. [PMID: 35398267 DOI: 10.1016/j.actbio.2022.03.057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 12/15/2022]
Abstract
Heterotopic ossification (HO) is a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues. Despite being a frequent complication of orthopedic and trauma surgery, brain and spinal injury, the etiology of HO is poorly understood. The aim of this study is to evaluate the hypothesis that a sustained local ionic homeostatic imbalance (SLIHI) created by mineral formation during tissue calcification modulates inflammation to trigger HO. This evaluation also considers the role SLIHI could play for the design of cell-free, drug-free osteoinductive bone graft substitutes. The evaluation contains five main sections. The first section defines relevant concepts in the context of HO and provides a summary of proposed causes of HO. The second section starts with a detailed analysis of the occurrence and involvement of calcification in HO. It is followed by an explanation of the causes of calcification and its consequences. This allows to speculate on the potential chemical modulators of inflammation and triggers of HO. The end of this second section is devoted to in vitro mineralization tests used to predict the ectopic potential of materials. The third section reviews the biological cascade of events occurring during pathological and material-induced HO, and attempts to propose a quantitative timeline of HO formation. The fourth section looks at potential ways to control HO formation, either acting on SLIHI or on inflammation. Chemical, physical, and drug-based approaches are considered. Finally, the evaluation finishes with a critical assessment of the definition of osteoinduction. STATEMENT OF SIGNIFICANCE: The ability to regenerate bone in a spatially controlled and reproducible manner is an essential prerequisite for the treatment of large bone defects. As such, understanding the mechanism leading to heterotopic ossification (HO), a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues, would be very useful. Unfortunately, the mechanism(s) behind HO is(are) poorly understood. The present study reviews the literature on HO and based on it, proposes that HO can be caused by a combination of inflammation and calcification. This mechanism helps to better understand current strategies to prevent and treat HO. It also shows new opportunities to improve the treatment of bone defects in orthopedic and dental procedures.
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17
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Wherry SJ, Blatchford PJ, Swanson CM, Wellington T, Boxer RS, Kohrt WM. Maintaining serum ionized calcium during brisk walking attenuates the increase in bone resorption in older adults. Bone 2021; 153:116108. [PMID: 34252605 PMCID: PMC8478867 DOI: 10.1016/j.bone.2021.116108] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/26/2021] [Accepted: 07/06/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Endurance exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and bone resorption, reflected by serum carboxy-terminal collagen crosslinks (CTX). We developed a calcium clamp to prevent the decrease in iCa during exercise, which attenuated increases in PTH and CTX during vigorous cycling in young men. The goal was to determine whether this occurs in older adults during brisk walking. METHODS Twelve older adults (6 men, 6 women) performed two identical 60-min treadmill walking bouts with Ca gluconate or half-normal saline infusion. Blood sampling for iCa, total calcium (tCa), phosphate (P), PTH, and CTX, occurred before, during, and for 4 h after exercise. RESULTS iCa decreased during exercise with the saline infusion (p = 0.04) and this provoked increases in PTH and CTX (both p < 0.01). The Ca clamp prevented the decrease in serum iCa during exercise and attenuated the PTH and CTX responses. CONCLUSIONS Preventing the exercise-induced decrease in iCa markedly attenuated the increases in PTH and CTX. The cause of the decrease in iCa during exercise remains unclear, but the increases in PTH and CTX are likely counter-regulatory responses to defend serum iCa. This contention is supported by previous observations that the disruption of Ca homeostasis during exercise occurs regardless of training status. It will be important to establish whether this acute catabolic effect of exercise diminishes the potential chronic anabolic effects of exercise on bone.
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Affiliation(s)
- Sarah J Wherry
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America; VA Eastern Colorado Geriatric Research, Education, and Clinical Center (GRECC), Aurora, CO 80045, United States of America.
| | - Patrick J Blatchford
- VA Eastern Colorado Geriatric Research, Education, and Clinical Center (GRECC), Aurora, CO 80045, United States of America; Department of Biostatistics and Bioinformatics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Christine M Swanson
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Toby Wellington
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Rebecca S Boxer
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America; VA Eastern Colorado Geriatric Research, Education, and Clinical Center (GRECC), Aurora, CO 80045, United States of America
| | - Wendy M Kohrt
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America; VA Eastern Colorado Geriatric Research, Education, and Clinical Center (GRECC), Aurora, CO 80045, United States of America
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18
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Pees A, Beaino W, Kooijman EJM, Schreurs M, Verlaan M, Schuit RC, Vosjan MJWD, Engelsman AF, Windhorst AD, Vugts DJ. Synthesis and evaluation of [ 18F]cinacalcet for the imaging of parathyroid hyperplasia. Nucl Med Biol 2021; 102-103:97-105. [PMID: 34743064 DOI: 10.1016/j.nucmedbio.2021.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/15/2021] [Accepted: 10/23/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the parathyroid glands is the standard treatment but requires precise pre-operative localization of the glands. However, currently available imaging modalities show limited sensitivity. Since positron emission tomography (PET) is a molecular imaging technique with high accuracy and sensitivity, our aim was to develop a new PET tracer for overactive parathyroid glands imaging by radiolabelling cinacalcet, a drug binding to the calcium-sensing receptor of the parathyroid glands. METHODS [18F]Cinacalcet was synthesized by copper-catalysed [18F]trifluoromethylation of a boronic acid precursor using high molar activity [18F]fluoroform. Ex vivo biodistribution and metabolism were evaluated in 12 healthy male Wistar rats at 5, 15, 45 and 90 min. PET scans were performed at baseline and after blocking with NPS R-568. RESULTS [18F]Cinacalcet was obtained in an overall radiosynthesis time of 1 h with a radiochemical purity of 98 ± 1%, a radiochemical yield of 8 ± 4% (overall, n = 7, corrected for decay) and a molar activity of 40 ± 11 GBq/μmol (n = 7, at EOS). The ex vivo biodistribution showed uptake in the thyroid and parathyroid glands as well as in other glands such as adrenals, salivary glands and pancreas. The tracer was rapidly cleared from the blood via liver and kidneys and showed fast metabolism. PET images confirmed uptake in the target organ. However, in a blocking study with NPS R-568 specific binding of [18F]cinacalcet to the CaSR could not be confirmed. CONCLUSIONS [18F]Cinacalcet was successfully synthesized. First in vivo experiments in healthy rats showed uptake of the tracer in the target organ and fast metabolism, encouraging further in vivo evaluation of this tracer.
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Affiliation(s)
- Anna Pees
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands
| | - Wissam Beaino
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands
| | - Esther J M Kooijman
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands
| | - Maxime Schreurs
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands
| | - Mariska Verlaan
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands
| | - Robert C Schuit
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands
| | | | - Anton F Engelsman
- Amsterdam UMC, VU Medical Center, Department of Surgery, Amsterdam, the Netherlands
| | - Albert D Windhorst
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands
| | - Danielle J Vugts
- Amsterdam UMC, VU University, Radiology and Nuclear Medicine, Radionuclide Center, De Boelelaan 1085c, Amsterdam, the Netherlands.
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Singh YP, Dasgupta S, Bhaskar R, Agrawal AK. Monetite addition into gelatin based freeze-dried scaffolds for improved mechanical and osteogenic properties. Biomed Mater 2021; 16. [PMID: 34624878 DOI: 10.1088/1748-605x/ac2e17] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/08/2021] [Indexed: 11/12/2022]
Abstract
This study was aimed at fabricating monetite nanoparticles impregnated gelatin-based composite scaffold to improve the chemical, mechanical and osteogenic properties. Scaffolds were fabricated using a freeze-drying technique of the slurry containing a varying proportion of gelatin and monetite. The lyophilized scaffolds were cross-linked with 0.25 wt% glutaraldehyde solution to obtain a three-dimensional (3D) interconnected porous microstructure with improved mechanical strength and stability in a physiological environment. The fabricated scaffolds possessed >80% porosity having 3D interconnected pore size distribution varying between 65 and 270 μm as evident from field emission scanning electron microscopy analysis. The average pore size of the prepared scaffold decreased with monetite addition as reflected in values of 210 μm for pure gelatin GM0scaffold and 118 μm registered by GM20scaffold. On increase in monetite content up to 20 wt% of total polymer concentration, compressive strength of the prepared scaffolds was increased from 0.92 MPa in pure gelatin-based GM0to 2.43 MPa in GM20. Up to 20 wt% of monetite reinforced composite scaffolds exhibited higher bioactivity as compared to that observed in pure gelatin-based GM0scaffold. Simulated body fluid (SBF) study and alizarin red assays confirmed higher bio-mineralization ability of GM20as compared to that exhibited by GM0. Human preosteoblast cells (MG-63) revealed higher degree of filopodia and lamellipodia extensions and excellent spreading behavior to anchor with GM20matrix as compared to that onto GM0and GM10. MTT assay and alkaline phosphatase staining study indicated that MG-63 cells found a more conducive environment to proliferate and subsequently differentiate into osteoblast lineage when exposed to GM20scaffolds rather than to GM0and GM10. This study revealed that up to 20 wt% monetite addition in gelatin could improve the performance of prepared scaffolds and serve as an efficient candidate to repair and regenerate bone tissues at musculoskeletal defect sites.
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Affiliation(s)
- Yogendra Pratap Singh
- Department of Ceramic Engineering, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Sudip Dasgupta
- Department of Ceramic Engineering, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Rakesh Bhaskar
- Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela, Odisha 769008, India
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Takashi Y, Sawatsubashi S, Endo I, Ohnishi Y, Abe M, Matsuhisa M, Kawanami D, Matsumoto T, Fukumoto S. Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span. Biochem Biophys Rep 2021; 27:101107. [PMID: 34458594 PMCID: PMC8379418 DOI: 10.1016/j.bbrep.2021.101107] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/02/2022] Open
Abstract
Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span.
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Affiliation(s)
- Yuichi Takashi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University School of Medicine, Fukuoka, Japan.,Department of Molecular Endocrinology, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.,Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.,Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Shun Sawatsubashi
- Department of Molecular Endocrinology, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Itsuro Endo
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yukiyo Ohnishi
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Abe
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Munehide Matsuhisa
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Daiji Kawanami
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Toshio Matsumoto
- Department of Molecular Endocrinology, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Seiji Fukumoto
- Department of Molecular Endocrinology, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
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21
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Vologzhannikova AA, Shevelyova MP, Kazakov AS, Sokolov AS, Borisova NI, Permyakov EA, Kircheva N, Nikolova V, Dudev T, Permyakov SE. Strontium Binding to α-Parvalbumin, a Canonical Calcium-Binding Protein of the "EF-Hand" Family. Biomolecules 2021; 11:biom11081158. [PMID: 34439824 PMCID: PMC8392015 DOI: 10.3390/biom11081158] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 07/30/2021] [Accepted: 07/31/2021] [Indexed: 02/07/2023] Open
Abstract
Strontium salts are used for treatment of osteoporosis and bone cancer, but their impact on calcium-mediated physiological processes remains obscure. To explore Sr2+ interference with Ca2+ binding to proteins of the EF-hand family, we studied Sr2+/Ca2+ interaction with a canonical EF-hand protein, α-parvalbumin (α-PA). Evaluation of the equilibrium metal association constants for the active Ca2+ binding sites of recombinant human α-PA (‘CD’ and ‘EF’ sites) from fluorimetric titration experiments and isothermal titration calorimetry data gave 4 × 109 M−1 and 4 × 109 M−1 for Ca2+, and 2 × 107 M−1 and 2 × 106 M−1 for Sr2+. Inactivation of the EF site by homologous substitution of the Ca2+-coordinating Glu in position 12 of the EF-loop by Gln decreased Ca2+/Sr2+ affinity of the protein by an order of magnitude, whereas the analogous inactivation of the CD site induced much deeper suppression of the Ca2+/Sr2+ affinity. These results suggest that Sr2+ and Ca2+ bind to CD/EF sites of α-PA and the Ca2+/Sr2+ binding are sequential processes with the CD site being occupied first. Spectrofluorimetric Sr2+ titration of the Ca2+-loaded α-PA revealed presence of secondary Sr2+ binding site(s) with an apparent equilibrium association constant of 4 × 105 M−1. Fourier-transform infrared spectroscopy data evidence that Ca2+/Sr2+-loaded forms of α-PA exhibit similar states of their COO− groups. Near-UV circular dichroism (CD) data show that Ca2+/Sr2+ binding to α-PA induce similar changes in symmetry of microenvironment of its Phe residues. Far-UV CD experiments reveal that Ca2+/Sr2+ binding are accompanied by nearly identical changes in secondary structure of α-PA. Meanwhile, scanning calorimetry measurements show markedly lower Sr2+-induced increase in stability of tertiary structure of α-PA, compared to the Ca2+-induced effect. Theoretical modeling using Density Functional Theory computations with Polarizable Continuum Model calculations confirms that Ca2+-binding sites of α-PA are well protected against exchange of Ca2+ for Sr2+ regardless of coordination number of Sr2+, solvent exposure or rigidity of sites. The latter appears to be a key determinant of the Ca2+/Sr2+ selectivity. Overall, despite lowered affinity of α-PA to Sr2+, the latter competes with Ca2+ for the same EF-hands and induces similar structural rearrangements. The presence of a secondary Sr2+ binding site(s) could be a factor contributing to Sr2+ impact on the functional activity of proteins.
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Affiliation(s)
- Alisa A. Vologzhannikova
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; (A.A.V.); (M.P.S.); (A.S.K.); (A.S.S.); (N.I.B.); (E.A.P.)
| | - Marina P. Shevelyova
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; (A.A.V.); (M.P.S.); (A.S.K.); (A.S.S.); (N.I.B.); (E.A.P.)
| | - Alexey S. Kazakov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; (A.A.V.); (M.P.S.); (A.S.K.); (A.S.S.); (N.I.B.); (E.A.P.)
| | - Andrey S. Sokolov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; (A.A.V.); (M.P.S.); (A.S.K.); (A.S.S.); (N.I.B.); (E.A.P.)
| | - Nadezhda I. Borisova
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; (A.A.V.); (M.P.S.); (A.S.K.); (A.S.S.); (N.I.B.); (E.A.P.)
| | - Eugene A. Permyakov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; (A.A.V.); (M.P.S.); (A.S.K.); (A.S.S.); (N.I.B.); (E.A.P.)
| | - Nikoleta Kircheva
- Institute of Optical Materials and Technologies “Acad. J. Malinowski”, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;
| | - Valya Nikolova
- Faculty of Chemistry and Pharmacy, Sofia University “St. Kl. Ohridski”, 1164 Sofia, Bulgaria; (V.N.); (T.D.)
| | - Todor Dudev
- Faculty of Chemistry and Pharmacy, Sofia University “St. Kl. Ohridski”, 1164 Sofia, Bulgaria; (V.N.); (T.D.)
| | - Sergei E. Permyakov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia; (A.A.V.); (M.P.S.); (A.S.K.); (A.S.S.); (N.I.B.); (E.A.P.)
- Correspondence: ; Tel.: +7-(4967)-143-7741
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22
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Kalinkovich A, Livshits G. Biased and allosteric modulation of bone cell-expressing G protein-coupled receptors as a novel approach to osteoporosis therapy. Pharmacol Res 2021; 171:105794. [PMID: 34329703 DOI: 10.1016/j.phrs.2021.105794] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/20/2021] [Accepted: 07/25/2021] [Indexed: 12/16/2022]
Abstract
On the cellular level, osteoporosis (OP) is a result of imbalanced bone remodeling, in which osteoclastic bone resorption outcompetes osteoblastic bone formation. Currently available OP medications include both antiresorptive and bone-forming drugs. However, their long-term use in OP patients, mainly in postmenopausal women, is accompanied by severe side effects. Notably, the fundamental coupling between bone resorption and formation processes underlies the existence of an undesirable secondary outcome that bone anabolic or anti-resorptive drugs also reduce bone formation. This drawback requires the development of anti-OP drugs capable of selectively stimulating osteoblastogenesis and concomitantly reducing osteoclastogenesis. We propose that the application of small synthetic biased and allosteric modulators of bone cell receptors, which belong to the G-protein coupled receptors (GPCR) family, could be the key to resolving the undesired anti-OP drug selectivity. This approach is based on the capacity of these GPCR modulators, unlike the natural ligands, to trigger signaling pathways that promote beneficial effects on bone remodeling while blocking potentially deleterious effects. Under the settings of OP, an optimal anti-OP drug should provide fine-tuned regulation of downstream effects, for example, intermittent cyclic AMP (cAMP) elevation, preservation of Ca2+ balance, stimulation of osteoprotegerin (OPG) and estrogen production, suppression of sclerostin secretion, and/or preserved/enhanced canonical β-catenin/Wnt signaling pathway. As such, selective modulation of GPCRs involved in bone remodeling presents a promising approach in OP treatment. This review focuses on the evidence for the validity of our hypothesis.
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Affiliation(s)
- Alexander Kalinkovich
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6905126, Israel
| | - Gregory Livshits
- Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6905126, Israel; Adelson School of Medicine, Ariel University, Ariel 4077625, Israel.
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23
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Mohonta SK, Maria KH, Rahman S, Das H, Hoque SM. Synthesis of hydroxyapatite nanoparticle and role of its size in hydroxyapatite/chitosan–gelatin biocomposite for bone grafting. INTERNATIONAL NANO LETTERS 2021. [DOI: 10.1007/s40089-021-00347-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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24
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The mTORC2 Regulator Homer1 Modulates Protein Levels and Sub-Cellular Localization of the CaSR in Osteoblast-Lineage Cells. Int J Mol Sci 2021; 22:ijms22126509. [PMID: 34204449 PMCID: PMC8234890 DOI: 10.3390/ijms22126509] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 11/17/2022] Open
Abstract
We recently found that, in human osteoblasts, Homer1 complexes to Calcium-sensing receptor (CaSR) and mediates AKT initiation via mechanistic target of rapamycin complex (mTOR) complex 2 (mTORC2) leading to beneficial effects in osteoblasts including β-catenin stabilization and mTOR complex 1 (mTORC1) activation. Herein we further investigated the relationship between Homer1 and CaSR and demonstrate a link between the protein levels of CaSR and Homer1 in human osteoblasts in primary culture. Thus, when siRNA was used to suppress the CaSR, we observed upregulated Homer1 levels, and when siRNA was used to suppress Homer1 we observed downregulated CaSR protein levels using immunofluorescence staining of cultured osteoblasts as well as Western blot analyses of cell protein extracts. This finding was confirmed in vivo as the bone cells from osteoblast specific CaSR-/- mice showed increased Homer1 expression compared to wild-type (wt). CaSR and Homer1 protein were both expressed in osteocytes embedded in the long bones of wt mice, and immunofluorescent studies of these cells revealed that Homer1 protein sub-cellular localization was markedly altered in the osteocytes of CaSR-/- mice compared to wt. The study identifies additional roles for Homer1 in the control of the protein level and subcellular localization of CaSR in cells of the osteoblast lineage, in addition to its established role of mTORC2 activation downstream of the receptor.
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25
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Butscheidt S, Tsourdi E, Rolvien T, Delsmann A, Stürznickel J, Barvencik F, Jakob F, Hofbauer LC, Mundlos S, Kornak U, Seefried L, Oheim R. Relevant genetic variants are common in women with pregnancy and lactation-associated osteoporosis (PLO) and predispose to more severe clinical manifestations. Bone 2021; 147:115911. [PMID: 33716164 DOI: 10.1016/j.bone.2021.115911] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/19/2021] [Accepted: 03/08/2021] [Indexed: 12/17/2022]
Abstract
Pregnancy and lactation-associated osteoporosis (PLO) is a rare skeletal disorder characterized by early-onset osteoporosis typically manifestating with vertebral compression fractures or transient osteoporosis of the hip. We hypothesized that genetic variants may play a role in the development of PLO. This study aimed to analyze the presence of genetic variants and a potential association with the clinical presentation in PLO. 42 women with PLO were included from 2013 to 2019 in a multicenter study in Germany. All cases underwent comprehensive genetic analysis based on a custom-designed gene panel including genes relevant for skeletal disorders. The skeletal status was assessed using dual-energy X-ray absorptiometry (DXA). Subgroups were further analyzed by serum bone turnover markers (n = 31) and high-resolution peripheral computed tomography (HR-pQCT; n = 23). We detected relevant genetic variants in 21 women (50%), with LRP5, WNT1 and COL1A1/A2 being the most commonly involved genes. The mean number of vertebral compression fractures was 3.3 ± 3.4 per case with a significantly higher occurrence in the subgroup with genetic variants (4.8 ± 3.7 vs. 1.8 ± 2.3, p = 0.02). Among the total cohort, DXA Z-scores were significantly lower at the lumbar spine compared to the femoral neck (p = 0.002). HR-pQCT revealed a pronounced reduction of trabecular and cortical thickness, while trabecular number was within the reference range. Eighteen women (43%) received a bone-specific therapy (primarily teriparatide). Overall, a steep increase in bone mass (+37.7%) was observed after 3 years. In conclusion, pregnancy and lactation represent skeletal risk factors, which may unmask hereditary bone disorders leading to PLO. These cases were affected more severely. Nevertheless, a timely diagnosis and adequate treatment can ensure a substantial recovery potential even without specific therapy. Patients with genetically induced low bone turnover (e.g.; LRP5, WNT1) may especially benefit from osteo-anabolic medication.
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Affiliation(s)
- Sebastian Butscheidt
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Division of Orthopaedics, Department of Trauma and Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elena Tsourdi
- Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany; Center for Healthy Aging, Technische Universität Dresden Medical Center, Dresden, Germany
| | - Tim Rolvien
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Division of Orthopaedics, Department of Trauma and Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alena Delsmann
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julian Stürznickel
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Barvencik
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franz Jakob
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany; Center for Healthy Aging, Technische Universität Dresden Medical Center, Dresden, Germany
| | - Stefan Mundlos
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Uwe Kornak
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany; Institute of Human Genetics, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Lothar Seefried
- Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Germany
| | - Ralf Oheim
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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26
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Odashima K, Shimizu Y, Sano Y, Yamamoto A, Mukai T, Takada Y, Yanagisawa Y, Imai Y, Takahashi T, Kumamoto H. Osteogenic response under the periosteum by magnesium implantation in rat tibia. Dent Mater J 2021; 40:498-507. [PMID: 33642444 DOI: 10.4012/dmj.2020-011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
This study was designed to examine osteoconductive effects of Mg in rats tibia. The animals were sacrificed after 1, 2, and 8 weeks. The elemental analysis was performed using SEM/EDX at week 1. Following X-ray micrography at weeks 2 and 8, samples were embedded in paraffin. The expression of osteocalcin was observed by immunohistochemical staining. The element concentrations of fibrous capsules around the specimens were also measured by ICP-MS. The concentrations of Ca and P on the surface of the Mg specimen increased in SEM/EDX. The tissue specimen showed new bone formation on the bone surface near the implanted area. The concentrations of Mg, Ca, and P were high in the fibrous capsules surrounding Mg. Implantation induced differentiation of osteoblasts, and this process was considered to be associated with new bone formation. Induction of cell differentiation may be influenced by corrosion products in addition to corroding magnesium.
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Affiliation(s)
- Kenji Odashima
- Division of Oral and Maxillofacial Surgery, Department of Oral and Medicine and Surgery, Graduate School of Dentistry, Tohoku University
| | - Yoshinaka Shimizu
- Division of Oral Pathology, Department of Oral Medicine and Surgery, Graduate School of Dentistry, Tohoku University
| | - Yuya Sano
- Division of Oral Pathology, Department of Oral Medicine and Surgery, Graduate School of Dentistry, Tohoku University
| | - Akiko Yamamoto
- Biometals Group, Biomaterials Unit, Nano-life Field, International Center for Materials Nanoarchitectonics, National Institute for Materials Science
| | - Toshiji Mukai
- Department of Mechanical Engineering, Kobe University
| | - Yukyo Takada
- Division of Dental Biomaterials, Tohoku University Graduate School of Dentistry, Tohoku University
| | - Yuta Yanagisawa
- Division of Oral and Maxillofacial Surgery, Department of Oral and Medicine and Surgery, Graduate School of Dentistry, Tohoku University
| | - Yoshimichi Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine
| | - Tetsu Takahashi
- Division of Oral and Maxillofacial Surgery, Department of Oral and Medicine and Surgery, Graduate School of Dentistry, Tohoku University
| | - Hiroyuki Kumamoto
- Division of Oral Pathology, Department of Oral Medicine and Surgery, Graduate School of Dentistry, Tohoku University
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27
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Zhu H, Wang H, Jia Y, Cheng L, Cheng X. Increased serum calcium levels are associated with carotid atherosclerotic plaque in normocalcaemic individuals with type 2 diabetes. Ther Adv Endocrinol Metab 2021; 12:2042018821995369. [PMID: 33854752 PMCID: PMC8010831 DOI: 10.1177/2042018821995369] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 01/22/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) have an elevated risk of atherosclerotic cardiovascular disease. Although previous data have suggested that serum calcium levels could be involved in T2DM and cardiovascular disease, whether this applies in T2DM patients with atherosclerosis remains unclear. This study therefore aimed to investigate the relationship between serum calcium levels within the physiological ranges and carotid atherosclerotic plaque in T2DM patients. METHODS A total of 594 normocalcaemic in-patients with T2DM were recruited, of whom 231 had carotid atherosclerotic plaque. Serum calcium levels were measured and carotid ultrasonography was performed. RESULTS Patients with plaque had significantly higher serum albumin-corrected calcium than those without plaque [9.02 (8.78-9.34) mg/dL versus 8.86 (8.66-9.06) mg/dL, p < 0.001]. As serum albumin-corrected calcium levels increased across tertiles, the percentage of plaque increased (27.6%, 35.5%, and 55.7%; p < 0.001). Logistic regression showed that serum albumin-corrected calcium levels were independently and positively correlated with the presence of plaque, but not parathyroid hormone levels. Compared with patients in the lowest serum calcium tertiles, the odds ratio for plaque in patients in the upper quartile was 2.47 (95% confidence interval 1.51-4.03, p < 0.001) after adjustment for potential confounders. CONCLUSION Serum albumin-corrected calcium levels are elevated in patients with T2DM and carotid atherosclerotic plaques.
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Affiliation(s)
- Huijing Zhu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Endocrinology & Metabolism, Heze Municipal Hospital, Heze, Shandong, China
| | - Huili Wang
- Department of Endocrinology & Metabolism, Heze Municipal Hospital, Heze, Shandong, China
| | | | - Lin Cheng
- Department of Endocrinology & Metabolism, Heze Municipal Hospital, Heze, Shandong, China
| | - Xingbo Cheng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu 215006, China
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28
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Gelatin-Modified Calcium/Strontium Hydrogen Phosphates Stimulate Bone Regeneration in Osteoblast/Osteoclast Co-Culture and in Osteoporotic Rat Femur Defects-In Vitro to In Vivo Translation. Molecules 2020; 25:molecules25215103. [PMID: 33153127 PMCID: PMC7662833 DOI: 10.3390/molecules25215103] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 10/29/2020] [Accepted: 10/31/2020] [Indexed: 12/13/2022] Open
Abstract
The development and characterization of biomaterials for bone replacement in case of large defects in preconditioned bone (e.g., osteoporosis) require close cooperation of various disciplines. Of particular interest are effects observed in vitro at the cellular level and their in vivo representation in animal experiments. In the present case, the material-based alteration of the ratio of osteoblasts to osteoclasts in vitro in the context of their co-cultivation was examined and showed equivalence to the material-based stimulation of bone regeneration in a bone defect of osteoporotic rats. Gelatin-modified calcium/strontium phosphates with a Ca:Sr ratio in their precipitation solutions of 5:5 and 3:7 caused a pro-osteogenic reaction on both levels in vitro and in vivo. Stimulation of osteoblasts and inhibition of osteoclast activity were proven during culture on materials with higher strontium content. The same material caused a decrease in osteoclast activity in vitro. In vivo, a positive effect of the material with increased strontium content was observed by immunohistochemistry, e.g., by significantly increased bone volume to tissue volume ratio, increased bone morphogenetic protein-2 (BMP2) expression, and significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. In addition, material degradation and bone regeneration were examined after 6 weeks using stage scans with ToF-SIMS and µ-CT imaging. The remaining material in the defects and strontium signals, which originate from areas exceeding the defect area, indicate the incorporation of strontium ions into the surrounding mineralized tissue. Thus, the material inherent properties (release of biologically active ions, solubility and degradability, mechanical strength) directly influenced the cellular reaction in vitro and also bone regeneration in vivo. Based on this, in the future, materials might be synthesized and specifically adapted to patient-specific needs and their bone status.
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29
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Bernardor J, Flammier S, Ranchin B, Gaillard S, Platel D, Peyruchaud O, Machuca-Gayet I, Bacchetta J. Inhibition of Osteoclast Differentiation by 1.25-D and the Calcimimetic KP2326 Reveals 1.25-D Resistance in Advanced CKD. J Bone Miner Res 2020; 35:2265-2274. [PMID: 32598518 DOI: 10.1002/jbmr.4122] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 06/16/2020] [Accepted: 06/21/2020] [Indexed: 12/20/2022]
Abstract
Active vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Julie Bernardor
- INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France.,Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France
| | - Sacha Flammier
- INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France.,Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Bruno Ranchin
- Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Ségolène Gaillard
- INSERM CIC 1407, CNRS UMR 5558 and Service de Pharmacotoxicologie Clinique, Hospices Civils de Lyon, Bron, France
| | - Diane Platel
- INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
| | - Olivier Peyruchaud
- INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
| | - Irma Machuca-Gayet
- INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
| | - Justine Bacchetta
- INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France.,Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
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Oral cinacalcet responsiveness in non-parathyroid hormone mediated hypercalcemia of malignancy. Med Hypotheses 2020; 143:110149. [DOI: 10.1016/j.mehy.2020.110149] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023]
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Zajíčková K, Dvořáková M, Moravcová J, Včelák J, Goltzman D. Familial hypocalciuric hypercalcemia in an index male: grey zones of the differential diagnosis from primary hyperparathyroidism in a 13-year clinical follow up. Physiol Res 2020; 69:S321-S328. [PMID: 33094630 DOI: 10.33549/physiolres.934522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Familial hypocalciuric hypercalcemia (FHH) type 1, caused by a heterozygous inactivating mutation of the gene encoding the calcium-sensing receptor (CaSR), is characterized by mild to moderate hypercalcemia, hypocalciuria and inappropriately normal or elevated parathyroid hormone (PTH). FHH must be differentiated from primary hyperparathyroidism (PHPT) because parathyroidectomy is ineffective in the former. Herein, we report a 39-year-old male patient with a 13-year history of asymptomatic PTH-dependent hypercalcemia (mean calcium of 2.88 mmol/l; reference range 2.15-2.55 mmol/l) and calcium-to-creatinine clearance ratio (Ca/Cr) ranging from 0.007 to 0.0198, which is consistent with either FHH or PHPT. Although a family history of hypercalcemia was negative, and PET-CT with fluorocholine was suggestive of a parathyroid adenoma, genetic analysis of the CaSR gene identified a heterozygous inactivating mutation NM_000388.4:c.1670G>A p. (Gly557Glu) in exon 6 and a polymorphism NM_000388.4:c.1192G>A p. (Asp398Asn) in exon 4. The G557E mutation has been previously reported in a Japanese family in which all family members with the mutation had Ca/Cr below 0.01 consistent with FHH. The biochemical profile of FHH and PHPT may overlap. Our FHH patient with a G557E CaSR mutation illustrates that the differential diagnosis can be difficult in an index case with no family history, (false) positive parathyroid imaging and higher calciuria than expected for FHH. Calcium intake, vitamin D status and bone resorption might have contributed to the Ca/Cr variations over a 13-year clinical follow up. This case thus emphasizes the irreplaceable role of genetic testing of the CaSR gene when clinical evaluation is inconclusive.
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Affiliation(s)
- K Zajíčková
- Institute of Endocrinology, Prague, Czech Republic.
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Chen G, Tang Q, Yu S, Xie Y, Sun J, Li S, Chen L. The biological function of BMAL1 in skeleton development and disorders. Life Sci 2020; 253:117636. [DOI: 10.1016/j.lfs.2020.117636] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/23/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022]
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Fabbri S, Zonefrati R, Galli G, Gronchi G, Perigli G, Borrelli A, Brandi ML. In Vitro Control of Genes Critical for Parathyroid Embryogenesis by Extracellular Calcium. J Endocr Soc 2020; 4:bvaa058. [PMID: 32666007 PMCID: PMC7326476 DOI: 10.1210/jendso/bvaa058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
Background The expression of the parathyroid transcription factors, encoded by the genes GATA3, GCM2, and MAFB, persists after parathyroid morphogenesis. This suggests a role of these genes in the regulatory program that governs parathyroid function in the adult. Indeed, these 3 genes form a transcriptional cascade able to activate PTH gene expression. Materials and Methods Adult adenoma parathyroid tissues were put in primary cell culture to evaluate the messenger ribonucleic acid (mRNA) expression of the PTH gene, of the genes involved in the calcium regulatory signaling pathway (CaSR, GNA11, and AP2S1), and of the 3 genes (GATA3, GCM2, and MAFB) involved in the parathyroid morphogenesis in the presence of different extracellular calcium concentrations from 0.1 mM to 3.0 mM. Aim The aim of the study was to investigate whether different extracellular calcium conditions could control the expression of transcription factors critical for parathyroid embryogenesis. Results The results of the experiments showed that the mRNA expression of GATA3, GCM2, and MAFB genes follows the same response as the PTH gene to extracellular calcium concentrations, with the highest expression at low calcium (0.1 mM) and the lowest at high calcium (3.0 mM). Conversely, the genes involved in the calcium signaling in the parathyroid cells showed a variable response to the extracellular calcium concentrations, with the CaSR and GNA11 genes exhibiting a sensitivity to low calcium concentrations. Conclusions These findings indicate that transcription factors recognized for their role in parathyroid embryogenesis show a response to extracellular calcium later in adulthood that parallels the behavior of the PTH gene.
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Affiliation(s)
- Sergio Fabbri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Roberto Zonefrati
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Gianna Galli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Giorgio Gronchi
- Department of Neuroscience, Psychology, Drug Research & Child Health, University of Florence, Florence, Italy
| | - Giuliano Perigli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Andrea Borrelli
- Bariatric, General Surgery and Metabolic Department, Santa Maria Nuova Hospital, Florence, Italy
| | - Maria Luisa Brandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
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Guo D, He H, Hou T. Purification and characterization of positive allosteric regulatory peptides of calcium sensing receptor (CaSR) from desalted duck egg white. Food Chem 2020; 325:126919. [PMID: 32387992 DOI: 10.1016/j.foodchem.2020.126919] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/21/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023]
Abstract
HPLC-ESI-MS/MS, molecular docking simulation and in situ single-pass intestinal perfusion (SPIP) study were used to identify, select, and confirm the binding affinities between peptides identified from desalted duck egg white peptides (DPs) and calcium sensing receptor (CaSR), respectively. F3 fraction from DPs possessed superior calcium binding activity (P < 0.05), and 16 peptides enriched aromatic amino acids and other 33 peptides were identified. FAE, FNE, INSW, FDPE and NFE presented well binding affinities with CaSR in molecular docking. Additionally, SPIP results showed that NFE and INSW significantly reduced the increased PTH levels by 45.8% and 48.8%, respectively (P < 0.05), and increased calcium percent absorption, calcium absorption rate constant (Ka) and calcium effective permeability (Peff) (P < 0.05), as well as up-regulated mRNA levels of CaSR (P < 0.05). Moreover, NFE and INSW could interact with the VFT domain of CaSR, which exhibited the potential activities in regulation of CaSR.
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Affiliation(s)
- Danjun Guo
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Hui He
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Tao Hou
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
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35
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Yan JF, Qin WP, Xiao BC, Wan QQ, Tay FR, Niu LN, Jiao K. Pathological calcification in osteoarthritis: an outcome or a disease initiator? Biol Rev Camb Philos Soc 2020; 95:960-985. [PMID: 32207559 DOI: 10.1111/brv.12595] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 02/27/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022]
Abstract
In the progression of osteoarthritis, pathological calcification in the affected joint is an important feature. The role of these crystallites in the pathogenesis and progression of osteoarthritis is controversial; it remains unclear whether they act as a disease initiator or are present as a result of joint damage. Recent studies reported that the molecular mechanisms regulating physiological calcification of skeletal tissues are similar to those regulating pathological or ectopic calcification of soft tissues. Pathological calcification takes place when the equilibrium is disrupted. Calcium phosphate crystallites are identified in most affected joints and the presence of these crystallites is closely correlated with the extent of joint destruction. These observations suggest that pathological calcification is most likely to be a disease initiator instead of an outcome of osteoarthritis progression. Inhibiting pathological crystallite deposition within joint tissues therefore represents a potential therapeutic target in the management of osteoarthritis.
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Affiliation(s)
- Jian-Fei Yan
- Department of Oral Mucosal Diseases, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 145 changle xi road, Xi'an, Shaanxi, 710032, China
| | - Wen-Pin Qin
- Department of Oral Mucosal Diseases, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 145 changle xi road, Xi'an, Shaanxi, 710032, China
| | - Bo-Cheng Xiao
- Department of Oral Mucosal Diseases, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 145 changle xi road, Xi'an, Shaanxi, 710032, China
| | - Qian-Qian Wan
- Department of Oral Mucosal Diseases, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 145 changle xi road, Xi'an, Shaanxi, 710032, China
| | - Franklin R Tay
- Department of Oral Mucosal Diseases, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 145 changle xi road, Xi'an, Shaanxi, 710032, China.,Department of Endodontics, College of Graduate Studies, Augusta University, 1430, John Wesley Gilbert Drive, Augusta, GA, 30912, U.S.A
| | - Li-Na Niu
- Department of Oral Mucosal Diseases, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 145 changle xi road, Xi'an, Shaanxi, 710032, China
| | - Kai Jiao
- Department of Oral Mucosal Diseases, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 145 changle xi road, Xi'an, Shaanxi, 710032, China
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Jung H, Akkus O. Diffuse microdamage in bone activates anabolic response by osteoblasts via involvement of voltage-gated calcium channels. J Bone Miner Metab 2020; 38:151-160. [PMID: 31493248 DOI: 10.1007/s00774-019-01042-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/03/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Matrix damage sustained by bone tissue is repaired by the concerted action of bone cells. Previous studies have reported extracellular calcium ([Ca2+]E) efflux to originate from regions of bone undergoing diffuse microdamage termed as "diffuse microdamage-induced calcium efflux" (DMICE). DMICE has also been shown to activate and increase intracellular calcium ([Ca2+]I) signaling in osteoblasts via the involvement of voltage-gated calcium channels (VGCC). Past studies have assessed early stage (< 1 h) responses of osteoblasts to DMICE. The current study tested the hypothesis that DMICE has longer-term sustained effect such that it induces anabolic response of osteoblasts. MATERIALS AND METHODS Osteoblasts derived from mouse calvariae were seeded on devitalized bovine bone wafers. Localized diffuse damage was induced in the vicinity of cells by bending. The response of osteoblasts to DMICE was evaluated by testing gene expression, protein synthesis and mineralized nodule formation. RESULTS Cells on damaged bone wafers showed a significant increase in RUNX2 and Osterix expression compared to non-loaded control. Also, RUNX2 and Osterix expression were suppressed significantly when the cells were treated with bepridil, a non-selective VGCC inhibitor, prior to loading. Significantly higher amounts of osteocalcin and mineralized nodules were synthesized by osteoblasts on diffuse damaged bone wafers, while bepridil treatment resulted in a significant decrease in osteocalcin production and mineralized nodule formation. CONCLUSION In conclusion, this study demonstrated that DMICE activates anabolic responses of osteoblasts through activation of VGCC. Future studies of osteoblast response to DMICE in vivo will help to clarify how bone cells repair diffuse microdamage.
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Affiliation(s)
- Hyungjin Jung
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Ozan Akkus
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
- Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
- Department of Orthopedics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
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Rößler S, Unbehau R, Gemming T, Kruppke B, Wiesmann HP, Hanke T. Calcite incorporated in silica/collagen xerogels mediates calcium release and enhances osteoblast proliferation and differentiation. Sci Rep 2020; 10:118. [PMID: 31924823 PMCID: PMC6954176 DOI: 10.1038/s41598-019-56023-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/05/2019] [Indexed: 11/13/2022] Open
Abstract
Multiphasic silica/collagen xerogels are biomaterials designed for bone regeneration. Biphasic silica/collagen xerogels (B30) and triphasic xerogels (B30H20 or B30CK20) additionally containing hydroxyapatite or calcite were demonstrated to exhibit several structural levels. On the first level, low fibrillar collagen serves as template for silica nanoparticle agglomerates. On second level, this silica-enriched matrix phase is fiber-reinforced by collagen fibrils. In case of hydroxyapatite incorporation in B30H20, resulting xerogels exhibit a hydroxyapatite-enriched phase consisting of hydroxyapatite particle agglomerates next to silica and low fibrillar collagen. Calcite in B30CK20 is incorporated as single non-agglomerated crystal into the silica/collagen matrix phase with embedded collagen fibrils. Both the structure of multiphasic xerogels and the manner of hydroxyapatite or calcite incorporation have an influence on the release of calcium from the xerogels. B30CK20 released a significantly higher amount of calcium into a calcium-free solution over a three-week period than B30H20. In calcium containing incubation media, all xerogels caused a decrease in calcium concentration as a result of their bioactivity, which was superimposed by the calcium release for B30CK20 and B30H20. Proliferation of human bone marrow stromal cells in direct contact to the materials was enhanced on B30CK20 compared to cells on both plain B30 and B30H20.
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Affiliation(s)
- S Rößler
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069, Dresden, Germany.
| | - R Unbehau
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069, Dresden, Germany
- Institute of Materials Research, Helmholtz-Zentrum Geesthacht, Postfach 1160, D-21494, Geesthacht, Germany
| | - T Gemming
- IFW Dresden, P.O. Box 270116, D-01171, Dresden, Germany
| | - B Kruppke
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069, Dresden, Germany
| | - H-P Wiesmann
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069, Dresden, Germany
| | - T Hanke
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069, Dresden, Germany
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38
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Kosiba AA, Wang Y, Chen D, Wong CKC, Gu J, Shi H. The roles of calcium-sensing receptor (CaSR) in heavy metals-induced nephrotoxicity. Life Sci 2019; 242:117183. [PMID: 31874167 DOI: 10.1016/j.lfs.2019.117183] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/15/2019] [Accepted: 12/16/2019] [Indexed: 02/06/2023]
Abstract
The kidney is a vital organ responsible for regulating water, electrolyte and acid-base balance as well as eliminating toxic substances from the blood in the body. Exposure of humans to heavy metals in their natural and occupational environments, foods, water, and drugs has serious implications on the kidney's health. The accumulation of heavy metals in the kidney has been linked to acute or chronic renal injury, kidney stones or even renal cancer, at the expense of expensive treatment options. Therefore, unearthing novel biomarkers and potential therapeutic agents or targets against kidney injury for efficient treatment are imperative. The calcium-sensing receptor (CaSR), a G-protein-coupled receptor (GPCR) is typically expressed in the parathyroid glands and renal tubules. It modulates parathyroid hormone secretion according to the serum calcium (Ca2+) concentration. In the kidney, it modulates electrolyte and water excretion by regulating the function of diverse tubular segments. Notably, CaSR lowers passive and active Ca2+ reabsorption in distal tubules, which facilitates phosphate reabsorption in proximal tubules and stimulates proton and water excretion in collecting ducts. Moreover, at the cellular level, modulation of the CaSR regulates cytosolic Ca2+ levels, reactive oxygen species (ROS) generation and the mitogen-activated protein kinase (MAPK) signaling cascades as well as autophagy and the suppression of apoptosis, an effect predominantly triggered by heavy metals. In this regard, we present a review on the CaSR at the cellular level and its potential as a therapeutic target for the development of new and efficient drugs against heavy metals-induced nephrotoxicity.
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Affiliation(s)
- Anthony A Kosiba
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Yanwei Wang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Dongfeng Chen
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China; Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Chris Kong Chu Wong
- Department of Biology, Hong Kong Baptist University, Hong Kong Special Administrative Region
| | - Jie Gu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
| | - Haifeng Shi
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
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Bretschneider H, Mettelsiefen J, Rentsch C, Gelinsky M, Link HD, Günther K, Lode A, Hofbauer C. Evaluation of topographical and chemical modified TiAl6V4 implant surfaces in a weight‐bearing intramedullary femur model in rabbit. J Biomed Mater Res B Appl Biomater 2019; 108:1117-1128. [PMID: 31407488 DOI: 10.1002/jbm.b.34463] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 07/04/2019] [Accepted: 07/24/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Henriette Bretschneider
- University Centre for Orthopaedics and Trauma SurgeryUniversity Hospital Carl Gustav Carus Dresden Dresden Germany
- Centre for Translational Bone, Joint and Soft Tissue ResearchUniversity Hospital Carl Gustav Carus and Faculty of Medicine of Technische Universität Dresden Dresden Germany
| | - Jan Mettelsiefen
- University Centre for Orthopaedics and Trauma SurgeryUniversity Hospital Carl Gustav Carus Dresden Dresden Germany
| | - Claudia Rentsch
- University Centre for Orthopaedics and Trauma SurgeryUniversity Hospital Carl Gustav Carus Dresden Dresden Germany
- Centre for Translational Bone, Joint and Soft Tissue ResearchUniversity Hospital Carl Gustav Carus and Faculty of Medicine of Technische Universität Dresden Dresden Germany
| | - Michael Gelinsky
- Centre for Translational Bone, Joint and Soft Tissue ResearchUniversity Hospital Carl Gustav Carus and Faculty of Medicine of Technische Universität Dresden Dresden Germany
| | | | - Klaus‐Peter Günther
- University Centre for Orthopaedics and Trauma SurgeryUniversity Hospital Carl Gustav Carus Dresden Dresden Germany
| | - Anja Lode
- Centre for Translational Bone, Joint and Soft Tissue ResearchUniversity Hospital Carl Gustav Carus and Faculty of Medicine of Technische Universität Dresden Dresden Germany
| | - Christine Hofbauer
- University Centre for Orthopaedics and Trauma SurgeryUniversity Hospital Carl Gustav Carus Dresden Dresden Germany
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40
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Biomaterial based treatment of osteoclastic/osteoblastic cell imbalance - Gelatin-modified calcium/strontium phosphates. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 104:109933. [PMID: 31499966 DOI: 10.1016/j.msec.2019.109933] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 06/28/2019] [Accepted: 07/01/2019] [Indexed: 12/11/2022]
Abstract
Osteoporotic bone represents - particularly in case of fractures - difficult conditions for its regeneration. In the present study, the focus was put on a degradable bone substitute material of gelatin-modified calcium and strontium phosphates facing the special demands of osteoporotic bone. The release of strontium ions from the material ought to stimulate osteoblastogenesis either direct by ion release or indirect after material resorption by increased presence and activity of osteoclasts, which subsequently stimulate osteoblasts. A new porous material was produced from calcium phosphate, strontium phosphate and a mixed phase of calcium/strontium phosphate precipitated in presence of gelatin. Initially, ion release was analyzed in standard‑calcium containing (2.0 mM) and low-calcium (0.4 mM) minimum essential medium. The cultivation of human peripheral blood mononuclear cells next to the material led to formation of osteoclast-like cells, able to migrate, fuse, and differentiate. Especially, the mixed gelatin-modified calcium/strontium phosphate allowed osteoclastogenesis as proven morphologically and by real-time quantitative polymerase chain reaction (RT-qPCR). It was precisely this material that led to the best osteoblastic reaction of human bone marrow stromal cells cultured on the material. The investigations of the bone substitute material indicate active involvement in the balance of cells of the bone morphogenetic unit.
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Humbert P, Brennan MÁ, Davison N, Rosset P, Trichet V, Blanchard F, Layrolle P. Immune Modulation by Transplanted Calcium Phosphate Biomaterials and Human Mesenchymal Stromal Cells in Bone Regeneration. Front Immunol 2019; 10:663. [PMID: 31001270 PMCID: PMC6455214 DOI: 10.3389/fimmu.2019.00663] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 03/11/2019] [Indexed: 12/22/2022] Open
Abstract
A wide variety of biomaterials have been developed as both stabilizing structures for the injured bone and inducers of bone neoformation. They differ in chemical composition, shape, porosity, and mechanical properties. The most extensively employed and studied subset of bioceramics are calcium phosphate materials (CaPs). These materials, when transplanted alongside mesenchymal stem cells (MSCs), lead to ectopic (intramuscular and subcutaneous) and orthotopic bone formation in preclinical studies, and effective fracture healing in clinical trials. Human MSC transplantation in pre-clinical and clinical trials reveals very low engraftment in spite of successful clinical outcomes and their therapeutic actions are thought to be primarily through paracrine mechanisms. The beneficial role of transplanted MSC could rely on their strong immunomodulatory effect since, even without long-term engraftment, they have the ability to alter both the innate and adaptive immune response which is critical to facilitate new bone formation. This study presents the current knowledge of the immune response to the implantation of CaP biomaterials alone or in combination with MSC. In particular the central role of monocyte-derived cells, both macrophages and osteoclasts, in MSC-CaP mediated bone formation is emphasized. Biomaterial properties, such as macroporosity and surface microstructure, dictate the host response, and the ultimate bone healing cascade. Understanding intercellular communications throughout the inflammation, its resolution and the bone regeneration phase, is crucial to improve the current therapeutic strategies or develop new approaches.
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Affiliation(s)
- Paul Humbert
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
| | - Meadhbh Á. Brennan
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
- Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States
| | - Noel Davison
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands
- Instructure Labs, B.V., The Hague, Netherlands
| | - Philippe Rosset
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
- Centre Hospitalier Universitaire de Tours, Tours, France
| | - Valérie Trichet
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
| | | | - Pierre Layrolle
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
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Ovejero D, Misof BM, Gafni RI, Dempster D, Zhou H, Klaushofer K, Collins MT, Roschger P. Bone Matrix Mineralization in Patients With Gain-of-Function Calcium-Sensing Receptor Mutations Is Distinctly Different From that in Postsurgical Hypoparathyroidism. J Bone Miner Res 2019; 34:661-668. [PMID: 30496603 DOI: 10.1002/jbmr.3638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/10/2018] [Accepted: 11/12/2018] [Indexed: 12/19/2022]
Abstract
The role of the calcium-sensing receptor (CaSR) as a regulator of parathyroid hormone secretion is well established, but its function in bone is less well defined. In an effort to elucidate the CaSR's skeletal role, bone tissue and material characteristics from patients with autosomal dominant hypocalcemia (ADH), a genetic form of primary hypoparathyroidism caused by CASR gain-of-function mutations, were compared to patients with postsurgical hypoparathyroidism (PSH). Bone structure and formation/resorption indices and mineralization density distribution (BMDD), were examined in transiliac biopsy samples from PSH (n = 13) and ADH (n = 6) patients by histomorphometry and quantitative backscatter electron imaging, respectively. Bone mineral density (BMD by DXA) and biochemical characteristics were measured at the time of the biopsy. Because both study groups comprised children and adults, all measured biopsy parameters and BMD outcomes were converted to Z-scores for comparison. Histomorphometric indices were normal and not different between ADH and PSH, with the exception of mineral apposition rate Z-score, which was higher in the ADH group. Similarly, average BMD Z-scores were normal and not different between ADH and PSH. Significant differences were observed for the BMDD: average Z-scores of mean and typical degree of mineralization (CaMean, CaPeak, respectively) were lower (p = 0.02 and p = 0.03, respectively), whereas the heterogeneity of mineralization (CaWidth) and percentage of lower mineralized areas (CaLow) were increased in ADH versus PSH (p = 0.01 and p = 0.002, respectively). The BMDD outcomes point toward a direct, PTH-independent role of the CaSR in the regulation of bone mineralization. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Diana Ovejero
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.,Musculoskeletal Research group, Hospital del Mar Research Institute, Barcelona, Barcelona (Spain).,National Research Council, Institute of Clinical Physiology, Lecce, Italy
| | - Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risk (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Rachel I Gafni
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - David Dempster
- Columbia University College of Physicians & Surgeons, New York, NY, USA.,Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, USA
| | - Hua Zhou
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, USA
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risk (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Michael T Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risk (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
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Zhang M, Yang H, Wan X, Lu L, Zhang J, Zhang H, Ye T, Liu Q, Xie M, Liu X, Yu S, Guo S, Chang W, Wang M. Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR. J Bone Miner Res 2019; 34:726-738. [PMID: 30496623 PMCID: PMC6482062 DOI: 10.1002/jbmr.3643] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 11/13/2018] [Accepted: 11/14/2018] [Indexed: 01/21/2023]
Abstract
Traumatic joint injuries produce osteoarthritic cartilage manifesting accelerated chondrocyte terminal differentiation and matrix degradation via unknown cellular and molecular mechanisms. Here we report the ability of biomechanical stress to increase expression of the calcium-sensing receptor (CaSR), a pivotal driver of chondrocyte terminal differentiation, in cultured chondrogenic cells subjected to fluid flow shear stress (FFSS) and in chondrocytes of rodent temporomandibular joint (TMJ) cartilage subjected to unilateral anterior cross-bite (UAC). In cultured ATDC5 cells or TMJ chondrocytes, FFSS induced Ca2+ loading and CaSR localization in endoplasmic reticulum (ER), casually accelerating cell differentiation that could be abrogated by emptying ER Ca2+ stores or CaSR knockdown. Likewise, acute chondrocyte-specific Casr knockout (KO) prevented the UAC-induced acceleration of chondrocyte terminal differentiation and matrix degradation in TMJ cartilage in mice. More importantly, local injections of CaSR antagonist, NPS2143, replicated the effects of Casr KO in preventing the development of osteoarthritic phenotypes in TMJ cartilage of the UAC-treated rats. Our study revealed a novel pathological action of CaSR in development of osteoarthritic cartilage due to aberrant mechanical stimuli and supports a therapeutic potential of calcilytics in preventing osteoarthritis in temporomandibular joints by targeting the CaSR. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Mian Zhang
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Hongxu Yang
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Xianghong Wan
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Lei Lu
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Jing Zhang
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Hongyun Zhang
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Tao Ye
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Qian Liu
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Mianjiao Xie
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Xiaodong Liu
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Shibin Yu
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Shaoxiong Guo
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
| | - Wenhan Chang
- Endocrine Research Unit, Department of Veterans Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Meiqing Wang
- State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, China
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Feng R, Ding F, Mi XH, Liu SF, Jiang AL, Liu BH, Lian Y, Shi Q, Wang YJ, Zhang Y. Protective Effects of Ligustroflavone, an Active Compound from Ligustrum lucidum, on Diabetes-Induced Osteoporosis in Mice: A Potential Candidate as Calcium-Sensing Receptor Antagonist. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:457-476. [PMID: 30834778 DOI: 10.1142/s0192415x1950023x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Ligustroflavone is one major compound contained in active fraction from Fructus Ligustri Lucidi (the fruit of Ligustrum lucidum), which could regulate parathyroid hormone (PTH) levels and improve calcium balance by acting on calcium-sensing receptors (CaSR). This study aimed to explore the potency of ligustroflavone as a CaSR antagonist and its protective effects against diabetic osteoporosis in mice. LF interacted well with the allosteric site of CaSR shown by molecular docking analysis, increased PTH release of primary parathyroid gland cells and suppressed extracellular calcium influx in HEK-293 cells. The serum level of PTH attained peak value at 2 h and maintained high during the period of 1 h and 3 h than that before treatment in mice after a single dose of LF. Treatment of diabetic mice with LF inhibited the decrease in calcium level of serum and bone and the enhancement in urinary calcium excretion as well as elevated circulating PTH levels. Trabecular bone mineral density and micro-architecture were markedly improved in diabetic mice upon to LF treatment for 8 weeks. LF reduced CaSR mRNA and protein expression in the kidneys of diabetic mice. Taken together, ligustroflavone could transiently increase PTH level and regulate calcium metabolism as well as prevent osteoporosis in diabetic mice, suggesting that ligustroflavone might be an effective antagonist on CaSR.
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Affiliation(s)
- Rui Feng
- * Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China
| | - Fan Ding
- * Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China
| | - Xiu-Hua Mi
- † Section of Nephrology, Yangpu Traditional Chinese Medicine Hospital, Shanghai 200090, P. R. China
| | - Shu-Fen Liu
- * Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,‡ Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Ai-Ling Jiang
- § School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, P. R. China
| | - Bi-Hui Liu
- ¶ Department of Orthopaedic, Shenzhen Pingle Orthopaedic Hospital, Shenzhen 518000, P. R. China
| | - Yin Lian
- ¶ Department of Orthopaedic, Shenzhen Pingle Orthopaedic Hospital, Shenzhen 518000, P. R. China
| | - Qi Shi
- * Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,‡ Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Yong-Jun Wang
- * Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,‡ Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
| | - Yan Zhang
- * Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P. R. China.,‡ Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, P. R. China
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Chen X, Chen Y, Shen J, Xu J, Zhu L, Gu X, He F, Wang H. Positive modulation of osteogenesis on a titanium oxide surface incorporating strontium oxide: An in vitro and in vivo study. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 99:710-718. [PMID: 30889744 DOI: 10.1016/j.msec.2019.02.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 01/15/2019] [Accepted: 02/04/2019] [Indexed: 02/06/2023]
Abstract
Surface chemistry and topography can determinatively affect the osseointegration of dental implants. Strontium (Sr) has a significant effect on the promotion of bone formation and inhibitation of bone resorption. The emphasis of this study lies on the evaluation of a new surface treatment that aims to improve the early osseointegration of dental implantation both in vitro and in vivo. A hydrothermal method was used to prepare an SrTiO3 incorporation on sandblasted large-grit double acid-etched (SLA) titanium surfaces in SrCl2 solution. The composition and morphology of the SrTiO3 doped surface were analyzed by X-ray diffraction, X-ray photoelectron spectroscopy，and scanning electron microscopy. In addition, the external release figure of Sr was examined by inductively coupled plasma mass spectrometry. The proliferation, adhesion and differentiation of MC3T3-E1 cells on this surface were evaluated in vitro and presented a significant increase in SLA-Sr group compared with that in SLA group. An in vivo study in 24 New Zealand rabbits indicated a remarkable growth in the volume of direct bone-to-implant contact and peri-implant bone in SLA-Sr group, which were compared with SLA group after 3 and 6 weeks, and removal torque tests exhibited a higher torque removal value of SLA-Sr implants. The study gave the result that the biological effect of SLA-Sr implants was significantly superior to that of the SLA implants at the early stage of osseointegration.
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Affiliation(s)
- Xiaoyi Chen
- Department of Oral Implantology, The Affiliated Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Yun Chen
- Department of oral Implantology, Xiamen Stomatology Hospital, Xiamen 361003, China
| | - Jianwei Shen
- Department of Oral Implantology, The Affiliated Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Junhua Xu
- Oral Medical Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Liqin Zhu
- Oral Medical Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Xinhua Gu
- Oral Medical Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Fuming He
- Department of Oral Implantology, The Affiliated Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
| | - Huiming Wang
- Department of Oral Implantology, The Affiliated Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
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Moine L, Rivoira M, Díaz de Barboza G, Pérez A, Tolosa de Talamoni N. Glutathione depleting drugs, antioxidants and intestinal calcium absorption. World J Gastroenterol 2018; 24:4979-4988. [PMID: 30510373 PMCID: PMC6262252 DOI: 10.3748/wjg.v24.i44.4979] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/24/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023] Open
Abstract
Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2+ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K3, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca2+ absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca2+ transport or the paracellular Ca2+ route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca2+ pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca2+ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca2+ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca2+ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.
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Affiliation(s)
- Luciana Moine
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - María Rivoira
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Gabriela Díaz de Barboza
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Adriana Pérez
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Nori Tolosa de Talamoni
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
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47
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Myosins in Osteoclast Formation and Function. Biomolecules 2018; 8:biom8040157. [PMID: 30467281 PMCID: PMC6317158 DOI: 10.3390/biom8040157] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/16/2018] [Accepted: 11/19/2018] [Indexed: 01/16/2023] Open
Abstract
Skeletal quantity and quality are determined by processes of bone modeling and remodeling, which are undertaken by cells that build and resorb bone as they respond to mechanical, hormonal, and other external and internal signals. As the sole bone resorptive cell type, osteoclasts possess a remarkably dynamic actin cytoskeleton that drives their function in this enterprise. Actin rearrangements guide osteoclasts’ capacity for precursor fusion during differentiation, for migration across bone surfaces and sensing of their composition, and for generation of unique actin superstructures required for the resorptive process. In this regard, it is not surprising that myosins, the superfamily of actin-based motor proteins, play key roles in osteoclast physiology. This review briefly summarizes current knowledge of the osteoclast actin cytoskeleton and describes myosins’ roles in osteoclast differentiation, migration, and actin superstructure patterning.
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An S. The emerging role of extracellular Ca
2+
in osteo/odontogenic differentiation and the involvement of intracellular Ca
2+
signaling: From osteoblastic cells to dental pulp cells and odontoblasts. J Cell Physiol 2018; 234:2169-2193. [DOI: 10.1002/jcp.27068] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 06/25/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Shaofeng An
- Department of Operative Dentistry and EndodonticsGuanghua School of Stomatology, Hospital of Stomatology, Sun Yat‐sen UniversityGuangzhou China
- Guangdong Province Key Laboratory of StomatologySun Yat‐Sen UniversityGuangzhou China
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Rößler S, Heinemann C, Kruppke B, Wagner AS, Wenisch S, Wiesmann HP, Hanke T. Manipulation of osteoclastogenesis: Bioactive multiphasic silica/collagen composites and their effects of surface and degradation products. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2018; 93:265-276. [PMID: 30274058 DOI: 10.1016/j.msec.2018.07.049] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 05/12/2018] [Accepted: 07/19/2018] [Indexed: 10/28/2022]
Abstract
The intent of the present study was to demonstrate that multiphasic silica/collagen xerogels are able to manipulate cellular processes. These xerogels were prepared by a sol-gel approach allowing the incorporation of mineral phases. The resulting nanocomposites are designed as biomaterial for bone regeneration. Human osteoclasts derived from peripheral blood mononuclear cells were cultured both indirectly and directly, either in presence of different xerogel types or on their surface, to investigate the factor with the main influence on osteoclastogenesis. To this end, the incorporation of a third phase to silica/collagen xerogels was used to affect osteoclastogenesis. In cell culture, ambient ion conditions controlled by both the degradation products of the xerogel and the bioactivity-dependent ion release and reprecipitation were shown to have the main effect on osteoclast specific enzyme tartrate-resistant acid phosphatase (TRAP) 5b. Late stage of osteoclastogenesis characterized by resorption was strongly dependent on the xerogels composition. Surface chemistry of the xerogels was displayed to play an important role in osteoclast resorption. Biphasic silica/collagen xerogels and triphasic xerogels with calcium carbonate offered widespread resorbed areas, whereas hydroxyapatite containing xerogels showed distinctly reduced resorption. The incorporation of strontium carbonate and phosphate, respectively, as third phase changed TRAP 5b activity dose-dependently and inhibited resorption within 21 days. Quantitative evaluation on osteoclast differentiation was carried out using biochemical methods (TRAP 5b, cathepsin K) and was supported by confocal laser scanning microscopy and scanning electron microscopy (SEM). Qualitative estimation of resorption was carried out by SEM.
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Affiliation(s)
- S Rößler
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069 Dresden, Germany.
| | - C Heinemann
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069 Dresden, Germany
| | - B Kruppke
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069 Dresden, Germany
| | - A S Wagner
- Department of Veterinary Clinical Science, Small Animal Clinic c/o Institute of Veterinary-Anatomy, -Histology and -Embryology, University Giessen, Frankfurter Str. 98, D-35392 Giessen, Germany
| | - S Wenisch
- Department of Veterinary Clinical Science, Small Animal Clinic c/o Institute of Veterinary-Anatomy, -Histology and -Embryology, University Giessen, Frankfurter Str. 98, D-35392 Giessen, Germany
| | - H P Wiesmann
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069 Dresden, Germany
| | - T Hanke
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technical University Dresden, Budapester Str. 27, D-01069 Dresden, Germany
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50
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Kohrt WM, Wherry SJ, Wolfe P, Sherk VD, Wellington T, Swanson CM, Weaver CM, Boxer RS. Maintenance of Serum Ionized Calcium During Exercise Attenuates Parathyroid Hormone and Bone Resorption Responses. J Bone Miner Res 2018; 33:1326-1334. [PMID: 29572961 PMCID: PMC6538281 DOI: 10.1002/jbmr.3428] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 03/08/2018] [Accepted: 03/15/2018] [Indexed: 01/12/2023]
Abstract
Exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and bone resorption. We used a novel intravenous iCa clamp technique to determine whether preventing a decline in serum iCa during exercise prevents increases in PTH and carboxy-terminal collagen crosslinks (CTX). Eleven cycling-trained men (aged 18 to 45 years) underwent two identical 60-min cycling bouts with infusion of Ca gluconate or saline. Blood sampling for iCa, total calcium (tCa), PTH, CTX, and procollagen type 1 amino-terminal propeptide (P1NP) occurred before, during, and for 4 hours after exercise; results are presented as unadjusted and adjusted for plasma volume shifts (denoted with subscript ADJ). iCa decreased during exercise with saline infusion (p = 0.01 at 60 min) and this was prevented by Ca infusion (interaction, p < 0.007); there were abrupt decreases in Ca content (iCaADJ and tCaADJ ) in the first 15 min of exercise under both conditions. PTH and CTX were increased at the end of exercise (both p < 0.01) on the saline day, and markedly attenuated (-65% and -71%; both p < 0.001) by Ca. CTX remained elevated for 4 hours after exercise on the saline day (p < 0.001), despite the return of PTH to baseline by 1 hour after exercise. P1NP increased in response to exercise (p < 0.001), with no difference between conditions, but the increase in P1NPADJ was not significant. Results for PTHADJ and CTXADJ were similar to unadjusted results. These findings demonstrate that bone resorption is stimulated early in exercise to defend serum iCa. Vascular Ca content decreased early in exercise, but neither the reason why this occurred, nor the fate of Ca, are known. The results suggest that the exercise-induced increase in PTH had an acute catabolic effect on bone. Future research should determine whether the increase in PTH generates an anabolic response that occurs more than 4 hours after exercise. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Wendy M Kohrt
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Eastern Colorado Geriatric Research, Education, and Clinical Center, VA Eastern Colorado Healthcare System, Denver, CO, USA
| | - Sarah J Wherry
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Pamela Wolfe
- Department of Preventive Medicine and Biometrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Vanessa D Sherk
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Toby Wellington
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Christine M Swanson
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Connie M Weaver
- Department of Nutrition Science, College of Health and Human Sciences, Purdue University, West Lafayette, IN, USA
| | - Rebecca S Boxer
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Eastern Colorado Geriatric Research, Education, and Clinical Center, VA Eastern Colorado Healthcare System, Denver, CO, USA
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