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Yu M, Qin K, Fan J, Zhao G, Zhao P, Zeng W, Chen C, Wang A, Wang Y, Zhong J, Zhu Y, Wagstaff W, Haydon RC, Luu HH, Ho S, Lee MJ, Strelzow J, Reid RR, He TC. The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities. Genes Dis 2024; 11:101026. [PMID: 38292186 PMCID: PMC10825312 DOI: 10.1016/j.gendis.2023.04.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 02/01/2024] Open
Abstract
The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
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Affiliation(s)
- Michael Yu
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Kevin Qin
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Jiamin Zhong
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yi Zhu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin Ho
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael J. Lee
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
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Qin K, Yu M, Fan J, Wang H, Zhao P, Zhao G, Zeng W, Chen C, Wang Y, Wang A, Schwartz Z, Hong J, Song L, Wagstaff W, Haydon RC, Luu HH, Ho SH, Strelzow J, Reid RR, He TC, Shi LL. Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk. Genes Dis 2024; 11:103-134. [PMID: 37588235 PMCID: PMC10425814 DOI: 10.1016/j.gendis.2023.01.030] [Citation(s) in RCA: 55] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/01/2022] [Accepted: 01/29/2023] [Indexed: 08/18/2023] Open
Abstract
Wnt signaling plays a major role in regulating cell proliferation and differentiation. The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either through β-catenin in the canonical pathway or through a series of other proteins in the noncanonical pathway. Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body, establishing the complex interplay between Wnt signaling and other signaling pathways. This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes. Dysregulation of this system has been implicated in many diseases affecting a wide array of organ systems, including cancer and embryological defects, and can even cause embryonic lethality. The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments. However, both stimulatory and inhibitory treatments come with potential risks that need to be addressed. This review synthesized much of the current knowledge on the Wnt signaling pathway, beginning with the history of Wnt signaling. It thoroughly described the different variants of Wnt signaling, including canonical, noncanonical Wnt/PCP, and the noncanonical Wnt/Ca2+ pathway. Further description involved each of its components and their involvement in other cellular processes. Finally, this review explained the various other pathways and processes that crosstalk with Wnt signaling.
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Affiliation(s)
- Kevin Qin
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael Yu
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Hongwei Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Departments of Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Departments of Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Interventional Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Zander Schwartz
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- School of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Jeffrey Hong
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Lily Song
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin H. Ho
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Lewis L. Shi
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
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Sun T, Yu X. FGF23 Actions in CKD-MBD and other Organs During CKD. Curr Med Chem 2023; 30:841-856. [PMID: 35761503 DOI: 10.2174/0929867329666220627122733] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/26/2022] [Accepted: 04/12/2022] [Indexed: 02/08/2023]
Abstract
Fibroblast growth factor 23 (FGF23) is a new endocrine product discovered in the past decade. In addition to being related to bone diseases, it has also been found to be related to kidney metabolism and parathyroid metabolism, especially as a biomarker and a key factor to be used in kidney diseases. FGF23 is upregulated as early as the second and third stages of chronic kidney disease (CKD) in response to relative phosphorus overload. The early rise of FGF23 has a protective effect on the body and is essential for maintaining phosphate balance. However, with the decline in renal function, eGFR (estimated glomerular filtration rate) declines, and the phosphorus excretion effect caused by FGF23 is weakened. It eventually leads to a variety of complications, such as bone disease (Chronic Kidney Disease-Mineral and Bone Metabolism Disorder), vascular calcification (VC), and more. Monoclonal antibodies against FGF23 are currently used to treat genetic diseases with increased FGF23. CKD is also a state of increased FGF23. This article reviews the current role of FGF23 in CKD and discusses the crosstalk between various organs under CKD conditions and FGF23. Studying the effect of hyperphosphatemia on different organs of CKD is important. The prospect of FGF23 for therapy is also discussed.
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Affiliation(s)
- Ting Sun
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, Rare Disease Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, Rare Disease Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
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Dai Z, Zhu R, Sheng Z, Qin G, Luo X, Qin Q, Song C, Li L, Jin P, Yang G, Cheng Y, Peng D, Zou C, Wang L, Shentu J, Zhang Q, Zhang Z, Yan X, Fang P, Yan Q, Yang L, Fan X, Liu W, Wu B, Cui R, Wu X, Xie Y, Shu C, Shen K, Wei W, Lu W, Chen H, Zhou Z. Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial. Front Endocrinol (Lausanne) 2023; 14:1168757. [PMID: 37091850 PMCID: PMC10116854 DOI: 10.3389/fendo.2023.1168757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 03/22/2023] [Indexed: 04/25/2023] Open
Abstract
SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (Cmax,ss and AUC0-tau,ss) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (β-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.
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Affiliation(s)
- Zhijie Dai
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ronghua Zhu
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhifeng Sheng
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Metabolism and Endocrinology, and Health Management Center, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Guijun Qin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xianghang Luo
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, China
| | - Qun Qin
- National Agency for Clinical Trial of Medicines, Xiangya Hospital of Central South University, Changsha, China
| | - Chunli Song
- Orthopedics Department, Peking University Third Hospital, Beijing, China
| | - Liping Li
- Endocrine Department, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Ping Jin
- Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Guoping Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yanxiang Cheng
- Department of Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Danhong Peng
- Department of Gynaecology and Obstetrics, Zhongda Hospital Southeast University, Nanjing, China
| | - Chong Zou
- Department of Clinical Pharmacology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Lijuan Wang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Jianzhong Shentu
- Clinical Pharmacy, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Qin Zhang
- Department of Geriatrics, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhe Zhang
- Endocrinology and Metabolism, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiang Yan
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Pingfei Fang
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qiangyong Yan
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lingfeng Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiao Fan
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wei Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Bo Wu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Rongrong Cui
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiyu Wu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yuting Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chang Shu
- Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Kai Shen
- Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Wenhua Wei
- Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Wei Lu
- Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Hong Chen
- Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Zhiguang Zhou,
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Zhang J, Tong Y, Liu Y, Lin M, Xiao Y, Liu C. Mechanical loading attenuated negative effects of nucleotide analogue reverse-transcriptase inhibitor TDF on bone repair via Wnt/β-catenin pathway. Bone 2022; 161:116449. [PMID: 35605959 DOI: 10.1016/j.bone.2022.116449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 05/15/2022] [Accepted: 05/17/2022] [Indexed: 12/19/2022]
Abstract
The nucleotide analog reverse-transcriptase inhibitor, tenofovir disoproxil fumarate (TDF), is widely used to treat hepatitis B virus (HBV) and human immunodeficiency virus infection (HIV). However, long-term TDF usage is associated with an increased incidence of bone loss, osteoporosis, fractures, and other adverse reactions. We investigated the effect of chronic TDF use on bone homeostasis and defect repair in mice. In vitro, TDF inhibited osteogenic differentiation and mineralization in MC3T3-E1 cells. In vivo, 8-week-old C57BL/6 female mice were treated with TDF for 38 days to simulate chronic medication. Four-point bending test and μCT showed reduced bone biomechanical properties and microarchitecture in long bones. To investigate the effects of TDF on bone defect repair, we utilized a bilateral tibial monocortical defect model. μCT showed that TDF reduced new bone mineral tissue and bone mineral density (BMD) in the defect. To verify whether mechanical stimulation may be a useful treatment to counteract the negative bone effects of TDF, controlled dynamic mechanical loading was applied to the whole tibia during the matrix deposition phase on post-surgery days (PSDs) 5 to 8. Second harmonic generation (SHG) of collagen fibers and μCT showed that the reduction of new bone volume and bone mineral density caused by TDF was reversed by mechanical loading in the defect. Immunofluorescent deep tissue imaging showed that chronic TDF treatment reduced the number of osteogenic cells and the volume of new vessels. In addition, chronic TDF treatment inhibited the expressions of periostin and β-catenin, but increased the expression of sclerostin. Both negative effects were reversed by mechanical loading. Our study provides strong evidence that chronic use of TDF exerts direct and inhibitory impacts on bone repair, but appropriate mechanical loading could reverse these adverse effects.
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Affiliation(s)
- Jianing Zhang
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Yanrong Tong
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Yang Liu
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Minmin Lin
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Yao Xiao
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Chao Liu
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
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Aryana IGPS, Rini SS, Soejono CH. The Importance of on Sclerostin as Bone-Muscle Mediator Crosstalk. Ann Geriatr Med Res 2022; 26:72-82. [PMID: 35599457 PMCID: PMC9271392 DOI: 10.4235/agmr.22.0036] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/14/2022] [Indexed: 11/12/2022] Open
Abstract
Loss of bone and muscle mass is a frequent aging condition and has become a growing public health problem. The term “osteosarcopenia” denotes close links between bone and muscle. Mechanical exercise was once thought to be the only mechanism of crosstalk between muscle and bone. Sclerostin is an important player in the process of unloading-induced bone loss and plays an important role in mechanotransduction in the bone. Furthermore, bones and muscles are categorized as endocrine organs because they produce hormone-like substances, resulting in “bone-muscle crosstalk.” Sclerostin, an inhibitor of bone development, has recently been shown to play a role in myogenesis. This review discusses the importance of sclerostin in bone-muscle crosstalk.
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Affiliation(s)
- I Gusti Putu Suka Aryana
- Division of Geriatric Medicine, Department of Internal Medicine, Sanglah Hospital–Faculty of Medicine Udayana University, Bali, Indonesia
- Corresponding Author: I Gusti Putu Suka Aryana, MD, PhD Division of Geriatrics, Department of Internal Medicine, Sanglah Hospital–Faculty of Medicine Udayana University, Jl. Pulau Tarakan No.1, Denpasar 80114, Bali, Indonesia E-mail:
| | - Sandra Surya Rini
- Department of Internal Medicine, North Lombok Regional Hospital, West Nusa Tenggara, Indonesia
| | - Czeresna Heriawan Soejono
- Division of Geriatric Medicine, Department of Internal Medicine, Cipto Mangunkusumo Hospital–Faculty of Medicine University of Indonesia, Jakarta, Indonesia
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Yadav AM, Bagade MM, Ghumnani S, Raman S, Saha B, Kubatzky KF, Ashma R. The phytochemical plumbagin reciprocally modulates osteoblasts and osteoclasts. Biol Chem 2021; 403:211-229. [PMID: 34882360 DOI: 10.1515/hsz-2021-0290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 11/08/2021] [Indexed: 12/28/2022]
Abstract
Bone metabolism is essential for maintaining bone mineral density and bone strength through a balance between bone formation and bone resorption. Bone formation is associated with osteoblast activity whereas bone resorption is linked to osteoclast differentiation. Osteoblast progenitors give rise to the formation of mature osteoblasts whereas monocytes are the precursors for multi-nucleated osteoclasts. Chronic inflammation, auto-inflammation, hormonal changes or adiposity have the potential to disturb the balance between bone formation and bone loss. Several plant-derived components are described to modulate bone metabolism and alleviate osteoporosis by enhancing bone formation and inhibiting bone resorption. The plant-derived naphthoquinone plumbagin is a bioactive compound that can be isolated from the roots of the Plumbago genus. It has been used as traditional medicine for treating infectious diseases, rheumatoid arthritis and dermatological diseases. Reportedly, plumbagin exerts its biological activities primarily through induction of reactive oxygen species and triggers osteoblast-mediated bone formation. It is plausible that plumbagin's reciprocal actions - inhibiting or inducing death in osteoclasts but promoting survival or growth of osteoblasts - are a function of the synergy with bone-metabolizing hormones calcitonin, Parathormone and vitamin D. Herein, we develop a framework for plausible molecular modus operandi of plumbagin in bone metabolism.
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Affiliation(s)
- Avinash M Yadav
- Department of Zoology, Savitribai Phule Pune University, Pune 411007, Maharashtra, India
| | - Manali M Bagade
- Department of Zoology, Savitribai Phule Pune University, Pune 411007, Maharashtra, India
| | - Soni Ghumnani
- Department of Zoology, Savitribai Phule Pune University, Pune 411007, Maharashtra, India
| | - Sujatha Raman
- Center for Complementary and Integrative Health (CCIH), Interdisciplinary School of Health Sciences (ISHS), Savitribai Phule Pune University, Pune 411007, Maharashtra, India
| | - Bhaskar Saha
- National Center for Cell Science, Pune-411007, Maharashtra, India
| | - Katharina F Kubatzky
- Zentrum für Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany
| | - Richa Ashma
- Department of Zoology, Savitribai Phule Pune University, Pune 411007, Maharashtra, India
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8
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Dai Z, Fang P, Yan X, Zhu R, Feng Q, Yan Q, Yang L, Fan X, Xie Y, Zhuang L, Feng S, Liu Y, Zhong S, Yang Z, Sheng Z, Zhou Z. Single Dose of SHR-1222, a Sclerostin Monoclonal Antibody, in Healthy Men and Postmenopausal Women With Low Bone Mass: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation, Phase I Study. Front Pharmacol 2021; 12:770073. [PMID: 34744750 PMCID: PMC8564351 DOI: 10.3389/fphar.2021.770073] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/07/2021] [Indexed: 11/17/2022] Open
Abstract
SHR-1222 is a humanized monoclonal antibody targeting sclerostin and has the potential to promote bone formation and reduce bone resorption. This study was aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1222 in healthy men and postmenopausal women with low bone mass (BMD). It was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Subjects received SHR-1222 at 50, 100, 200, 300, and 400 mg sequentially or matching placebo subcutaneously. Totally, 50 subjects with low BMD were enrolled and randomly assigned; 10 received placebo and 40 received SHR-1222 (50 mg, n = 4; 100, 200, 300, or 400 mg, n = 9). The most common adverse events that occurred at least 10% higher in subjects with SHR-1222 treatment than those with placebo were decreased blood calcium, blood urine present, increased blood cholesterol, electrocardiogram T wave abnormal, urinary tract infection, increased blood pressure diastolic, and positive bacterial test. All the above adverse events were mild in severity and well resolved except one of increased blood cholesterol in a subject lost to follow-up. The serum SHR-1222 concentration increased in a dose-dependent manner. Administration of SHR-1222 upregulated the bone-formation markers N-terminal propeptide of type 1 procollagen, osteocalcin, and bone-specific alkaline phosphatase, while downregulated the bone-resorption marker β-C-telopeptide. The BMD at the lumbar spine notably rose after a single dose of SHR-1222. The largest increase occurred in the 400 mg cohort (3.8, 6.7, and 6.1% on day 29, 57, and 85, respectively; compared with 1.4, 0.8, and 1.0% in the placebo group). Although 10.0% of subjects receiving SHR-1222 tested positive for anti–SHR-1222 antibodies, no obvious effects of antibody formation were found on pharmacokinetics. Overall, SHR-1222 was well tolerated at doses from 50 to 400 mg and is a promising new remedy for osteoporosis. Clinical Trial Registration:http://www.clinicaltrials.gov, NCT03870100.
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Affiliation(s)
- Zhijie Dai
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Pingfei Fang
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiang Yan
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ronghua Zhu
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qiong Feng
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qiangyong Yan
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lingfeng Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiao Fan
- Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yuting Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lihong Zhuang
- Department of Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China
| | - Sheng Feng
- Department of Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China
| | - Yantao Liu
- Department of Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China
| | - Sheng Zhong
- Department of Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China
| | - Zeyu Yang
- Department of Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China
| | - Zhifeng Sheng
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Metabolism and Endocrinology, and Health Management Center, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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9
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Gao Y, Chen Z, Yang C, Zhong D. Liquid chromatography-mass spectrometry method for the quantification of an anti-sclerostin monoclonal antibody in cynomolgus monkey serum. J Pharm Anal 2021; 11:472-479. [PMID: 34513123 PMCID: PMC8424367 DOI: 10.1016/j.jpha.2020.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/01/2020] [Accepted: 08/09/2020] [Indexed: 11/20/2022] Open
Abstract
Liquid chromatography tandem mass spectrometry (LC-MS/MS) has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules, due to its rapid method development and high accuracy. In this study, we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody (SHR-1222) in cynomolgus monkey serum, and compared it to a previous electrochemiluminescence method. The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion. The surrogate peptide was carefully selected by investigating its uniqueness, stability and MS response. The quantitative range of the proposed method was 2.00-500 μg/mL, and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum. It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods (ratios of drug exposure, 0.8-1.0). Notably, two monkeys in the 60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample. Combining the high-level anti-drug antibodies (ADAs) in these samples and the consistent quantitative results of the two methods, we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform. Taken together, we successfully developed an accurate, efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples, which could serve as a powerful tool to improve the preclinical development of antibody drugs.
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Affiliation(s)
- Yuxiong Gao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhendong Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Changyong Yang
- Preclinical Department, Hengrui Medicine Co., Ltd., Lianyungang, Jiangsu Province, 222047, China
| | - Dafang Zhong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
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10
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Abstract
Glucocorticoids are widely prescribed to treat various allergic and autoimmune diseases; however, long-term use results in glucocorticoid-induced osteoporosis, characterized by consistent changes in bone remodeling with decreased bone formation as well as increased bone resorption. Not only bone mass but also bone quality decrease, resulting in an increased incidence of fractures. The primary role of autophagy is to clear up damaged cellular components such as long-lived proteins and organelles, thus participating in the conservation of different cells. Apoptosis is the physiological death of cells, and plays a crucial role in the stability of the environment inside a tissue. Available basic and clinical studies indicate that autophagy and apoptosis induced by glucocorticoids can regulate bone metabolism through complex mechanisms. In this review, we summarize the relationship between apoptosis, autophagy and bone metabolism related to glucocorticoids, providing a theoretical basis for therapeutic targets to rescue bone mass and bone quality in glucocorticoid-induced osteoporosis.
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11
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Abstract
Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms that are independent of the bone forming osteoblasts and bone-resorbing osteoclasts. Osteocytes communicate with osteoclasts and osteoblasts via distinct signaling molecules that include the RankL/OPG axis and the Sost/Dkk1/Wnt axis, among others. Osteocytes also extend their influence beyond the local bone environment by functioning as an endocrine cell that controls phosphate reabsorption in the kidney, insulin secretion in the pancreas, and skeletal muscle function. These cells are also finely tuned sensors of mechanical stimulation to coordinate with effector cells to adjust bone mass, size, and shape to conform to mechanical demands.
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Affiliation(s)
- Alexander G Robling
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
| | - Lynda F Bonewald
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
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12
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Lim KE, Hoggatt AM, Bullock WA, Horan DJ, Yokota H, Pavalko FM, Robling AG. Pten deletion in Dmp1-expressing cells does not rescue the osteopenic effects of Wnt/β-catenin suppression. J Cell Physiol 2020; 235:9785-9794. [PMID: 32529635 DOI: 10.1002/jcp.29792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 05/01/2020] [Accepted: 05/02/2020] [Indexed: 11/06/2022]
Abstract
Skeletal homeostasis is sensitive to perturbations in Wnt signaling. Beyond its role in the bone, Wnt is a major target for pharmaceutical inhibition in a wide range of diseases, most notably cancers. Numerous clinical trials for Wnt-based candidates are currently underway, and Wnt inhibitors will likely soon be approved for clinical use. Given the bone-suppressive effects accompanying Wnt inhibition, there is a need to expose alternate pathways/molecules that can be targeted to counter the deleterious effects of Wnt inhibition on bone properties. Activation of the Pi3k/Akt pathway via Pten deletion is one possible osteoanabolic pathway to exploit. We investigated whether the osteopenic effects of β-catenin deletion from bone cells could be rescued by Pten deletion in the same cells. Mice carrying floxed alleles for Pten and β-catenin were bred to Dmp1-Cre mice to delete Pten alone, β-catenin alone, or both genes from the late-stage osteoblast/osteocyte population. The mice were assessed for bone mass, density, strength, and formation parameters to evaluate the potential rescue effect of Pten deletion in Wnt-impaired mice. Pten deletion resulted in high bone mass and β-catenin deletion resulted in low bone mass. Compound mutants had bone properties similar to β-catenin mutant mice, or surprisingly in some assays, were further compromised beyond β-catenin mutants. Pten inhibition, or one of its downstream nodes, is unlikely to protect against the bone-wasting effects of Wnt/βcat inhibition. Other avenues for preserving bone mass in the presence of Wnt inhibition should be explored to alleviate the skeletal side effects of Wnt inhibitor-based therapies.
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Affiliation(s)
- Kyung-Eun Lim
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| | - April M Hoggatt
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Whitney A Bullock
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Daniel J Horan
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Hiroki Yokota
- Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.,Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana
| | - Frederick M Pavalko
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Center for Musculoskeletal Health, Indianapolis, Indiana
| | - Alexander G Robling
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Center for Musculoskeletal Health, Indianapolis, Indiana.,Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana.,Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
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13
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Galluccio F, Allam AES, Perdisa F, Chang KV. Short-Term Teriparatide for Bone Marrow Edema Secondary to Complex Regional Pain Syndrome: Case Reports on Efficacy After Two Years of Follow-Up. Cureus 2020; 12:e8119. [PMID: 32426199 PMCID: PMC7228803 DOI: 10.7759/cureus.8119] [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] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Bone marrow edema secondary to chronic pain syndrome after knee trauma is a disabling condition that presents with localized pain, allodynia, edema, decreased range of motion and osteopenia. The management includes a variety of medications and rehabilitation. The treatment of refractory diseases is challenging for most physicians. We present two cases of refractory bone edema secondary to complex regional pain syndrome that were successfully treated with a short-term regimen of teriparatide (TPT), a biosynthetic analogue (PTH 1-34) of the human parathormone. The rapid and sustained pain reduction with recovery of knee function for two years following administration of TPT demonstrated its potential for the treatment of bone edema due to complex regional pain syndrome.
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Affiliation(s)
- Felice Galluccio
- Rheumatology - Experimental and Clinical Medicine, University of Florence, Florence, ITA
| | - Abdallah El Sayed Allam
- Physical Medicine, Rheumatology and Rehabilitation, Tanta University Hospitals & Faculty of Medicine, Tanta University, Tanta, EGY
| | - Francesco Perdisa
- Hip and Knee Replacement, IRCCS Istituto Ortopedico Rizzoli, Bologna, ITA
| | - Ke-Vin Chang
- Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei, TWN
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14
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Wang T, He H, Liu S, Jia C, Fan Z, Zhong C, Yu J, Liu H, He C. Autophagy: A Promising Target for Age-related Osteoporosis. Curr Drug Targets 2020; 20:354-365. [PMID: 29943700 DOI: 10.2174/1389450119666180626120852] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 06/07/2018] [Accepted: 06/18/2018] [Indexed: 02/08/2023]
Abstract
Autophagy is a process the primary role of which is to clear up damaged cellular components such as long-lived proteins and organelles, thus participating in the conservation of different cells. Osteoporosis associated with aging is characterized by consistent changes in bone metabolism with suppression of bone formation as well as increased bone resorption. In advanced age, not only bone mass but also bone strength decrease in both sexes, resulting in an increased incidence of fractures. Clinical and animal experiments reveal that age-related bone loss is associated with many factors such as accumulation of autophagy, increased levels of reactive oxygen species, sex hormone deficiency, and high levels of endogenous glucocorticoids. Available basic and clinical studies indicate that age-associated factors can regulate autophagy. Those factors play important roles in bone remodeling and contribute to decreased bone mass and bone strength with aging. In this review, we summarize the mechanisms involved in bone metabolism related to aging and autophagy, supplying a theory for therapeutic targets to rescue bone mass and bone strength in older people.
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Affiliation(s)
- Tiantian Wang
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Hongchen He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shaxin Liu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chengsen Jia
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Ziyan Fan
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Can Zhong
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Jiadan Yu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Honghong Liu
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chengqi He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
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15
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Twist1 Inactivation in Dmp1-Expressing Cells Increases Bone Mass but Does Not Affect the Anabolic Response to Sclerostin Neutralization. Int J Mol Sci 2019; 20:ijms20184427. [PMID: 31505764 PMCID: PMC6769567 DOI: 10.3390/ijms20184427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 08/28/2019] [Accepted: 08/31/2019] [Indexed: 01/21/2023] Open
Abstract
Wnt signaling plays a major role in bone metabolism. Advances in our understanding of secreted regulators of Wnt have yielded several therapeutic targets to stimulate osteoanabolism—the most promising of which is the Wnt inhibitor sclerostin. Sclerostin antibody recently gained approval for clinical use to treat osteoporosis, but the biology surrounding sclerostin antagonism is still incompletely understood. Numerous factors regulate the efficacy of sclerostin inhibition on bone formation, a process known as self-regulation. In previous communications we reported that the basic helix-loop-helix transcription factor Twist1—a gene know to regulate skeletal development—is highly upregulated among the osteocyte cell population in mice treated with sclerostin antibody. In this communication, we tested the hypothesis that preventing Twist1 upregulation by deletion of Twist1 from late-stage osteoblasts and osteocytes would increase the efficacy of sclerostin antibody treatment, since Twist1 is known to restrain osteoblast activity in many models. Twist1-floxed loss-of-function mice were crossed to the Dmp1-Cre driver to delete Twist1 in Dmp1-expressing cells. Conditional Twist1 deletion was associated with a mild but significant increase in bone mass, as assessed by dual energy x-ray absorptiometry (DXA) and microCT (µCT) for many endpoints in both male and female mice. Biomechanical properties of the femur were not affected by conditional mutation of Twist1. Sclerostin antibody improved all bone properties significantly, regardless of Twist1 status, sex, or endpoint examined. No interactions were detected when Twist1 status and antibody treatment were examined together, suggesting that Twist1 upregulation in the osteocyte population is not an endogenous mechanism that restrains the osteoanabolic effect of sclerostin antibody treatment. In summary, Twist1 inhibition in the late-stage osteoblast/osteocyte increases bone mass but does not affect the anabolic response to sclerostin neutralization.
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16
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Li F, Cain JD, Tombran-Tink J, Niyibizi C. Pigment epithelium-derived factor (PEDF) reduced expression and synthesis of SOST/sclerostin in bone explant cultures: implication of PEDF-osteocyte gene regulation in vivo. J Bone Miner Metab 2019; 37:773-779. [PMID: 30607618 DOI: 10.1007/s00774-018-0982-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 11/21/2018] [Indexed: 12/13/2022]
Abstract
Mutations in Serpinf1 gene which encodes pigment epithelium-derived factor (PEDF) lead to osteogenesis imperfecta type VI whose hallmark is defective matrix mineralization. We reported previously that PEDF reduced expression and synthesis of Sost/Sclerostin as well as other osteocytes genes encoding proteins that regulate matrix mineralization [1]. To determine whether PEDF had an effect on osteocyte gene expression in bone, we used bone explant cultures. First, osteocytes were isolated from surgical waste of bone fragments obtained from patients undergoing elective foot surgeries under approved IRB protocol by Penn State College of Medicine IRB committee. Primary osteocytes treated with PEDF reduced expression and synthesis of Sost/Sclerostin and matrix phosphoglycoprotein (MEPE) as well as dentin matrix protein (DMP-1). On the whole, PEDF reduced osteocyte protein synthesis by 50% and by 75% on mRNA levels. For bone explants, following collagenase digestion, bone fragments were incubated in alpha-MEM supplemented with 250 ng/ml of PEDF or BSA. After 7 days of incubation in a medium supplemented with PEDF, analysis of mRNA by PCR and protein by western blotting of encoded osteocyte proteins showed reduced Sclerostin synthesis by 39% and MEPE by 27% when compared to fragments incubated in medium supplemented with BSA. mRNA expression levels of osteocytes in bone fragments treated with PEDF were reduced by 50% for both SOST and MEPE when compared to BSA-treated bone fragments. Taken together, the data indicate that PEDF has an effect on osteocyte gene expression in bone and encourage further studies to examine effect of PEDF on bone formation indices in animal models and its effect on osteocyte gene expression in vivo following PEDF administration.
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Affiliation(s)
- Feng Li
- Department of Orthopaedics and Rehabilitation H089, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033, USA
| | - Jarrett D Cain
- Department of Orthopaedics and Rehabilitation H089, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033, USA
| | - Joyce Tombran-Tink
- Department of Orthopaedics and Rehabilitation H089, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033, USA
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Christopher Niyibizi
- Department of Orthopaedics and Rehabilitation H089, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
- Biochemistry and Molecular Biology, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
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17
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Choy MHV, Wong RMY, Chow SKH, Li MC, Chim YN, Li TK, Ho WT, Cheng JCY, Cheung WH. How much do we know about the role of osteocytes in different phases of fracture healing? A systematic review. J Orthop Translat 2019; 21:111-121. [PMID: 32309136 PMCID: PMC7152791 DOI: 10.1016/j.jot.2019.07.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 05/22/2019] [Accepted: 07/15/2019] [Indexed: 12/21/2022] Open
Abstract
Background Although emerging studies have provided evidence that osteocytes are actively involved in fracture healing, there is a general lack of a detailed understanding of the mechanistic pathway, cellular events and expression of markers at different phases of healing. Methods This systematic review describes the role of osteocytes in fracture healing from early to late phase. Literature search was performed in PubMed and Embase. Original animal and clinical studies with available English full-text were included. Information was retrieved from the selected studies. Results A total of 23 articles were selected in this systematic review. Most of the studies investigated changes of various genes and proteins expression patterns related to osteocytes. Several studies have described a constant expression of osteocyte-specific marker genes throughout the fracture healing cascade followed by decline phase with the progress of healing, denoting the important physiological role of the osteocyte and the osteocyte lacuno-canalicular network in fracture healing. The reports of various markers suggested that osteocytes could trigger coordinated bone healing responses from cell death and expression of proinflammatory markers cyclooxygenase-2 and interleukin 6 at early phase of fracture healing. This is followed by the expression of growth factors bone morphogenetic protein-2 and cysteine-rich angiogenic inducer 61 that matched with the neo-angiogenesis, chondrogenesis and callus formation during the intermediate phase. Tightly controlled regulation of osteocyte-specific markers E11/Podoplanin (E11), dentin matrix protein 1 and sclerostin modulate and promote osteogenesis, mineralisation and remodelling across different phases of fracture healing. Stabilised fixation was associated with the finding of higher number of osteocytes with little detectable bone morphogenetic proteins expressions in osteocytes. Sclerostin-antibody treatment was found to result in improvement in bone mass, bone strength and mineralisation. Conclusion To further illustrate the function of osteocytes, additional longitudinal studies with appropriate clinically relevant model to study osteoporotic fractures are crucial. Future investigations on the morphological changes of osteocyte lacuno-canalicular network during healing, osteocyte-mediated signalling molecules in the transforming growth factor-beta-Smad3 pathway, perilacunar remodelling, type of fixation and putative biomarkers to monitor fracture healing are highly desirable to bridge the current gaps of knowledge.The translational potential of this article: This systematic review provides an up-to-date chronological overview and highlights the osteocyte-regulated events at gene, protein, cellular and tissue levels throughout the fracture healing cascade, with the hope of informing and developing potential new therapeutic strategies that could improve the timing and quality of fracture healing in the future.
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Affiliation(s)
- Man Huen Victoria Choy
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
| | - Ronald Man Yeung Wong
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
| | - Simon Kwoon Ho Chow
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, PR China
| | - Meng Chen Li
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
| | - Yu Ning Chim
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
| | - Tsz Kiu Li
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
| | - Wing Tung Ho
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
| | - Jack Chun Yiu Cheng
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
| | - Wing Ho Cheung
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, PR China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, PR China
- Corresponding author. Department of Orthopaedics and Traumatology, 5/F, Lui Che Woo Clinical Sciences Building, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, PR China.
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18
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Holdsworth G, Roberts SJ, Ke HZ. Novel actions of sclerostin on bone. J Mol Endocrinol 2019; 62:R167-R185. [PMID: 30532996 DOI: 10.1530/jme-18-0176] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/17/2018] [Indexed: 12/11/2022]
Abstract
The discovery that two rare autosomal recessive high bone mass conditions were caused by the loss of sclerostin expression prompted studies into its role in bone homeostasis. In this article, we aim to bring together the wealth of information relating to sclerostin in bone though discussion of rare human disorders in which sclerostin is reduced or absent, sclerostin manipulation via genetic approaches and treatment with antibodies that neutralise sclerostin in animal models and in human. Together, these findings demonstrate the importance of sclerostin as a regulator of bone homeostasis and provide valuable insights into its biological mechanism of action. We summarise the current state of knowledge in the field, including the current understanding of the direct effects of sclerostin on the canonical WNT signalling pathway and the actions of sclerostin as an inhibitor of bone formation. We review the effects of sclerostin, and its inhibition, on bone at the cellular and tissue level and discuss new findings that suggest that sclerostin may also regulate adipose tissue. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of sclerostin.
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Affiliation(s)
| | | | - Hua Zhu Ke
- Bone Therapeutic Area, UCB Pharma, Slough, United Kingdom
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Lemaire V, Cox DR. Dynamics of Bone Cell Interactions and Differential Responses to PTH and Antibody-Based Therapies. Bull Math Biol 2018; 81:3575-3622. [PMID: 30460589 DOI: 10.1007/s11538-018-0533-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Accepted: 11/01/2018] [Indexed: 01/04/2023]
Abstract
We propose a mathematical model describing the dynamics of osteoblasts and osteoclasts in bone remodeling. The goal of this work is to develop an integrated modeling framework for bone remodeling and bone cell signaling dynamics that could be used to explore qualitatively combination treatments for osteoporosis in humans. The model has been calibrated using 57 checks from the literature. Specific global optimization methods based on qualitative objectives have been developed to perform the model calibration. We also added pharmacokinetics representations of three drugs to the model, which are teriparatide (PTH(1-34)), denosumab (a RANKL antibody) and romosozumab (a sclerostin antibody), achieving excellent goodness-of-fit of human clinical data. The model reproduces the paradoxical effects of PTH on the bone mass, where continuous administration of PTH results in bone loss but intermittent administration of PTH leads to bone gain, thus proposing an explanation of this phenomenon. We used the model to simulate different categories of osteoporosis. The main attributes of each disease are qualitatively well captured by the model, for example changes in bone turnover in the disease states. We explored dosing regimens for each disease based on the combination of denosumab and romosozumab, identifying adequate ratios and doses of both drugs for subpopulations of patients in function of categories of osteoporosis and the degree of severity of the disease.
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Affiliation(s)
- Vincent Lemaire
- Rinat (Pfizer Inc.), 230 East Grand Avenue, South San Francisco, CA, 94080, USA. .,Genentech, 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
| | - David R Cox
- Rinat (Pfizer Inc.), 230 East Grand Avenue, South San Francisco, CA, 94080, USA
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Li F, Cain JD, Tombran-Tink J, Niyibizi C. Pigment epithelium derived factor regulates human Sost/Sclerostin and other osteocyte gene expression via the receptor and induction of Erk/GSK-3beta/beta-catenin signaling. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3449-3458. [PMID: 30076958 DOI: 10.1016/j.bbadis.2018.07.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/11/2018] [Accepted: 07/30/2018] [Indexed: 10/28/2022]
Abstract
Mutations in Serpinf1 gene which encodes pigment epithelium derived factor (PEDF) lead to osteogenesis imperfecta type VI whose hallmark is defective mineralization. We reported that PEDF suppressed expression of Sost/Sclerostin and other osteocyte related genes in mineralizing osteoblast cultures and suggested that this could be part of the mechanisms by which PEDF regulates matrix mineralization (Li et al. J Cellular Phys. 2014). We have used a long-term differentiated mineralizing osteoblast culture (LTD) to define mechanisms by which PEDF regulates osteocyte gene expression. LTD cultures were established by culturing human osteoblasts in an osteogenic medium for 4 months followed by analysis of osteocytes related genes and encoded proteins. LTD cells synthesized Sclerostin, matrix extracellular phosphoglycoprotein (MEPE) and dentin matrix protein (DMP-1) and their synthesis was reduced by treatment with PEDF. Treatment of the cultures with PEDF induced phosphorylation of Erk and glycogen synthase kinase 3-beta (GSK-3β), and accumulation of nonphosphorylated β-catenin. Inhibition of Erk activation and neutralizing antibodies to the pigment epithelium derived receptor (PEDF-R) suppressed GSK-3β phosphorylation and accumulation of nonphosphorylated β-catenin in presence of PEDF. Topflash assays demonstrated that PEDF activated luciferase reporter activity and this activity was inhibited by treatment with Erk inhibitor or neutralizing antibodies to PEDF-R. Dickkopf-related protein 1 treatment of the cells in presence of PEDF had minimal effect suggesting that GSK-3β phosphorylation and accumulation of nonphosphorylayted β-catenin may not involve LRP5/6 in osteocytes. Taken together, the data demonstrate that PEDF regulates osteocyte gene expression through its receptor and possible involvement of Erk/GSK-3β/β-catenin signaling pathway.
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Affiliation(s)
- Feng Li
- Penn State College of Medicine, Department of Orthopaedics and Rehabilitation, Hershey, PA, USA
| | - Jarret D Cain
- Penn State College of Medicine, Department of Orthopaedics and Rehabilitation, Hershey, PA, USA
| | - Joyce Tombran-Tink
- Penn State College of Medicine, Department of Orthopaedics and Rehabilitation, Hershey, PA, USA; Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Christopher Niyibizi
- Penn State College of Medicine, Department of Orthopaedics and Rehabilitation, Hershey, PA, USA; Department of Biochemistry and Molecular Biology, Penn State college of Medicine, Hershey, PA, USA.
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21
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A bridging immunogenicity assay for monoclonal antibody: case study with SHR-1222. Bioanalysis 2018; 10:1115-1127. [DOI: 10.4155/bio-2017-0289] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Aim: SHR-1222 is a humanized monoclonal antibody targeted to soluble sclerostin. To support the preclinical study of SHR-1222 in cynomolgus monkeys, a method for the detection of anti-drug antibodies is required. Results: A bridging immunogenicity method for the detection of anti-SHR-1222 antibodies was developed and validated. In the method, minimal required dilution, normalization factor and confirmatory cut point were 1:20, 4.35 and 10.45%, respectively. The method was successfully applied to evaluate a multiple-dose toxicity study in monkeys. Conclusion: The proposed method allows for the detection of anti-SHR-1222 antibodies in preclinical studies and aids in the interpretation of pharmacokinetic changes in certain animals. The soluble targets interference on anti-drug antibody detection can be blocked or decreased by the therapeutic drug.
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Bhattacharyya S, Pal S, Chattopadhyay N. Targeted inhibition of sclerostin for post-menopausal osteoporosis therapy: A critical assessment of the mechanism of action. Eur J Pharmacol 2018; 826:39-47. [PMID: 29476877 DOI: 10.1016/j.ejphar.2018.02.028] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 02/15/2018] [Accepted: 02/19/2018] [Indexed: 01/01/2023]
Abstract
Promising news in the treatment of osteoporosis is that sequestering sclerostin from circulation with antibodies stimulates robust bone formation. Pre-clinical studies on rodents and monkeys have confirmed that treatment with anti-sclerostin monoclonal antibody (Scl-Ab) increases bone mass, improves bone strength and enhances fracture repair. Clinical trials show that bone gain (anabolic effect) is transient and are primarily at central (spine and hips) than peripheral (wrist) sites. Interestingly Scl-Ab also inhibited bone resorption. Thus Scl-Ab is being regarded as the pharmacologic agent with dual properties - stimulating bone formation and decreasing bone resorption. Sclerostin neutralization transiently increases bone formation markers in post-menopausal women and like parathyroid hormone (PTH) activates osteoblasts and lining cells resulting in bone anabolic effect. However, unlike PTH, sclerostin antibody also decreases bone resorption (anti-catabolic). Although, the U.S. Food and Drug Administration have accepted the Biologics License Application for one of the monoclonal antibodies against sclerostin (romosozumab) for review, many questions remain before romosozumab can be introduced as a skeletal anabolic agent to clinical practice. For example, neutralizing sclerostin alters calcium homeostasis and increases PTH. In addition, sclerostin depletion in preclinical studies has been reported to severely compromises B cell depletion in bone marrow. We have reviewed the currently available evidences that support the use of sclerostin antibody in treating osteoporosis and compare its efficacy and mechanism of action with the currently available anabolic drug, human PTH.
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Affiliation(s)
- Sharmistha Bhattacharyya
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Women Scientist, DBT-BIO-Care, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Subhashis Pal
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
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Luo Z, Liu Y, Liu Y, Chen H, Shi S, Liu Y. Cellular and molecular mechanisms of alcohol-induced osteopenia. Cell Mol Life Sci 2017; 74:4443-4453. [PMID: 28674727 PMCID: PMC11107754 DOI: 10.1007/s00018-017-2585-y] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/24/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023]
Abstract
Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.
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Affiliation(s)
- Zhenhua Luo
- Laboratory of Tissue Regeneration and Immunology, Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No. 4, Beijing, 100050, People's Republic of China
| | - Yao Liu
- Liaoning Province Key Laboratory of Oral Disease, 117 Nanjing North Street, Shenyang, 110002, People's Republic of China
| | - Yitong Liu
- Laboratory of Tissue Regeneration and Immunology, Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No. 4, Beijing, 100050, People's Republic of China
| | - Hui Chen
- Liaoning Province Key Laboratory of Oral Disease, 117 Nanjing North Street, Shenyang, 110002, People's Republic of China
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology, Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No. 4, Beijing, 100050, People's Republic of China.
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25
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Bullock WA, Robling AG. WNT-mediated Modulation of Bone Metabolism: Implications for WNT Targeting to Treat Extraskeletal Disorders. Toxicol Pathol 2017; 45:864-868. [PMID: 29105581 DOI: 10.1177/0192623317738170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The WNT-signaling pathway is involved in cellular and tissue functions that control such diverse processes as body axis patterning, cellular proliferation, differentiation, and life span. The long list of molecules that can participate or modify WNT signaling makes this pathway one of the most complex in cell biology. In bone tissues, WNT signaling is required for proper skeletal development, and human mutations in various components of the cascade revealed insights into pharmacologic targeting that can be harnessed to improve skeletal health. In particular, mutations in genes that code for the WNT-signaling inhibitor sclerostin or the WNT coreceptor lipoprotein receptor-related protein 5 have highlighted the potential therapeutic value of recapitulating those effects in patients with low bone mass. A constant challenge in this area is selectively modifying WNT components in the tissue of interest, as WNT has manifold effects in nearly every tissue.
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Affiliation(s)
- Whitney A Bullock
- 1 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Alexander G Robling
- 1 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,2 Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA.,3 Indiana Center for Musculoskeletal Health, Indianapolis, Indiana, USA.,4 Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
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26
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Colaianni G, Mongelli T, Cuscito C, Pignataro P, Lippo L, Spiro G, Notarnicola A, Severi I, Passeri G, Mori G, Brunetti G, Moretti B, Tarantino U, Colucci SC, Reseland JE, Vettor R, Cinti S, Grano M. Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Sci Rep 2017; 7:2811. [PMID: 28588307 PMCID: PMC5460172 DOI: 10.1038/s41598-017-02557-8] [Citation(s) in RCA: 219] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 04/13/2017] [Indexed: 01/12/2023] Open
Abstract
We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Here we report that treatment with recombinant Irisin prevented bone loss in hind-limb suspended mice when administered during suspension (preventive protocol) and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks (curative protocol). MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented a dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin protected against muscle mass decline in the hind-limb suspended mice, and maintained the fiber cross-sectional area. Notably, the decrease of myosin type II expression in unloaded mice was completely prevented by r-Irisin administration. Our data reveal for the first time that Irisin retrieves disuse-induced bone loss and muscle atrophy. These findings may lead to development of an Irisin-based therapy for elderly immobile osteoporotic and physically disable patients, and might represent a countermeasure for astronauts subjected to microgravity-induced bone and muscle losses.
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Affiliation(s)
- Graziana Colaianni
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Teresa Mongelli
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Concetta Cuscito
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Paolo Pignataro
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Luciana Lippo
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Giovanna Spiro
- Department of Medicine-DIMED, Internal Medicine 3, University of Padova, 35128, Padova, Italy
| | - Angela Notarnicola
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Ilenia Severi
- Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020, Ancona, Italy
| | - Giovanni Passeri
- Department of Clinical and Experimental Medicine, University of Parma, 43126, Parma, Italy
| | - Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, 71100, Foggia, Italy
| | - Giacomina Brunetti
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Biagio Moretti
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Umberto Tarantino
- Department of Orthopedics and Traumatology, Tor Vergata University of Rome, 00133, Rome, Italy
| | - Silvia C Colucci
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - Janne E Reseland
- Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Blindern, N-0317, Oslo, Norway
| | - Roberto Vettor
- Department of Medicine-DIMED, Internal Medicine 3, University of Padova, 35128, Padova, Italy
| | - Saverio Cinti
- Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020, Ancona, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, University of Bari, 70124, Bari, Italy.
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Affiliation(s)
- Alexander G Robling
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
| | - Matthew T Drake
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, United States
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Hinton PS, Nigh P, Thyfault J. Serum sclerostin decreases following 12months of resistance- or jump-training in men with low bone mass. Bone 2017; 96:85-90. [PMID: 27744012 PMCID: PMC5328803 DOI: 10.1016/j.bone.2016.10.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 09/07/2016] [Accepted: 10/10/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE We previously reported that 12months of resistance training (RT, 2×/wk, N=19) or jump training (JUMP, 3×/wk, N=19) increased whole body and lumbar spine BMD and increased serum bone formation markers relative to resorption in physically active (≥4h/wk) men (mean age: 44±2y; median: 44y) with osteopenia of the hip or spine. The purpose of this secondary analysis was to examine the effects of the RT or JUMP intervention on potential endocrine mediators of the exercise effects on bone, specifically IGF-I, PTH and sclerostin. METHODS Fasting blood samples were collected after a 24-h period of no exercise at baseline and after 12months of RT or JUMP. IGF-I, PTH and sclerostin were measured in serum by ELISA. The effects of RT or JUMP on IGF-I, PTH and sclerostin were evaluated using 2×2 repeated measures ANOVA (time, group). This study was conducted in accordance with the Declaration of Helsinki and was approved by the University of Missouri IRB. RESULTS Sclerostin concentrations in serum significantly decreased and IGF-I significantly increased after 12months of RT or JUMP; while PTH remained unchanged. CONCLUSION The beneficial effects of long-term, progressive-intensity RT or JUMP on BMD in moderately active men with low bone mass are associated with decreased sclerostin and increased IGF-I.
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Affiliation(s)
- Pamela S Hinton
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, United States.
| | - Peggy Nigh
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, United States
| | - John Thyfault
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, United States; Internal Medicine - Division of GI and Hepatology, University of Missouri, Columbia, MO 65211, United States
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Zhang Y, Wang L, Liu JX, Wang XL, Shi Q, Wang YJ. Involvement of skeletal renin-angiotensin system and kallikrein-kinin system in bone deteriorations of type 1 diabetic mice with estrogen deficiency. J Diabetes Complications 2016; 30:1419-1425. [PMID: 27614725 DOI: 10.1016/j.jdiacomp.2016.08.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 07/21/2016] [Accepted: 08/19/2016] [Indexed: 01/06/2023]
Abstract
AIMS This study was aimed to investigate the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) in bone deteriorations of mice in response to the combination treatment of estrogen deficiency and hyperglycemia. METHODS The female C57BL/6J mice were sham-operated or ovariectomized with vehicle or streptozotocin (STZ) treatment. Two weeks later, the biochemistries in serum and urine were determined by standard colorimetric methods or ELISA. The H&E and TRAP staining were performed at the tibial proximal metaphysis. The polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression. RESULTS The mice after treating with ovariectomy and STZ showed the decreased level of serum Ca and the increased level of serum PTH and urine Ca. The H&E staining showed trabecular bone abnormalities as demonstrated by the loss, disconnection and separation of trabecular bone network as well as the loss of chondrocytes and appearance of chondrocyte cluster at growth plate of tibia. The significant increase of matured osteoclast number was shown in group with double treatments. The combination treatment significantly up-regulated mRNA expression of AGT, ACE, renin receptor, MMP-9 and CAII, and protein expression of renin, and decreased the ratio of OPG/RANKL and the expression of bradykinin receptors in bone tissue. CONCLUSION Ovariectomy combined with STZ induction produced more detrimental actions on bone through the activation of local bone RAS and the down-regulation of bradykinin receptors, as compared to the respective single treatment.
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Affiliation(s)
- Yan Zhang
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Liang Wang
- Department of Orthopaedics, The 309th hospital of Chinese People's Liberation Army, Beijing 100091, China
| | - Jin-Xin Liu
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Xin-Luan Wang
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Qi Shi
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yong-Jun Wang
- Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Montesi M, Jähn K, Bonewald L, Stea S, Bordini B, Beraudi A. Hypoxia mediates osteocyte ORP150 expression and cell death in vitro. Mol Med Rep 2016; 14:4248-4254. [DOI: 10.3892/mmr.2016.5790] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 06/07/2016] [Indexed: 11/05/2022] Open
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Colaianni G, Mongelli T, Colucci S, Cinti S, Grano M. Crosstalk Between Muscle and Bone Via the Muscle-Myokine Irisin. Curr Osteoporos Rep 2016; 14:132-137. [PMID: 27299471 DOI: 10.1007/s11914-016-0313-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Several lines of evidence have recently established that skeletal muscle is an endocrine organ producing and releasing myokines acting in a paracrine or endocrine fashion. Among these, the newly identified myokine Irisin, produced by skeletal muscle after physical exercise, was originally described as molecule able to promote energy expenditure in white adipose tissue. Recently, it has been shown that the myokine Irisin affects skeletal metabolism in vivo. Thus, mice treated with a micro-dose of r-Irisin displayed improved cortical bone mass, geometry and strength, resembling the effect of physical activity in developing an efficient load-bearing skeleton. Further studies highlighted the autocrine effect of Irisin on skeletal muscle, and research performed in humans has definitively established that Irisin is a circulating hormone-like myokine, increased by physical activity. Albeit there are still few, since Irisin has been very recently discovered, herein are summarized the most relevant research findings published on this topic.
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Affiliation(s)
- G Colaianni
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - T Mongelli
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - S Colucci
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124, Bari, Italy
| | - S Cinti
- Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020, Ancona, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
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Xu Y, Wang L, Sun Y, Han X, Gao T, Xu X, Chen T, Zhao X, Zeng H, Wang Y, Bai D. Sclerostin is essential for alveolar bone loss in occlusal hypofunction. Exp Ther Med 2016; 11:1812-1818. [PMID: 27168809 DOI: 10.3892/etm.2016.3124] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Accepted: 12/23/2015] [Indexed: 02/05/2023] Open
Abstract
Bone loss is caused by occlusal hypofunction and is a serious health concern. This is particularly true of tooth loss, which is common in the elderly. However, the cellular and molecular mechanisms underlying bone loss have yet to be fully elucidated. Sclerostin and Wnt/β-catenin signaling have previously been reported to serve important roles in regulating bone remodeling. Therefore, the present study aimed to investigate the involvement of sclerostin and Wnt/β-catenin signaling in occlusal hypofunction-induced alveolar bone remodeling. The unilateral maxillary molars of 14 male Sprague-Dawley rats were extracted in order to establish a model of occlusal hypofunction. For each rat, the non-extraction side was treated as the control group for comparisons with the extraction side. At 8 weeks after tooth extraction, the rats were sacrificed and alveolar bone specimens were harvested for X-ray radiography, micro-computed tomography (CT) and histological and immunohistochemical examinations. Bone loss and architecture deterioration were observed at the occlusal hypofunction side. The bone mineral density was markedly decreased and the ratio of bone volume to total volume was significantly decreased at the hypofunction side, as compared with the control side (P<0.001). In addition, the number of osteoclasts at the hypofunction side were significantly increased compared with that in the control side (P<0.001), as demonstrated using tartrate-resistant acid phosphatase staining. Furthermore, the protein expression levels of sclerostin and receptor activator of nuclear factor-κB ligand were increased, whereas those of β-catenin were decreased, at the hypofunction side when compared with the control side. In conclusion, the results of the present study suggested that occlusal hypofunction-induced bone loss may be associated with upregulated expression of sclerostin, which, in turn, may inhibit the activity of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Yang Xu
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lufei Wang
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yao Sun
- Department of Oral Implantology, Dental Transformation Medical Center, College of Stomatology, Tongji University, Shanghai 200011, P.R. China
| | - Xianglong Han
- Department of Oral Implantology, Dental Transformation Medical Center, College of Stomatology, Tongji University, Shanghai 200011, P.R. China
| | - Tian Gao
- Department of Obstetrics and Gynecology, Transformation Medical Center, Tongji University, Shanghai 200011, P.R. China
| | - Xin Xu
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Tian Chen
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xuefeng Zhao
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Huan Zeng
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yanmin Wang
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ding Bai
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Gohin S, Carriero A, Chenu C, Pitsillides AA, Arnett TR, Marenzana M. The anabolic action of intermittent parathyroid hormone on cortical bone depends partly on its ability to induce nitric oxide-mediated vasorelaxation in BALB/c mice. Cell Biochem Funct 2016; 34:52-62. [PMID: 26834008 PMCID: PMC4949522 DOI: 10.1002/cbf.3164] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 12/17/2015] [Accepted: 01/01/2016] [Indexed: 11/21/2022]
Abstract
There is strong evidence that vasodilatory nitric oxide (NO) donors have anabolic effects on bone in humans. Parathyroid hormone (PTH), the only osteoanabolic drug currently approved, is also a vasodilator. We investigated whether the NO synthase inhibitor L‐NAME might alter the effect of PTH on bone by blocking its vasodilatory effect. BALB/c mice received 28 daily injections of PTH[1–34] (80 µg/kg/day) or L‐NAME (30 mg/kg/day), alone or in combination. Hindlimb blood perfusion was measured by laser Doppler imaging. Bone architecture, turnover and mechanical properties in the femur were analysed respectively by micro‐CT, histomorphometry and three‐point bending. PTH increased hindlimb blood flow by >30% within 10 min of injection (P < 0.001). Co‐treatment with L‐NAME blocked the action of PTH on blood flow, whereas L‐NAME alone had no effect. PTH treatment increased femoral cortical bone volume and formation rate by 20% and 110%, respectively (P < 0.001). PTH had no effect on trabecular bone volume in the femoral metaphysis although trabecular thickness and number were increased and decreased by 25%, respectively. Co‐treatment with L‐NAME restricted the PTH‐stimulated increase in cortical bone formation but had no clear‐cut effects in trabecular bone. Co‐treatment with L‐NAME did not affect the mechanical strength in femurs induced by iPTH. These results suggest that NO‐mediated vasorelaxation plays partly a role in the anabolic action of PTH on cortical bone. © 2016 The Authors. Cell Biochemistry and Function published by John Wiley & Sons, Ltd.
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Affiliation(s)
- S Gohin
- Department of Bioengineering, Imperial College London, London, UK.,Department of Cell and Developmental Biology, University College London, London, UK.,Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - A Carriero
- Department of Biomedical Engineering, Florida Institute of Technology, Florida, USA
| | - C Chenu
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - A A Pitsillides
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - T R Arnett
- Department of Cell and Developmental Biology, University College London, London, UK
| | - M Marenzana
- Department of Bioengineering, Imperial College London, London, UK.,Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
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Yao W, Dai W, Jiang L, Lay EYA, Zhong Z, Ritchie RO, Li X, Ke H, Lane NE. Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. Osteoporos Int 2016; 27:283-294. [PMID: 26384674 PMCID: PMC4958115 DOI: 10.1007/s00198-015-3308-6] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 08/25/2015] [Indexed: 12/18/2022]
Abstract
UNLABELLED This study was to determine if antibody against sclerostin (Scl-Ab) could prevent glucocorticoid (GC)-induced osteoporosis in mice. We found that Scl-Ab prevented GC-induced reduction in bone mass and bone strength and that the anabolic effects of Scl-Ab might be partially achieved through the preservation of osteoblast activity through autophagy. INTRODUCTION Glucocorticoids (GCs) inhibit bone formation by altering osteoblast and osteocyte cell activity and lifespan. A monoclonal antibody against sclerostin, Scl-Ab, increased bone mass in both preclinical animal and clinical studies in subjects with low bone mass. The objectives of this study were to determine if treatment with the Scl-Ab could prevent loss of bone mass and strength in a mouse model of GC excess and to elucidate if Scl-Ab modulated bone cell activity through autophagy. METHODS We generated reporter mice that globally expressed dsRed fused to LC3, a protein marker for autophagosomes, and evaluated the dose-dependent effects of GCs (0, 0.8, 2.8, and 4 mg/kg/day) and Scl-Ab on autophagic osteoblasts, bone mass, and bone strength. RESULTS GC treatment at 2.8 and 4 mg/kg/day of methylprednisolone significantly lowered trabecular bone volume (Tb-BV/TV) at the lumbar vertebrae and distal femurs, cortical bone mass at the mid-shaft femur (FS), and cortical bone strength compared to placebo (PL). In mice treated with GC and Scl-Ab, Tb-BV/TV increased by 60-125 %, apparent bone strength of the lumbar vertebrae by 30-70 %, FS-BV by 10-18 %, and FS-apparent strength by 13-15 %, as compared to GC vehicle-treated mice. GC treatment at 4 mg/kg/day reduced the number of autophagic osteoblasts by 70 % on the vertebral trabecular bone surface compared to the placebo group (PL, GC 0 mg), and GC + Scl-Ab treatment. CONCLUSIONS Treatment with Scl-Ab prevented GC-induced reduction in both trabecular and cortical bone mass and strength and appeared to maintain osteoblast activity through autophagy.
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Affiliation(s)
- W. Yao
- Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA
| | - W. Dai
- Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA
- Science and Technology Experimental Center, Integrative Medicine Discipline, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - L. Jiang
- Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA
| | - E. Y.-A. Lay
- Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA
| | - Z. Zhong
- Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA
| | - R. O. Ritchie
- Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, CA 94720, USA
| | - X. Li
- Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA
| | - H. Ke
- Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA
| | - N. E. Lane
- Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA
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Role of Irisin on the bone-muscle functional unit. BONEKEY REPORTS 2015; 4:765. [PMID: 26788285 DOI: 10.1038/bonekey.2015.134] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 10/30/2015] [Indexed: 01/04/2023]
Abstract
Irisin was originally recognized as a hormone-like myokine secreted as a product of fibronectin type III domain containing 5 from skeletal muscle in response to exercise both in mice and humans. The first role attributed to Irisin was its ability to induce trans-differentiation of white adipose tissue into brown, but we recently demonstrated that Irisin also has a central role in the control of bone mass, even at lower concentration than required to induce the browning response. Considering how physical exercise is important for the development of an efficient load-bearing skeleton, we can now consider this myokine as one of the molecules responsible for the positive correlation between exercise and healthy bone, linking to the well-established relationship between muscle and bone. Recombinant Irisin (r-Irisin), administered at low dose in young mice, increases cortical bone mineral density and positively modifies bone geometry. Irisin exerts its effect prevalently on osteoblast lineage by enhancing differentiation and activity of bone-forming cells, through the increase in activating transcription factor 4 expression. Low-dose r-Irisin also increases osteopontin and decreases sclerostin synthesis but did not affect Uncoupling protein 1 expression in white adipose tissue, whose upregulation is known to cause browning of fat, when Irisin is administered at a higher dose. These findings offer an explanation to the positive outcome on the skeleton triggered by skeletal muscle during physical activity and prove that the bone tissue is more sensitive than the adipose tissue to the Irisin action.
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Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, Lu P, Sartini L, Di Comite M, Mori G, Di Benedetto A, Brunetti G, Yuen T, Sun L, Reseland JE, Colucci S, New MI, Zaidi M, Cinti S, Grano M. The myokine irisin increases cortical bone mass. Proc Natl Acad Sci U S A 2015; 112:12157-12162. [PMID: 26374841 PMCID: PMC4593131 DOI: 10.1073/pnas.1516622112] [Citation(s) in RCA: 365] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity.
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Affiliation(s)
- Graziana Colaianni
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Concetta Cuscito
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Teresa Mongelli
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Paolo Pignataro
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Cinzia Buccoliero
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Peng Liu
- The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029
| | - Ping Lu
- The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029
| | - Loris Sartini
- Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020 Ancona, Italy
| | - Mariasevera Di Comite
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy
| | - Adriana Di Benedetto
- Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy
| | - Giacomina Brunetti
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Tony Yuen
- The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029
| | - Li Sun
- The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029
| | - Janne E Reseland
- Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Blindern, N-0317 Oslo, Norway
| | - Silvia Colucci
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy
| | - Maria I New
- The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029;
| | - Mone Zaidi
- The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029;
| | - Saverio Cinti
- Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020 Ancona, Italy
| | - Maria Grano
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
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Single-pulsed electromagnetic field therapy increases osteogenic differentiation through Wnt signaling pathway and sclerostin downregulation. Bioelectromagnetics 2015; 36:494-505. [DOI: 10.1002/bem.21933] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 07/15/2015] [Indexed: 01/20/2023]
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Papathanasiou I, Kostopoulou F, Malizos KN, Tsezou A. DNA methylation regulates sclerostin (SOST) expression in osteoarthritic chondrocytes by bone morphogenetic protein 2 (BMP-2) induced changes in Smads binding affinity to the CpG region of SOST promoter. Arthritis Res Ther 2015; 17:160. [PMID: 26071314 PMCID: PMC4491261 DOI: 10.1186/s13075-015-0674-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 06/05/2015] [Indexed: 11/10/2022] Open
Abstract
Introduction Sclerostin (SOST), a soluble antagonist of Wnt signaling, is expressed in chondrocytes and contributes to chondrocytes’ hypertrophic differentiation; however its role in osteoarthritis (OA) pathogenesis is not well known. Based on our previous findings on the interaction between Wnt/β-catenin pathway and BMP-2 in OA, we aimed to investigate the role of DNA methylation and BMP-2 on SOST’s expression in OA chondrocytes. Methods SOST mRNA and protein expression levels were investigated using real-time polymerase chain reaction (PCR) and Western blot, respectively. The methylation status of SOST promoter was analysed using methylation-specific PCR (MSP), quantitative methylation-specific PCR (qMSP) and bisulfite sequencing analysis. The effect of BMP-2 and 5’-Aza-2-deoxycytidine (5-AzadC) on SOST’s expression levels were investigated and Smad1/5/8 binding to SOST promoter was assessed by Chromatin Immunoprecipitation (ChΙP). Results We observed that SOST’s expression was upregulated in OA chondrocytes compared to normal. Moreover, we found that the CpG region of SOST promoter was hypomethylated in OA chondrocytes and 5-AzadC treatment in normal chondrocytes resulted in decreased SOST methylation, whereas its expression was upregulated. BMP-2 treatment in 5-AzadC-treated normal chondrocytes resulted in SOST upregulation, which was mediated through Smad 1/5/8 binding on the CpG region of SOST promoter. Conclusions We report novel findings that DNA methylation regulates SOST’s expression in OA, by changing Smad 1/5/8 binding affinity to SOST promoter, providing evidence that changes in DNA methylation pattern could underlie changes in genes’ expression observed in OA.
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Affiliation(s)
- Ioanna Papathanasiou
- Laboratory of Cytogenetics and Molecular Genetics, University of Thessaly, Faculty of Medicine, Biopolis, Larissa, 41500, Greece.
| | - Fotini Kostopoulou
- Laboratory of Cytogenetics and Molecular Genetics, University of Thessaly, Faculty of Medicine, Biopolis, Larissa, 41500, Greece.
| | - Konstantinos N Malizos
- Department of Orthopaedic Surgery, University of Thessaly, Faculty of Medicine, Biopolis, Larissa, 41500, Greece.
| | - Aspasia Tsezou
- Laboratory of Cytogenetics and Molecular Genetics, University of Thessaly, Faculty of Medicine, Biopolis, Larissa, 41500, Greece. .,Department of Biology, University of Thessaly, Faculty of Medicine, Biopolis, Larissa, 41500, Greece.
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Spatz JM, Wein MN, Gooi JH, Qu Y, Garr JL, Liu S, Barry KJ, Uda Y, Lai F, Dedic C, Balcells-Camps M, Kronenberg HM, Babij P, Pajevic PD. The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro. J Biol Chem 2015; 290:16744-58. [PMID: 25953900 DOI: 10.1074/jbc.m114.628313] [Citation(s) in RCA: 214] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Indexed: 11/06/2022] Open
Abstract
Although bone responds to its mechanical environment, the cellular and molecular mechanisms underlying the response of the skeleton to mechanical unloading are not completely understood. Osteocytes are the most abundant but least understood cells in bones and are thought to be responsible for sensing stresses and strains in bone. Sclerostin, a product of the SOST gene, is produced postnatally primarily by osteocytes and is a negative regulator of bone formation. Recent studies show that SOST is mechanically regulated at both the mRNA and protein levels. During prolonged bed rest and immobilization, circulating sclerostin increases both in humans and in animal models, and its increase is associated with a decrease in parathyroid hormone. To investigate whether SOST/sclerostin up-regulation in mechanical unloading is a cell-autonomous response or a hormonal response to decreased parathyroid hormone levels, we subjected osteocytes to an in vitro unloading environment achieved by the NASA rotating wall vessel system. To perform these studies, we generated a novel osteocytic cell line (Ocy454) that produces high levels of SOST/sclerostin at early time points and in the absence of differentiation factors. Importantly, these osteocytes recapitulated the in vivo response to mechanical unloading with increased expression of SOST (3.4 ± 1.9-fold, p < 0.001), sclerostin (4.7 ± 0.1-fold, p < 0.001), and the receptor activator of nuclear factor κΒ ligand (RANKL)/osteoprotegerin (OPG) (2.5 ± 0.7-fold, p < 0.001) ratio. These data demonstrate for the first time a cell-autonomous increase in SOST/sclerostin and RANKL/OPG ratio in the setting of unloading. Thus, targeted osteocyte therapies could hold promise as novel osteoporosis and disuse-induced bone loss treatments by directly modulating the mechanosensing cells in bone.
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Affiliation(s)
- Jordan M Spatz
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, Harvard-MIT Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| | - Marc N Wein
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Jonathan H Gooi
- NorthWest Academic Centre, The University of Melbourne, St. Albans, Victoria 3065, Australia, and
| | - Yili Qu
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Jenna L Garr
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Shawn Liu
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Kevin J Barry
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Yuhei Uda
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Forest Lai
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Christopher Dedic
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Mercedes Balcells-Camps
- Harvard-MIT Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Bioengineering Department, Institut Quimic de Sarria, Ramon Llull University, 08017 Barcelona, Spain
| | - Henry M Kronenberg
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | | | - Paola Divieti Pajevic
- From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114,
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Marie PJ. Osteoblast dysfunctions in bone diseases: from cellular and molecular mechanisms to therapeutic strategies. Cell Mol Life Sci 2015; 72:1347-61. [PMID: 25487608 PMCID: PMC11113967 DOI: 10.1007/s00018-014-1801-2] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/13/2014] [Accepted: 12/01/2014] [Indexed: 12/27/2022]
Abstract
Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.
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Affiliation(s)
- Pierre J Marie
- INSERM UMR-1132, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475, Paris Cedex 10, France,
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Jin H, Wang B, Li J, Xie W, Mao Q, Li S, Dong F, Sun Y, Ke HZ, Babij P, Tong P, Chen D. Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling. Bone 2015; 71:63-75. [PMID: 25263522 PMCID: PMC4376475 DOI: 10.1016/j.bone.2014.07.039] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 07/11/2014] [Accepted: 07/12/2014] [Indexed: 12/17/2022]
Abstract
In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-catenin(Prx1ER) conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing process in CD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-catenin(Prx1ER) conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention.
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Affiliation(s)
- Hongting Jin
- Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China
| | - Baoli Wang
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Jia Li
- Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA; Liaoning University of Traditional Chinese Medicine, Liaoning, China
| | - Wanqing Xie
- Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA; Liaoning University of Traditional Chinese Medicine, Liaoning, China
| | - Qiang Mao
- Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China
| | - Shan Li
- Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA
| | - Fuqiang Dong
- Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA
| | - Yan Sun
- Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China
| | | | | | - Peijian Tong
- Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China; Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China.
| | - Di Chen
- Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
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44
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Yongtao Z, Kunzheng W, Jingjing Z, Hu S, Jianqiang K, Ruiyu L, Chunsheng W. Glucocorticoids activate the local renin-angiotensin system in bone: possible mechanism for glucocorticoid-induced osteoporosis. Endocrine 2014; 47:598-608. [PMID: 24519760 DOI: 10.1007/s12020-014-0196-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Accepted: 01/28/2014] [Indexed: 11/26/2022]
Abstract
Bone metabolism disorder has been identified to play a vital role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP). The local renin-angiotensin system (RAS) in bone is newly defined to be closely related to the bone metabolism. However, it is unknown whether the local RAS is involved in GIOP. Adult male New Zealand white rabbits were treated with saline, dexamethasone (DXM) alone, or DXM combined with perindopril. The expression of main RAS components in trabecular bone was examined at mRNA and/or protein levels. Bone metabolism was analyzed using dual-energy X-ray absorptiometry, histomorphometry, biomechanics, biochemical techniques, and quantitative RT-PCR. The expressions of local bone angiotensin II, angiotensin types 1 and 2 receptors, and angiotensin-converting enzyme at mRNA and/or protein levels increased when DXM-induced osteoporosis was present. Whereas, perindopril significantly blocked the activation of the local RAS and partially reversed GIOP. Mineralizing surface, mineral apposition rate, and bone formation rate were decreased by DXM, along with serum osteocalcin being downregulated. These changes were then reversed by the use of perindopril. Osteoclast number, osteoclast surface, and eroded surface increased after the administration of DXM, and urinary deoxypyridinoline was upregulated. These were also inhibited when perindopril was given. Quantitative RT-PCR using RNA isolated from the lumbar vertebrae revealed an increase in the SOST expression and a decrease in the Runx2 expression, whereas the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and the expression of tartrate resistant acid phosphatase were increased, which were all inhibited by perindopril. The results of this study provide evidence for the role of local RAS is involved in GIOP, and GIOP may be ameliorated by blocking the activation of local RAS in the bone.
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Affiliation(s)
- Zhang Yongtao
- Department of Orthopaedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
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Fumoto T, Ito M, Ikeda K. Lanthanum carbonate stimulates bone formation in a rat model of renal insufficiency with low bone turnover. J Bone Miner Metab 2014; 32:484-93. [PMID: 24126694 DOI: 10.1007/s00774-013-0521-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 09/15/2013] [Indexed: 10/26/2022]
Abstract
Control of phosphate is important in the management of chronic kidney disease with mineral and bone disorder (CKD-MBD), for which lanthanum carbonate, a non-calcium phosphate-binding agent, has recently been introduced; however, it remains to be determined whether it has any beneficial or deleterious effect on bone remodeling. In the present study, the effects of lanthanum carbonate were examined in an animal model that mimics low turnover bone disease in CKD, i.e., thyroparathyroidectomized (TPTX) and 5/6 nephrectomized (NX) rats undergoing a constant infusion of parathyroid hormone (PTH) and thyroxine injections (TPTX-PTH-5/6NX). Bone histomorphometry at the second lumbar vertebra and tibial metaphysis revealed that both bone formation and resorption were markedly suppressed in the TPTX-PTH-5/6NX model compared with the sham-operated control group, and treatment with lanthanum carbonate was associated with the stimulation of bone formation but not an acceleration of bone resorption. Lanthanum treatment caused a robust stimulation of bone formation with an activation of osteoblasts on the endosteal surface of femoral diaphysis, leading to an increase in cortical bone volume. Thus, lanthanum carbonate has the potential to stimulate bone formation in cases of CKD-MBD with suppressed bone turnover.
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Affiliation(s)
- Toshio Fumoto
- Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka, Obu, Aichi, 474-8511, Japan
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Marenzana M, Vugler A, Moore A, Robinson M. Effect of sclerostin-neutralising antibody on periarticular and systemic bone in a murine model of rheumatoid arthritis: a microCT study. Arthritis Res Ther 2014; 15:R125. [PMID: 24432364 PMCID: PMC3979059 DOI: 10.1186/ar4305] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Introduction Patients with chronic inflammatory diseases have increased bone loss and bone fragility and are at increased risk of fracture. Although anti-resorptive drugs are effective in blocking inflammation-induced bone loss, they are less effective at rebuilding bone. We have previously shown that treatment with sclerostin antibody (Scl-AbI) builds bone and can prevent or restore bone loss in a murine model of inflammatory bowel disease. In this study, we tested the effect of Scl-AbI in a murine model of rheumatoid arthritis (the collagen-induced arthritis model, CIA). We hypothesised that sclerostin blockade can protect and restore bone both locally and systemically without affecting progression of inflammation. Methods CIA was induced in male DBA/1 mice, which were treated with either PBS or Scl-AbI (10 mg/kg, weekly) prophylactically for 55 days or therapeutically for 21 days (starting 14 days post onset of arthritis). Systemic inflammation was assessed by measuring the serum concentration of anti-CII IgG1, IgG2a and IgG2b by ELISA. Changes in bone mass and structure, either at sites remote from the joints or at periarticular sites, were measured using DEXA and microCT. Bone focal erosion was assessed in microCT scans of ankle and knee joints. Results Circulating anti-CII immunoglobulins were significantly elevated in mice with CIA and there were no significant differences in the levels of anti-CII immunoglobulins in mice treated with PBS or Scl-ABI. Prophylactic Scl-AbI treatment prevented the decrease in whole body bone mineral density (BMD) and in the bone volume fraction at axial (vertebral body) and appendicular (tibial proximal metaphysis trabecular and mid-diaphysis cortical bone) sites seen in PBS-treated CIA mice, but did not prevent the formation of focal bone erosions on the periarticular bone in the knee and ankle joints. In the therapeutic study, Scl-AbI restored BMD and bone volume fraction at all assessed sites but was unable to repair focal erosions. Conclusions Sclerostin blockade prevented or reversed the decrease in axial and appendicular bone mass in the murine model of rheumatoid arthritis, but did not affect systemic inflammation and was unable to prevent or repair local focal erosion.
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Uremic toxicity and sclerostin in chronic kidney disease patients. Nephrol Ther 2014; 10:463-70. [PMID: 25070604 DOI: 10.1016/j.nephro.2014.04.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Revised: 04/10/2014] [Accepted: 04/10/2014] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIMS Sclerostin is a circulating inhibitor of the Wnt/β-catenin pathway and may have a role in chronic kidney disease (CKD)-mineral and bone disorder. Blood sclerostin levels are known to be elevated in patients undergoing maintenance dialysis. The aims of the present study were to evaluate sclerostin levels in patients at different CKD stages and study potential associations between sclerostin levels and (i) biochemical parameters that are disturbed in CKD, (ii) markers of vascular disease and (iii) mortality. METHODS One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry tests and assays for sclerostin, protein-bound uremic toxins (indoxylsulphate [IS] and p-cresyl sulphate [PCS]) and the toxin β2 microglobulin (β2M) were performed. Aortic and coronary calcification and arterial stiffness were assessed by multislice spiral computed tomography and pulse wave velocity measurements. The enrolled patients were prospectively monitored for mortality. RESULTS Sclerostin levels were found to be elevated in CKD patients (especially those on hemodialysis). Furthermore, sclerostin levels were positively correlated with inflammation markers, phosphate, fibroblast growth factor 23, IS, PCS, β2M and arterial stiffness. A multivariate linear regression analysis indicated that sclerostin levels were independently associated with IS, PCS and β2M levels. Elevated serum sclerostin appeared to be associated with mortality (independently of age and inflammation). However, this association disappeared after adjustment for a propensity score including age, phosphate, interleukin-6, CKD stage and PCS. CONCLUSION Our results indicate that sclerostin levels are elevated in CKD patients and are associated with inflammation, vascular lesions, uremia and (potentially) mortality.
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Scott JPR, Sale C, Greeves JP, Casey A, Dutton J, Fraser WD. Treadmill running reduces parathyroid hormone concentrations during recovery compared with a nonexercising control group. J Clin Endocrinol Metab 2014; 99:1774-82. [PMID: 24476072 DOI: 10.1210/jc.2013-3027] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Lower PTH concentrations reported in the hours after acute, endurance exercise compared with preexercise levels might be influenced by factors such as circadian fluctuations. OBJECTIVE The objective of the study was to compare postexercise PTH concentrations with a nonexercising control group. DESIGN AND SETTING A laboratory-based study with a crossover design, comparing a 60-minute (at 10:30 am) bout of treadmill running at 65% of the maximal rate of oxygen uptake (exercise) with semirecumbent rest (CON). Blood samples were obtained immediately before (baseline 10:15 am) and after (11:30 am) exercise and during recovery (12:30 am, 1:30 pm, and 2:15 pm). PARTICIPANTS Ten physically active men (mean ± 1 SD, age 26 ± 5 y; body mass 78.3 ± 5.8 kg; maximal rate of oxygen uptake 57.3 ± 6.9 mL/kg(-1) · min(-1)) participated in the study. MAIN OUTCOME MEASURES PTH, albumin-adjusted calcium, and phosphate concentrations were measured. RESULTS PTH concentrations increased (+85%, P < .01) during exercise and were higher than in CON immediately at the end of exercise (4.5 ± 1.9 vs 2.6 ± 0.9 pmol/L(-1), P < .05). In the postexercise period (12:30-2:15 pm), PTH was not different compared with baseline but was lower compared with CON at 1:30 pm (-22%; P < .01) and tended to be lower at both 12:30 pm (-12%; P = .063) and 2:15 pm (-13%; P = .057). Exercise did not significantly affect the albumin-adjusted calcium concentrations, whereas phosphate was higher than CON immediately after exercise (1.47 ± 0.17 vs 1.03 ± 0.17 pmol/L(-1), P < .001) and was lower at 1:30 pm (-16%: P < .05). CONCLUSIONS Lower PTH concentrations after acute endurance running compared with a rested control condition suggest a true effect of exercise.
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Affiliation(s)
- Jonathan P R Scott
- Human Sciences (J.P.R.S., A.C.), QinetiQ Ltd, Farnborough GU14 0LX, United Kingdom; Biomedical, Life, and Health Sciences Research Centre (C.S.), School of Science and Technology, Nottingham Trent University, NG1 4BU Nottingham, United Kingdom; Department of Occupational Medicine (J.P.G.), Headquarters Army Recruiting and Training Division, Upavon SN9 6BE, Wiltshire, United Kingdom; Department of Musculoskeletal Biology (J.D.), University of Liverpool, Liverpool L69 7ZX, United Kingdom; and Norwich Medical School (W.D.F.), University of East Anglia, Norwich NR4 7TJ United Kingdom
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Al-Zifzaf DS, Hamza SA, Kaddah EA, Abo-Shady RA. Type 2 diabetes raises serum sclerostin levels and disturbs the relation between sclerostin and bone mineral density: a call for caution with antisclerostin therapy in osteoporosis. EGYPTIAN RHEUMATOLOGY AND REHABILITATION 2014. [DOI: 10.4103/1110-161x.128136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Mantyh PW. The neurobiology of skeletal pain. Eur J Neurosci 2014; 39:508-19. [PMID: 24494689 PMCID: PMC4453827 DOI: 10.1111/ejn.12462] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 11/19/2013] [Accepted: 11/25/2013] [Indexed: 12/13/2022]
Abstract
Disorders of the skeleton are one of the most common causes of chronic pain and long-term physical disability in the world. Chronic skeletal pain is caused by a remarkably diverse group of conditions including trauma-induced fracture, osteoarthritis, osteoporosis, low back pain, orthopedic procedures, celiac disease, sickle cell disease and bone cancer. While these disorders are diverse, what they share in common is that when chronic skeletal pain occurs in these disorders, there are currently few therapies that can fully control the pain without significant unwanted side effects. In this review we focus on recent advances in our knowledge concerning the unique population of primary afferent sensory nerve fibers that innervate the skeleton, the nociceptive and neuropathic mechanisms that are involved in driving skeletal pain, and the neurochemical and structural changes that can occur in sensory and sympathetic nerve fibers and the CNS in chronic skeletal pain. We also discuss therapies targeting nerve growth factor or sclerostin for treating skeletal pain. These therapies have provided unique insight into the factors that drive skeletal pain and the structural decline that occurs in the aging skeleton. We conclude by discussing how these advances have changed our understanding and potentially the therapeutic options for treating and/or preventing chronic pain in the injured, diseased and aged skeleton.
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Affiliation(s)
- Patrick W Mantyh
- Department of Pharmacology and Arizona Cancer Center, University of Arizona, Tucson, AZ, 85716, USA
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