1
|
Liu L, Luo S, Li Q, Huang K, Jiang Y, Zeng L, Lan X, Li Q, Xiao J. Role of Wnt5a in modulation of osteoporotic adipose-derived stem cells and osteogenesis. Cell Prolif 2025; 58:e13747. [PMID: 39288944 PMCID: PMC11839189 DOI: 10.1111/cpr.13747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/28/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024] Open
Abstract
Osteoporosis, a condition marked by the deterioration of bone microarchitecture and increased facture risk, arises from a disruption in bone metabolism, with osteoclasts surpassing osteoblasts in bone resorption versus formation. The Wnt signalling pathway, a key regulator of bone maintenance, remains partially understood in osteoporosis. Our research delves into the role of Wnt-related molecules in this disease. In osteoporotic adipose-derived stem cells (OP-ASCs), we detected a significant decrease in Ctnnb1 and Frizzled-6 (Fzd6), contrasted by an increase in Gsk-3β and Wnt5a. Activation of the Wnt pathway by LiCl resulted in elevated Ctnnb1 and Fzd6, but decreased Gsk-3β and Wnt5a levels, promoting OP-ASCs' bone-formation capacity. In contrast, inhibition of this pathway by DKK-1 led to diminished Ctnnb1 and Fzd6, and increased Gsk-3β and Wnt5a, adversely affecting osteogenesis. Furthermore, our findings show that overexpressing Wnt5a impedes, while silencing it enhances the bone-forming capability of OP-ASCs. In a cranial bone defect model, the implantation of Wnt5a-silenced OP-ASCs with biphasic calcium phosphate scaffolds significantly promoted new bone formation. These observations indicated a repression of the canonical Wnt pathway and a stimulation of the non-canonical pathway in OP-ASCs. Silencing Wnt5a increased the osteogenic and regenerative abilities of OP-ASCs. Our study suggests targeting Wnt5a could be a promising strategy for enhancing bone regeneration in post-menopausal osteoporosis.
Collapse
Affiliation(s)
- Lin Liu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological HospitalSouthwest Medical UniversityLuzhouChina
| | - Shihong Luo
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and RegenerationLuzhouChina
- Department of Oral Implantology, The Affiliated Stomatological HospitalSouthwest Medical UniversityLuzhouChina
| | - Qiumei Li
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and RegenerationLuzhouChina
| | - Kui Huang
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological HospitalSouthwest Medical UniversityLuzhouChina
| | - Yuan Jiang
- Medical Service Center of Sichuan ProvinceChengduChina
| | - Lu Zeng
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and RegenerationLuzhouChina
| | - Xiaorong Lan
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and RegenerationLuzhouChina
| | - Qing Li
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and RegenerationLuzhouChina
| | - Jingang Xiao
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological HospitalSouthwest Medical UniversityLuzhouChina
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and RegenerationLuzhouChina
- Department of Oral Implantology, The Affiliated Stomatological HospitalSouthwest Medical UniversityLuzhouChina
- Department of Oral and Maxillofacial SurgeryThe Affiliated Hospital of Southwest Medical UniversityLuzhouChina
| |
Collapse
|
2
|
Wanionok NE, Morel GR, Fernández JM. Osteoporosis and Alzheimer´s disease (or Alzheimer´s disease and Osteoporosis). Ageing Res Rev 2024; 99:102408. [PMID: 38969142 DOI: 10.1016/j.arr.2024.102408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/07/2024]
Abstract
Alzheimer's disease (AD) and osteoporosis are two diseases that mainly affect elderly people, with increases in the occurrence of cases due to a longer life expectancy. Several epidemiological studies have shown a reciprocal association between both diseases, finding an increase in incidence of osteoporosis in patients with AD, and a higher burden of AD in osteoporotic patients. This epidemiological relationship has motivated the search for molecules, genes, signaling pathways and mechanisms that are related to both pathologies. The mechanisms found in these studies can serve to improve treatments and establish better patient care protocols.
Collapse
Affiliation(s)
- Nahuel E Wanionok
- Laboratorio de Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Cs. Exactas. Universidad Nacional de La Plata UNLP-CIC, Argentina
| | - Gustavo R Morel
- Biochemistry Research Institute of La Plata "Professor Doctor Rodolfo R. Brenner" (INIBIOLP), Argentina
| | - Juan M Fernández
- Laboratorio de Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Cs. Exactas. Universidad Nacional de La Plata UNLP-CIC, Argentina.
| |
Collapse
|
3
|
Hu L, Chen W, Qian A, Li YP. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease. Bone Res 2024; 12:39. [PMID: 38987555 PMCID: PMC11237130 DOI: 10.1038/s41413-024-00342-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 04/27/2024] [Accepted: 05/12/2024] [Indexed: 07/12/2024] Open
Abstract
Wnts are secreted, lipid-modified proteins that bind to different receptors on the cell surface to activate canonical or non-canonical Wnt signaling pathways, which control various biological processes throughout embryonic development and adult life. Aberrant Wnt signaling pathway underlies a wide range of human disease pathogeneses. In this review, we provide an update of Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and diseases. The Wnt proteins, receptors, activators, inhibitors, and the crosstalk of Wnt signaling pathways with other signaling pathways are summarized and discussed. We mainly review Wnt signaling functions in bone formation, homeostasis, and related diseases, and summarize mouse models carrying genetic modifications of Wnt signaling components. Moreover, the therapeutic strategies for treating bone diseases by targeting Wnt signaling, including the extracellular molecules, cytosol components, and nuclear components of Wnt signaling are reviewed. In summary, this paper reviews our current understanding of the mechanisms by which Wnt signaling regulates bone formation, homeostasis, and the efforts targeting Wnt signaling for treating bone diseases. Finally, the paper evaluates the important questions in Wnt signaling to be further explored based on the progress of new biological analytical technologies.
Collapse
Affiliation(s)
- Lifang Hu
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
| | - Wei Chen
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Airong Qian
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China.
| | - Yi-Ping Li
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
| |
Collapse
|
4
|
Deng AF, Wang FX, Wang SC, Zhang YZ, Bai L, Su JC. Bone-organ axes: bidirectional crosstalk. Mil Med Res 2024; 11:37. [PMID: 38867330 PMCID: PMC11167910 DOI: 10.1186/s40779-024-00540-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 05/31/2024] [Indexed: 06/14/2024] Open
Abstract
In addition to its recognized role in providing structural support, bone plays a crucial role in maintaining the functionality and balance of various organs by secreting specific cytokines (also known as osteokines). This reciprocal influence extends to these organs modulating bone homeostasis and development, although this aspect has yet to be systematically reviewed. This review aims to elucidate this bidirectional crosstalk, with a particular focus on the role of osteokines. Additionally, it presents a unique compilation of evidence highlighting the critical function of extracellular vesicles (EVs) within bone-organ axes for the first time. Moreover, it explores the implications of this crosstalk for designing and implementing bone-on-chips and assembloids, underscoring the importance of comprehending these interactions for advancing physiologically relevant in vitro models. Consequently, this review establishes a robust theoretical foundation for preventing, diagnosing, and treating diseases related to the bone-organ axis from the perspective of cytokines, EVs, hormones, and metabolites.
Collapse
Affiliation(s)
- An-Fu Deng
- Institute of Translational Medicine, Organoid Research Center, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Fu-Xiao Wang
- Institute of Translational Medicine, Organoid Research Center, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, China
| | - Si-Cheng Wang
- Institute of Translational Medicine, Organoid Research Center, Shanghai University, Shanghai, 200444, China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, China
- Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai, 200444, China
| | - Ying-Ze Zhang
- Department of Orthopaedics, the Third Hospital of Hebei Medical University, Orthopaedic Research Institution of Hebei Province, NHC Key Laboratory of Intelligent Orthopaedic Equipment, Shijiazhuang, 050051, China.
| | - Long Bai
- Institute of Translational Medicine, Organoid Research Center, Shanghai University, Shanghai, 200444, China.
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, China.
- School of Medicine, Shanghai University, Shanghai, 200444, China.
- Wenzhou Institute of Shanghai University, Wenzhou, 325000, Zhejiang, China.
| | - Jia-Can Su
- Institute of Translational Medicine, Organoid Research Center, Shanghai University, Shanghai, 200444, China.
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, China.
- Department of Orthopaedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| |
Collapse
|
5
|
Chen Y, Zhao R, Yang L, Guo XE. The roles of extracellular vesicles released by mechanically stimulated osteocytes in regulating osteoblast and osteoclast functions. MECHANOBIOLOGY IN MEDICINE 2024; 2:100065. [PMID: 40207251 PMCID: PMC11981633 DOI: 10.1016/j.mbm.2024.100065] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
Bone adapts to mechanical loading by changing its shape and mass. Osteocytes, as major mechanosensors, are critical for bone modeling/remodeling in response to mechanical stimuli. Intracellular calcium oscillation is one of the early responses in osteocytes, and this further facilitates bone cell communication through released biochemical signals. Our previous study has found that mechanically induced calcium oscillations in osteocytes enhance the release of extracellular vesicles (EVs), and those released EVs can elevate bone formation activity. However, the mechanism of mechanically stimulated EVs' regulation of bone formation and resorption is still unclear. Here, using in vitro studies, we exposed OCY454 cells, with relatively high sclerostin expression, to steady fluid flow (SFF) and characterized the functions of rapidly released EVs in osteoblast and osteoclast regulation. Our study demonstrates that SFF stimulates intracellular calcium response in OCY454 cells and further induces sclerostin, osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL) inside or outside EVs to regulate osteoblast and osteoclast activities. This load-induced protein and EVs release is load-duration dependent. Moreover, stimulated osteocytes rapidly regulate osteoclast maturation through EVs capsulated RANKL. In contrast, other regulating proteins, OPG, and sclerostin, are mainly released directly into the medium without EV capsulation.
Collapse
Affiliation(s)
- Yumei Chen
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Runze Zhao
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
- Bioengineering College, Chongqing University, Chongqing City, China
- Center of Translational Medicine and Clinical Laboratory, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215028, China
| | - Li Yang
- Bioengineering College, Chongqing University, Chongqing City, China
| | - X. Edward Guo
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA
| |
Collapse
|
6
|
Wolfe PN, Stoker AM, Leary E, Crist BD, Bozynski CC, Cook JL. Evaluation of Serum and Urine Biomarker Panels for Developmental Dysplasia of the Hip Prior to Onset of Secondary Osteoarthritis. Cartilage 2024; 15:164-174. [PMID: 37051936 PMCID: PMC11368892 DOI: 10.1177/19476035231163032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 04/14/2023] Open
Abstract
OBJECTIVE Evaluate serum and urine biomarker panels for their capabilities in discriminating between individuals (13- to 34-years-olds) with healthy hips versus those with developmental dysplasia of the hip (DDH) prior to diagnosis of secondary hip osteoarthritis (OA). DESIGN Urine and serum were collected from individuals (15-33 years old) with DDH, prior to and following diagnosis of hip OA, and from age-matched healthy-hip controls. Samples were analyzed for panels of protein biomarkers with potential for differentiation of hip status using receiver operator characteristic curve (area under curve [AUC]) assessments. RESULTS Multiple urine and serum biomarker panels effectively differentiated individuals with DDH from healthy-hip controls in a population at risk for developing secondary hip OA with the best performing panel demonstrating an AUC of 0.959. The panel comprised of two serum and two urinary biomarkers provided the highest combined values for sensitivity, 0.85, and specificity, 1.00, while a panel of four serum biomarkers provided the highest sensitivity, 0.93, while maintaining adequate specificity, 0.71. CONCLUSION Results of this study indicate that panels of protein biomarkers measured in urine and serum may be able to differentiate young adults with DDH from young adults with healthy hips. These data suggest the potential for clinical application of a routine diagnostic method for cost-effective and timely screening for DDH in at-risk populations. Further development and validation of these biomarker panels may result in highly sensitive and specific tools for early diagnosis, staging, and prognostication of DDH, as well as treatment decision making and monitoring capabilities. LEVEL OF EVIDENCE III.
Collapse
Affiliation(s)
- Preston N. Wolfe
- Thompson Laboratory for Regenerative Orthopaedics, University of Missouri, Columbia, MO, USA
| | - Aaron M. Stoker
- Thompson Laboratory for Regenerative Orthopaedics, University of Missouri, Columbia, MO, USA
| | - Emily Leary
- Thompson Laboratory for Regenerative Orthopaedics, University of Missouri, Columbia, MO, USA
- School of Medicine, University of Missouri, Columbia, MO, USA
| | - Brett D. Crist
- Department of Orthopaedic Surgery, University of Missouri, Columbia, MO, USA
| | - Chantelle C. Bozynski
- Thompson Laboratory for Regenerative Orthopaedics, University of Missouri, Columbia, MO, USA
| | - James L. Cook
- Thompson Laboratory for Regenerative Orthopaedics, University of Missouri, Columbia, MO, USA
- Department of Orthopaedic Surgery, University of Missouri, Columbia, MO, USA
| |
Collapse
|
7
|
Patel MA, Fraser DD, Daley M, Cepinskas G, Veraldi N, Grazioli S. The plasma proteome differentiates the multisystem inflammatory syndrome in children (MIS-C) from children with SARS-CoV-2 negative sepsis. Mol Med 2024; 30:51. [PMID: 38632526 PMCID: PMC11022403 DOI: 10.1186/s10020-024-00806-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 03/09/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND The Multi-System Inflammatory Syndrome in Children (MIS-C) can develop several weeks after SARS-CoV-2 infection and requires a distinct treatment protocol. Distinguishing MIS-C from SARS-CoV-2 negative sepsis (SCNS) patients is important to quickly institute the correct therapies. We performed targeted proteomics and machine learning analysis to identify novel plasma proteins of MIS-C for early disease recognition. METHODS A case-control study comparing the expression of 2,870 unique blood proteins in MIS-C versus SCNS patients, measured using proximity extension assays. The 2,870 proteins were reduced in number with either feature selection alone or with a prior COMBAT-Seq batch effect adjustment. The leading proteins were correlated with demographic and clinical variables. Organ system and cell type expression patterns were analyzed with Natural Language Processing (NLP). RESULTS The cohorts were well-balanced for age and sex. Of the 2,870 unique blood proteins, 58 proteins were identified with feature selection (FDR-adjusted P < 0.005, P < 0.0001; accuracy = 0.96, AUC = 1.00, F1 = 0.95), and 15 proteins were identified with a COMBAT-Seq batch effect adjusted feature selection (FDR-adjusted P < 0.05, P < 0.0001; accuracy = 0.92, AUC = 1.00, F1 = 0.89). All of the latter 15 proteins were present in the former 58-protein model. Several proteins were correlated with illness severity scores, length of stay, and interventions (LTA4H, PTN, PPBP, and EGF; P < 0.001). NLP analysis highlighted the multi-system nature of MIS-C, with the 58-protein set expressed in all organ systems; the highest levels of expression were found in the digestive system. The cell types most involved included leukocytes not yet determined, lymphocytes, macrophages, and platelets. CONCLUSIONS The plasma proteome of MIS-C patients was distinct from that of SCNS. The key proteins demonstrated expression in all organ systems and most cell types. The unique proteomic signature identified in MIS-C patients could aid future diagnostic and therapeutic advancements, as well as predict hospital length of stays, interventions, and mortality risks.
Collapse
Affiliation(s)
- Maitray A Patel
- Epidemiology and Biostatistics, Western University, N6A 3K7, London, ON, Canada
| | - Douglas D Fraser
- Lawson Health Research Institute, N6C 2R5, London, ON, Canada.
- Children's Health Research Institute, N6C 4V3, London, ON, Canada.
- Pediatrics, Western University, N6A 3K7, London, ON, Canada.
- Clinical Neurological Sciences, Western University, N6A 3K7, London, ON, Canada.
- Physiology & Pharmacology, Western University, N6A 3K7, London, ON, Canada.
- London Health Sciences Centre, Room C2-C82, 800 Commissioners Road East, N6A 5W9, London, ON, Canada.
| | - Mark Daley
- Epidemiology and Biostatistics, Western University, N6A 3K7, London, ON, Canada
- Computer Science, Western University, N6A 3K7, London, ON, Canada
| | - Gediminas Cepinskas
- Lawson Health Research Institute, N6C 2R5, London, ON, Canada
- Medical Biophysics, Western University, N6A 3K7, London, ON, Canada
| | - Noemi Veraldi
- Department of Pediatrics, Gynaecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Serge Grazioli
- Department of Pediatrics, Gynaecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Division of Neonatal and Pediatric Intensive Care, Department of Child, Woman, and Adolescent Medicine, Geneva University Hospitals, Geneva, Switzerland
| |
Collapse
|
8
|
Drapkina OM, Kontsevaya AV, Kalinina AM, Avdeev SN, Agaltsov MV, Alekseeva LI, Almazova II, Andreenko EY, Antipushina DN, Balanova YA, Berns SA, Budnevsky AV, Gainitdinova VV, Garanin AA, Gorbunov VM, Gorshkov AY, Grigorenko EA, Jonova BY, Drozdova LY, Druk IV, Eliashevich SO, Eliseev MS, Zharylkasynova GZ, Zabrovskaya SA, Imaeva AE, Kamilova UK, Kaprin AD, Kobalava ZD, Korsunsky DV, Kulikova OV, Kurekhyan AS, Kutishenko NP, Lavrenova EA, Lopatina MV, Lukina YV, Lukyanov MM, Lyusina EO, Mamedov MN, Mardanov BU, Mareev YV, Martsevich SY, Mitkovskaya NP, Myasnikov RP, Nebieridze DV, Orlov SA, Pereverzeva KG, Popovkina OE, Potievskaya VI, Skripnikova IA, Smirnova MI, Sooronbaev TM, Toroptsova NV, Khailova ZV, Khoronenko VE, Chashchin MG, Chernik TA, Shalnova SA, Shapovalova MM, Shepel RN, Sheptulina AF, Shishkova VN, Yuldashova RU, Yavelov IS, Yakushin SS. Comorbidity of patients with noncommunicable diseases in general practice. Eurasian guidelines. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2024; 23:3696. [DOI: 10.15829/1728-8800-2024-3996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024] Open
Abstract
Создание руководства поддержано Советом по терапевтическим наукам отделения клинической медицины Российской академии наук.
Collapse
|
9
|
Jiang N, Jin H, Yang K, Zhang Z, Xu W, Chen X, Zhang Z, Xu H. The mechanism of metformin combined with total flavonoids of Rhizoma Drynariae on ovariectomy-induced osteoporotic rats. Biomed Pharmacother 2023; 165:115181. [PMID: 37473680 DOI: 10.1016/j.biopha.2023.115181] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/03/2023] [Accepted: 07/12/2023] [Indexed: 07/22/2023] Open
Abstract
The present study evaluated the in vitro effect of metformin (Met) and total flavonoids of Rhizoma Drynariae (TFRD) on osteoclasts, osteocytes, and osteoblasts at different stages. We also assessed the effect and mechanism of treatment with Met combined with TFRD on ovariectomy (OVX)-induced osteoporosis in rats. The results showed that Met combined with TFRD significantly promoted the migration of osteoprogenitor cells and stimulated the differentiation and maturation of osteoblast precursor cells. Furthermore, Met combined with TFRD treatment significantly inhibited the osteogenic inhibitor sclerostin (SOST)/dickkopf 1 (DKK1) protein expression and the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio in osteocytes. In the in vivo study, Met combined with TFRD effectively reduced bone resorption markers levels, including type-I collagen carboxy-terminal peptide (CTX-1) and tartrate-resistant acid phosphatase (TRAP), and remarkably increased the bone formation marker propeptide of type I procollagen (PINP) level in the serum of rats with osteoporosis. Met combined with TFRD treatment improved bone mineral density (BMD), trabecular microstructure, and mechanical properties of osteoporotic rats. Mechanistically, Met combined with TFRD downregulated SOST and DKK1 levels, and upregulated Wnt10b, β-catenin, runt-related transcription factor 2 (Runx2) et al. Meanwhile, Met combined with TFRD treatment reduced the RANKL/OPG ratio, and reduced the receptor activator of nuclear factor-κB (RANK), nuclear factor of activated T cells c1 (NFATC1), and TRAP levels. In conclusion, Met combined with TFRD ameliorated bone mass in osteoporotic rats through regulating Wnt/β-catenin signaling pathway and OPG/RANKL/RANK axis.
Collapse
Affiliation(s)
- Ningning Jiang
- Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Hui Jin
- Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Kun Yang
- Aviation University of Air Force, Changchun 130022, People's Republic of China
| | - Zhongyuan Zhang
- Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Wenshu Xu
- Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Xiaoxue Chen
- Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Zhenhua Zhang
- Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People's Republic of China
| | - Hui Xu
- Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People's Republic of China.
| |
Collapse
|
10
|
Florio M, Kostenuik PJ, Stolina M, Asuncion FJ, Grisanti M, Ke HZ, Ominsky MS. Dual Inhibition of the Wnt Inhibitors DKK1 and Sclerostin Promotes Fracture Healing and Increases the Density and Strength of Uninjured Bone: An Experimental Study in Nonhuman Primates. J Bone Joint Surg Am 2023; 105:1145-1155. [PMID: 37159527 DOI: 10.2106/jbjs.22.01092] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
BACKGROUND Fracture repair involves the reactivation of developmental signaling cascades, including Wnt signaling that stimulates bone formation and bone regeneration. Rodent data indicate that dual inhibition of the Wnt signaling antagonists sclerostin and Dickkopf-1 (DKK1) increases callus bone volume and strength while increasing bone mass systemically. METHODS We evaluated the effects of 16 weeks of subcutaneously administered carrier solution (vehicle, VEH), anti-sclerostin antibody (Scl-Ab), anti-DKK1 antibody (DKK1-Ab), or Scl-Ab plus DKK1-Ab combination therapy (COMBO) on ulnar osteotomy healing in nonhuman primates (cynomolgus monkeys; 20 to 22 per group). RESULTS Scl-Ab and COMBO therapy increased systemic markers of bone formation versus VEH, with COMBO leading to synergistic increases versus Scl-Ab or DKK1-Ab monotherapies. The COMBO and Scl-Ab groups showed reduced serum markers of bone resorption versus VEH. The COMBO and DKK1-Ab groups exhibited greater callus bone mineral density (BMD), torsional stiffness, and torsional rigidity versus VEH. Lumbar vertebrae from the Scl-Ab and COMBO groups showed greater BMD and bone formation rate versus VEH, and the femoral mid-diaphysis of the Scl-Ab and COMBO groups showed greater periosteal and endocortical bone formation rates versus VEH. CONCLUSIONS DKK1-Ab increased BMD and strength at the ulnar osteotomy site, Scl-Ab increased bone formation and BMD at uninjured skeletal sites, and Scl-Ab plus DKK1-Ab combination therapy induced all of these effects, in some cases to a greater degree versus 1 or both monotherapies. These results in nonhuman primates suggest that DKK1 preferentially regulates bone healing while sclerostin preferentially regulates systemic bone mass. CLINICAL RELEVANCE Combination therapy with antibodies against sclerostin and DKK1 may offer a promising therapeutic strategy for both fracture treatment and fracture prevention.
Collapse
Affiliation(s)
- Monica Florio
- Discovery Research, Amgen, Thousand Oaks, California
| | - Paul J Kostenuik
- Discovery Research, Amgen, Thousand Oaks, California
- Phylon Pharma Services, Thousand Oaks, California
- University of Michigan School of Dentistry, Ann Arbor, Michigan
| | | | | | | | - Hua Zhu Ke
- Discovery Research, Amgen, Thousand Oaks, California
- Angitia Biopharmaceuticals, Guangzhou, Guangdong, People's Republic of China
| | - Michael S Ominsky
- Discovery Research, Amgen, Thousand Oaks, California
- Ascendis Pharma, Palo Alto, California
| |
Collapse
|
11
|
Sarver AL, Mills LJ, Makielski KM, Temiz NA, Wang J, Spector LG, Subramanian S, Modiano JF. Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma. Cancer Genet 2023; 276-277:1-11. [PMID: 37267683 PMCID: PMC11694714 DOI: 10.1016/j.cancergen.2023.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/02/2023] [Accepted: 05/19/2023] [Indexed: 06/04/2023]
Abstract
A hallmark of osteosarcoma in both human and canine tumors is somatic fragmentation and rearrangement of chromosome structure which leads to recurrent increases and decreases in DNA copy number. The PTEN gene has been implicated as an important tumor suppressor in osteosarcoma via forward genetic screens. Here, we analyzed copy number changes, promoter methylation and transcriptomes to better understand the role of PTEN in canine and human osteosarcoma. Reduction in PTEN copy number was observed in 23 of 95 (25%) of the canine tumors examined leading to corresponding decreases in PTEN transcript levels from RNA-Seq samples. Unexpectedly, canine tumors with an intact PTEN locus had higher levels of PTEN transcripts than human tumors. This variation in transcript abundance was used to evaluate the role of PTEN in osteosarcoma biology. Decreased PTEN copy number and transcript level was observed in - and likely an important driver of - increases in cell cycle transcripts in four independent canine transcriptional datasets. In human osteosarcoma, homozygous copy number loss was not observed, instead increased methylation of the PTEN promoter was associated with increased cell cycle transcripts. Somatic modification of PTEN, either by homozygous deletion in dogs or by promoter methylation in humans, is clinically relevant to osteosarcoma, because the cell cycle related transcripts are associated with patient outcomes. The PTEN gene is part of a syntenic rearrangement unique to the canine genome, making it susceptible to somatic loss of both copies of distal chromosome 26 which also includes the FAS death receptor. SIGNIFICANCE STATEMENT: PTEN function is abrogated by different mechanisms in canine and human osteosarcoma tumors leading to uncontrolled cell cycling. Somatic loss of this canine specific syntenic region may help explain why the canine genome appears to be uniquely susceptible to osteosarcoma. Syntenic arrangement, in the context of copy number change, may lead to synergistic interactions that in turn modify species specific cancer risk. Comparative models of tumorigenesis may utilize different driver mechanisms.
Collapse
Affiliation(s)
- Aaron L Sarver
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA.
| | - Lauren J Mills
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Kelly M Makielski
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN 55108, USA
| | - Nuri A Temiz
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jinhua Wang
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Logan G Spector
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA
| | - Subbaya Subramanian
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Surgery, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA
| | - Jaime F Modiano
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN 55108, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA; Center for Engineering and Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| |
Collapse
|
12
|
Urbano F, Farella I, Brunetti G, Faienza MF. Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy. Int J Mol Sci 2023; 24:11980. [PMID: 37569354 PMCID: PMC10418611 DOI: 10.3390/ijms241511980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation.
Collapse
Affiliation(s)
- Flavia Urbano
- Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Ilaria Farella
- Clinica Medica “A. Murri”, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies, and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| |
Collapse
|
13
|
Kitase Y, Prideaux M. Regulation of the Osteocyte Secretome with Aging and Disease. Calcif Tissue Int 2023; 113:48-67. [PMID: 37148298 DOI: 10.1007/s00223-023-01089-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/21/2023] [Indexed: 05/08/2023]
Abstract
As the most numerous and long-lived of all bone cells, osteocytes have essential functions in regulating skeletal health. Through the lacunar-canalicular system, secreted proteins from osteocytes can reach cells throughout the bone. Furthermore, the intimate connectivity between the lacunar-canalicular system and the bone vasculature allows for the transport of osteocyte-secreted factors into the circulation to reach the entire body. Local and endocrine osteocyte signaling regulates physiological processes such as bone remodeling, bone mechanoadaptation, and mineral homeostasis. However, these processes are disrupted by impaired osteocyte function induced by aging and disease. Dysfunctional osteocyte signaling is now associated with the pathogenesis of many disorders, including chronic kidney disease, cancer, diabetes mellitus, and periodontitis. In this review, we focus on the targeting of bone and extraskeletal tissues by the osteocyte secretome. In particular, we highlight the secreted osteocyte proteins, which are known to be dysregulated during aging and disease, and their roles during disease progression. We also discuss how therapeutic or genetic targeting of osteocyte-secreted proteins can improve both skeletal and systemic health.
Collapse
Affiliation(s)
- Yukiko Kitase
- Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA
- Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA
| | - Matthew Prideaux
- Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
- Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
| |
Collapse
|
14
|
Ruan X, Zhang Z, Aili M, Luo X, Wei Q, Zhang D, Bai M. Activin receptor-like kinase 3: a critical modulator of development and function of mineralized tissues. Front Cell Dev Biol 2023; 11:1209817. [PMID: 37457289 PMCID: PMC10347416 DOI: 10.3389/fcell.2023.1209817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 06/22/2023] [Indexed: 07/18/2023] Open
Abstract
Mineralized tissues, such as teeth and bones, pose significant challenges for repair due to their hardness, low permeability, and limited blood flow compared to soft tissues. Bone morphogenetic proteins (BMPs) have been identified as playing a crucial role in mineralized tissue formation and repair. However, the application of large amounts of exogenous BMPs may cause side effects such as inflammation. Therefore, it is necessary to identify a more precise molecular target downstream of the ligands. Activin receptor-like kinase 3 (ALK3), a key transmembrane receptor, serves as a vital gateway for the transmission of BMP signals, triggering cellular responses. Recent research has yielded new insights into the regulatory roles of ALK3 in mineralized tissues. Experimental knockout or mutation of ALK3 has been shown to result in skeletal dysmorphisms and failure of tooth formation, eruption, and orthodontic tooth movement. This review summarizes the roles of ALK3 in mineralized tissue regulation and elucidates how ALK3-mediated signaling influences the physiology and pathology of teeth and bones. Additionally, this review provides a reference for recommended basic research and potential future treatment strategies for the repair and regeneration of mineralized tissues.
Collapse
Affiliation(s)
- Xianchun Ruan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhaowei Zhang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Munire Aili
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiang Luo
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Qiang Wei
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Demao Zhang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Mingru Bai
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
15
|
Aguilar A, Gifre L, Ureña-Torres P, Carrillo-López N, Rodriguez-García M, Massó E, da Silva I, López-Báez V, Sánchez-Bayá M, Prior-Español Á, Urrutia M, Paul J, Bustos MC, Vila A, Garnica-León I, Navarro-González JF, Mateo L, Bover J. Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis. Front Physiol 2023; 14:1177829. [PMID: 37342799 PMCID: PMC10277623 DOI: 10.3389/fphys.2023.1177829] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/23/2023] [Indexed: 06/23/2023] Open
Abstract
Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.
Collapse
Affiliation(s)
- Armando Aguilar
- Autonomous University of Chiapas, Tuxtla Gutiérrez, Mexico
- Department of Nephrology, Mexican Social Security, IMSS General Hospital of Zone No 2, Tuxtla Gutiérrez, Mexico
| | - Laia Gifre
- Department of Rheumatology, Hospital Germans Trias i Pujol, Badalona (Barcelona), Catalonia, Spain
| | - Pablo Ureña-Torres
- AURA Saint Ouen, Department of Nephrology and Dialysis and Department of Renal Physiology, Necker Hospital, University of Paris Descartes, Paris, France
| | - Natalia Carrillo-López
- Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Minerva Rodriguez-García
- Nephrology Clinical Management Unit, Central University Hospital of Asturias (HUCA), Oviedo, Asturias, Spain
| | - Elisabeth Massó
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| | - Iara da Silva
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| | - Víctor López-Báez
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| | - Maya Sánchez-Bayá
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| | - Águeda Prior-Español
- Department of Rheumatology, Hospital Germans Trias i Pujol, Badalona (Barcelona), Catalonia, Spain
| | - Marina Urrutia
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| | - Javier Paul
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| | - Misael C. Bustos
- Department of Nephrology, Pontificia Catholic University of Chile, Santiago, Chile
| | - Anna Vila
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| | - Isa Garnica-León
- Department of Nephrology, Mexican Social Security, IMSS General Hospital of Zone No 2, Tuxtla Gutiérrez, Mexico
| | - Juan F. Navarro-González
- Research Unit and Nephrology Service, University Hospital of Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Islas Canarias, Spain
- Instituto de Tecnologías Biomédicas, Universidad de la Laguna, Islas Canarias, Spain
| | - Lourdes Mateo
- Department of Rheumatology, Hospital Germans Trias i Pujol, Badalona (Barcelona), Catalonia, Spain
| | - Jordi Bover
- Department of Nephrology, University Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain
| |
Collapse
|
16
|
Pinto Tasende JA, Fernandez-Moreno M, Vazquez-Mosquera ME, Fernandez-Lopez JC, Oreiro-Villar N, De Toro Santos FJ, Blanco-García FJ. Increased synovial immunohistochemistry reactivity of TGF-β1 in erosive peripheral psoriatic arthritis. BMC Musculoskelet Disord 2023; 24:246. [PMID: 36997896 PMCID: PMC10061727 DOI: 10.1186/s12891-023-06339-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 03/20/2023] [Indexed: 04/01/2023] Open
Abstract
BACKGROUND Immune and non-immune cells contribute to the pathology of chronic arthritis, and they can contribute to tissue remodeling and repair as well as disease pathogenesis. The present research aimed to analyze inflammation and bone destruction/regeneration biomarkers in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and ankylosing spondylitis (AS). METHODS Samples were obtained from the inflamed knee of patients with knee arthritis who had been referred for undergoing arthroscopies. The synovial membrane was processed for pathological description, IHC analysis, and quantification of mRNA expression ratio by qRT-PCR. Serum levels of TGF-β1, IL-23, IL-6, IL-17 A, IL-22, Dkk1, Sclerostin, BMP2, BMP4, Wnt1, and Wnt5a were measured by ELISA. All these data were analyzed and compared with the demographic, clinical, blood tests, and radiological characteristics of the patients. RESULTS The synovial membrane samples were obtained from 42 patients for IHC, extraction, and purification of RNA for synovial mRNA expression analysis, and serum for measuring protein levels from 38 patients. IHC reactivity for TGF-β1 in the synovial tissue was higher in patients with psoriatic arthritis (p 0.036) and was positively correlated with IL-17 A (r = 0.389, p = 0.012), and Dkk1 (r = 0.388, p = 0.012). Gene expression of the IL-17 A was higher in PsA patients (p = 0.018) and was positively correlated with Dkk1 (r = 0.424, p = 0.022) and negatively correlated with BMP2 (r = -0.396, p = 0.033) and BMP4 (r = -0.472, p = 0.010). It was observed that IHC reactivity for TGF-β1 was higher in patients with erosive PsA (p = 0.024). CONCLUSIONS The IHC reactivity of TGF-β1 in synovial tissue was higher in patients with erosive psoriatic arthritis, and TGF-β1 was in relation to higher levels of gene expression of IL-17 A and Dkk1.
Collapse
Affiliation(s)
- Jose A Pinto Tasende
- Department of Rheumatology-INIBIC, Complexo Hospitalario Universitario de A Coruña, 84 Xubias de Arriba Road, 15006, A Coruña, Spain.
| | - M Fernandez-Moreno
- INIBIC, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | | | - J C Fernandez-Lopez
- Department of Rheumatology-INIBIC, Complexo Hospitalario Universitario de A Coruña, 84 Xubias de Arriba Road, 15006, A Coruña, Spain
| | - N Oreiro-Villar
- Department of Rheumatology-INIBIC, Complexo Hospitalario Universitario de A Coruña, 84 Xubias de Arriba Road, 15006, A Coruña, Spain
| | - F J De Toro Santos
- Department of Rheumatology, Complexo Hospitalario Universitario de A Coruña, Universidade de A Coruña, A Coruña, Spain
| | - F J Blanco-García
- Department of Rheumatology-INIBIC, Complexo Hospitalario Universitario de A Coruña, Universidade de A Coruña, A Coruña, Spain
| |
Collapse
|
17
|
Mudri D, Bilić Ćurčić I, Meštrović L, Mihaljević I, Kizivat T. Hyperthyroidism and Wnt Signaling Pathway: Influence on Bone Remodeling. Metabolites 2023; 13:metabo13020241. [PMID: 36837860 PMCID: PMC9968154 DOI: 10.3390/metabo13020241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/28/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Graves' disease is an autoimmune disease of the thyroid gland, characterized by increased production of thyroid hormones, which can affect many different organ systems in the body. Among other problems, it can cause disorders of the skeletal system, shortening the bone remodeling cycle and causing a decrease in bone density. The Wnt cascade signaling pathway and the β-catenin, as a part of the canonical Wnt pathway, also play roles in maintaining bone mass. Inhibition of the Wnt pathway can cause bone loss, and its stimulation can increase it. The Wnt signaling pathway influences the effectiveness of thyroid hormones by affecting receptors for thyroid hormones and deiodinase, while thyroid hormones can change levels of β-catenin within the cell cytoplasm. This indicates that the Wnt pathway and thyroid hormone levels, including hyperthyroidism, are linked and may act together to change bone density. In this review article, we attempt to explain the interplay between thyroid hormones and the Wnt pathway on bone density, with a focus on directions for further research and treatment options.
Collapse
Affiliation(s)
- Dunja Mudri
- Department of Nuclear Medicine and Oncology, Faculty of Medicine, University of Osijek, 31000 Osijek, Croatia
- Clinical Institute of Nuclear Medicine and Radiation Protection, University Hospital Osijek, 31000 Osijek, Croatia
| | - Ines Bilić Ćurčić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, 31000 Osijek, Croatia
- Department of Endocrinology and Metabolism Disorders, University Hospital Osijek, 31000 Osijek, Croatia
- Correspondence: (I.B.Ć.); (T.K.)
| | - Lucija Meštrović
- Faculty of Medicine, University of Osijek, 31000 Osijek, Croatia
| | - Ivica Mihaljević
- Department of Nuclear Medicine and Oncology, Faculty of Medicine, University of Osijek, 31000 Osijek, Croatia
- Clinical Institute of Nuclear Medicine and Radiation Protection, University Hospital Osijek, 31000 Osijek, Croatia
- Academy of Medical Sciences of Croatia, 31000 Osijek, Croatia
| | - Tomislav Kizivat
- Department of Nuclear Medicine and Oncology, Faculty of Medicine, University of Osijek, 31000 Osijek, Croatia
- Clinical Institute of Nuclear Medicine and Radiation Protection, University Hospital Osijek, 31000 Osijek, Croatia
- Correspondence: (I.B.Ć.); (T.K.)
| |
Collapse
|
18
|
Choi H, Yang L, Liu Y, Jeong JK, Cho ES. Inactivation of Sufu in cementoblasts accelerates external tooth root resorption. J Cell Physiol 2023; 238:447-458. [PMID: 36598878 DOI: 10.1002/jcp.30943] [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: 09/28/2022] [Revised: 12/20/2022] [Accepted: 12/24/2022] [Indexed: 01/05/2023]
Abstract
Cementum has been empirically regarded as an antiresorptive barrier against tooth roots. However, little is known about the factors of homeostasis and resistant mechanisms of tooth roots against resorption. Here, we investigated cementum factors and their interaction against resorption using transgenic mice exhibiting external cervical root resorption (ECRR). Ectopically thickened cervical cementum caused by functional inactivation of ectonucleotide pyrophosphotase/phosphodiesterase 1 (Enpp1) was susceptible to ECRR with aging. In addition, the inactivation of the suppressor of fused (Sufu), a Hedgehog signaling inhibitor, in cementoblasts led to ECRR. Interestingly, concurrent inactivation of Sufu and Enpp1 in cementoblasts remarkably exacerbated ECRR with higher Rankl expression. Cellular and molecular analyses using cementoblasts and bone marrow-derived macrophages indicated that Dickkopf-related protein 1 (Dkk1) induced by the inactivation of Sufu in cementoblasts has roles in the acceleration of ECRR triggered by Enpp1 inactivation. Using compound mutant mice for concurrent Wntless and Enpp1 inactivation, this synergistic cooperation of Dkk1 and Npp1 for resorption found in double mutant Sufu and Enpp1 mice was confirmed by the reproduction of amplified ECRR. On the basis of these findings, we conclude that proper Npp1 function and sustained Wnt activity in the cervical cementum are essential for the homeostasis of tooth roots against resorption in a physiological state.
Collapse
Affiliation(s)
- Hwajung Choi
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Liu Yang
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Yudong Liu
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Ju-Kyung Jeong
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Eui-Sic Cho
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| |
Collapse
|
19
|
Atkinson EG, Adaway M, Horan DJ, Korff C, Klunk A, Orr AL, Ratz K, Bellido T, Plotkin LI, Robling AG, Bidwell JP. Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation. J Bone Miner Res 2023; 38:70-85. [PMID: 36321253 PMCID: PMC9825665 DOI: 10.1002/jbmr.4732] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/12/2022] [Accepted: 10/29/2022] [Indexed: 11/24/2022]
Abstract
Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis, yet FDA-approved osteoanabolics, eg, parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl/fl ) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+ to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+ targeting mature osteoblasts, and (iii) Dmp1Cre+ to disable Nmp4 in osteocytes. Virgin female Cre+ and Cre- mice (10 weeks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1-34 at 30 μg/kg or vehicle for 4 weeks or 7 weeks. Skeletal response was assessed using dual-energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4fl/fl ;Prx1Cre+ mice virtually phenocopied the global Nmp4-/- skeleton in the femur, ie, a mild baseline phenotype but significantly enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared with their Nmp4fl/fl ;Prx1Cre- controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl ;BglapCre+ ) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl ;Dmp1Cre+ ) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4-/- Prx1-expressing MSPCs drive the improved response to PTH therapy and that this gene has stage-specific effects on osteoanabolism. © 2022 American Society for Bone and Mineral Research (ASBMR).
Collapse
Affiliation(s)
- Emily G. Atkinson
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
| | - Michele Adaway
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
| | - Daniel J. Horan
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
- Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA
| | | | - Angela Klunk
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
| | - Ashley L. Orr
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
- Present Address: Division of Biomedical Sciences, College of Osteopathic Medicine, Marian University Indianapolis, IN 46222
| | - Katherine Ratz
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
- Present Address: Division of Biomedical Sciences, College of Osteopathic Medicine, Marian University Indianapolis, IN 46222
| | - Teresita Bellido
- Department of Physiology and Cell Biology University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72205
- Central Arkansas Veterans Healthcare System, Little Rock, AR 72205
| | - Lilian I. Plotkin
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
- Indiana Center for Musculoskeletal Health, IUSM
| | - Alexander G. Robling
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
- Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA
- Indiana Center for Musculoskeletal Health, IUSM
| | - Joseph P. Bidwell
- Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202
- Indiana Center for Musculoskeletal Health, IUSM
| |
Collapse
|
20
|
Jaschke NP, Pählig S, Sinha A, Adolph TE, Colunga ML, Hofmann M, Wang A, Thiele S, Schwärzler J, Kleymann A, Gentzel M, Tilg H, Wielockx B, Hofbauer LC, Rauner M, Göbel A, Rachner TD. Dickkopf1 fuels inflammatory cytokine responses. Commun Biol 2022; 5:1391. [PMID: 36539532 PMCID: PMC9765382 DOI: 10.1038/s42003-022-04368-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1-controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3-restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and non-malignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.
Collapse
Affiliation(s)
- Nikolai P Jaschke
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.
| | - Sophie Pählig
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Anupam Sinha
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Innsbruck Medical University, Innsbruck, Austria
| | - Maria Ledesma Colunga
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Maura Hofmann
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Andrew Wang
- Department of Medicine (Rheumatology, Allergy & Immunology), Yale University School of Medicine, New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Sylvia Thiele
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Innsbruck Medical University, Innsbruck, Austria
| | - Alexander Kleymann
- Division of Rheumatology, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Marc Gentzel
- Molecular Analysis - Mass Spectrometry, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Innsbruck Medical University, Innsbruck, Austria
| | - Ben Wielockx
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Andy Göbel
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Tilman D Rachner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| |
Collapse
|
21
|
Bertuglia G, Cani L, Larocca A, Gay F, D'Agostino M. Normalization of the Immunological Microenvironment and Sustained Minimal Residual Disease Negativity: Do We Need Both for Long-Term Control of Multiple Myeloma? Int J Mol Sci 2022; 23:15879. [PMID: 36555520 PMCID: PMC9781462 DOI: 10.3390/ijms232415879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Over the past two decades, the treatment landscape for multiple myeloma (MM) has progressed significantly, with the introduction of several new drug classes that have greatly improved patient outcomes. At present, it is well known how the bone marrow (BM) microenvironment (ME) exerts an immunosuppressive action leading to an exhaustion of the immune system cells and promoting the proliferation and sustenance of tumor plasma cells. Therefore, having drugs that can reconstitute a healthy BM ME can improve results in MM patients. Recent findings clearly demonstrated that achieving minimal residual disease (MRD) negativity and sustaining MRD negativity over time play a pivotal prognostic role. However, despite the achievement of MRD negativity, patients may still relapse. The understanding of immunologic changes in the BM ME during treatment, complemented by a deeper knowledge of plasma cell genomics and biology, will be critical to develop future therapies to sustain MRD negativity over time and possibly achieve an operational cure. In this review, we focus on the components of the BM ME and their role in MM, on the prognostic significance of MRD negativity and, finally, on the relative contribution of tumor plasma cell biology and BM ME to long-term disease control.
Collapse
Affiliation(s)
- Giuseppe Bertuglia
- Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
- Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, 10126 Torino, Italy
| | - Lorenzo Cani
- Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
- Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, 10126 Torino, Italy
| | - Alessandra Larocca
- Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
- Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, 10126 Torino, Italy
| | - Francesca Gay
- Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
- Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, 10126 Torino, Italy
| | - Mattia D'Agostino
- Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
- Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, 10126 Torino, Italy
| |
Collapse
|
22
|
Dickkopf-1 exerts protective effects by inhibiting PANoptosis and retinal neovascularization in diabetic retinopathy. Biochem Biophys Res Commun 2022; 617:69-76. [PMID: 35691117 DOI: 10.1016/j.bbrc.2022.05.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 04/27/2022] [Accepted: 05/01/2022] [Indexed: 11/22/2022]
Abstract
Diabetic retinopathy (DR) is a key reason for legal blindness worldwide. Currently, it is urgently necessary to determine the etiology and pathological molecular mechanism of DR to search for resultful therapies. Dickkopf-1 (DKK1) is inhibitive for canonical Wnt signaling via negative feedback, and has been reported as a biomarker for DR. However, the related mechanisms are still unclear. In this work, our data showed that DKK1 was decreased in the vitreous tissues at an early stage of diabetes triggered by streptozotocin (STZ) injection in rats. We subsequently found that DKK1 intravitreal injection significantly ameliorated the physiological function of retina in STZ-challenged rats, accompanied by improved retinal structure. Surprisingly, our results indicated that DKK1 injection remarkably suppressed PANoptosis in retinal tissues of STZ-challenged rats with DR, as proved by ameliorated pyroptosis, apoptosis and necroptosis, which were mainly through the blockage of cleaved Gasdermin-D (GSDMD), Caspase-3 and receptor-interacting protein kinase-3 (RIPK3). Additionally, Wnt signaling including the expression of Wnt, β-catenin and LDL receptor-related protein 5/6 (LRP5/6) was also highly prohibited in retina of DKK1-injected rats with DR. Furthermore, retinal neovascularization and acellular vessel in DR rats were also considerably abolished after DKK1 injection, accompanied by reduced expression levels of retinal vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9). More in vitro experiments showed that DKK1 treatment markedly repressed the proliferative and migratory ability of endothelial cells via inhibiting angiogenesis-related molecules. Together, all our results broaden the knowledge of the correlation between DKK1 and DR, and then provide a novel therapeutic strategy for the suppression of management of DR.
Collapse
|
23
|
Huang J, Zhai D, Xue J, Li T, Ren D, Wu C. Bioinspired Laminated Bioceramics with High Toughness for Bone Tissue Engineering. Regen Biomater 2022; 9:rbac055. [PMID: 36072263 PMCID: PMC9438744 DOI: 10.1093/rb/rbac055] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/15/2022] [Accepted: 07/30/2022] [Indexed: 11/16/2022] Open
Abstract
For the research of biomaterials in bone tissue engineering, it is still a challenge to fabricate bioceramics that overcome brittleness while maintaining the great biological performance. Here, inspired by the toughness of natural materials with hierarchical laminated structure, we presented a directional assembly-sintering approach to fabricate laminated MXene/calcium silicate-based (L-M/CS) bioceramics. Benefiting from the orderly laminated structure, the L-M/CS bioceramics exhibited significantly enhanced toughness (2.23 MPa·m1/2) and high flexural strength (145 MPa), which were close to the mechanical properties of cortical bone. Furthermore, the L-M/CS bioceramics possessed more suitable degradability than traditional CaSiO3 bioceramics due to the newly formed CaTiSiO5 after sintering. Moreover, the L-M/CS bioceramics showed good biocompatibility and could stimulate the expression of osteogenesis-related genes. The mechanism of promoting osteogenic differentiation had been shown to be related to the Wnt signaling pathway. This work not only fabricated calcium silicate-based bioceramics with excellent mechanical and biological properties for bone tissue engineering but also provided a strategy for the combination of bionics and bioceramics.
Collapse
Affiliation(s)
- Jinzhou Huang
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences , 1295 Dingxi Road, Shanghai, 200050, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences , 19A Yuquan Road, Beijing, 100049, P. R. China
| | - Dong Zhai
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences , 1295 Dingxi Road, Shanghai, 200050, P. R. China
| | - Jianmin Xue
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences , 1295 Dingxi Road, Shanghai, 200050, P. R. China
| | - Tian Li
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences , 1295 Dingxi Road, Shanghai, 200050, P. R. China
| | - Dudi Ren
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences , 1295 Dingxi Road, Shanghai, 200050, P. R. China
| | - Chengtie Wu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences , 1295 Dingxi Road, Shanghai, 200050, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences , 19A Yuquan Road, Beijing, 100049, P. R. China
| |
Collapse
|
24
|
Vlashi R, Zhang X, Wu M, Chen G. Wnt signaling: essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
|
25
|
Wnt Inhibitors and Bone Mineral Density in Patients with Graves' Disease Treated with Antithyroid Drugs: A Preliminary Prospective Study. Metabolites 2022; 12:metabo12080711. [PMID: 36005583 PMCID: PMC9413978 DOI: 10.3390/metabo12080711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/19/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022] Open
Abstract
This study aimed to investigate the association of Wnt inhibitors with thyroid hormones, bone turnover markers, and bone mineral density (BMD) in patients with newly diagnosed Graves’ disease (GD) at the beginning of the antithyroid treatment and after a follow-up period of one year. The study included 37 patients with newly diagnosed GD who were treated with antithyroid drugs (ATD). At baseline and after one year, thyroid hormones and thyroid-stimulating hormone (TSH), serum concentrations of sclerostin, and Dickkopf-1 (DKK1) were measured by an enzyme-linked immunosorbent assay (ELISA). In addition, BMD was measured by dual-energy X-ray absorptiometry (DXA), and markers of bone turnover including osteocalcin (OC), beta-cross laps (β-CTX), and deoxypyridinoline (DPD) were determined. After one year of ATD therapy sclerostin levels were significantly decreased (p < 0.001), whereas DKK1 levels were significantly increased (p = 0.01). In addition, BMD of the lumbar spine, total hip, and femoral neck was significantly improved (p < 0.001), accompanied by an increase in OC, β-CTX, and DPD concentrations (p < 0.001). At baseline, sclerostin levels were positively associated with free triiodothyronine (FT3). Following ATD therapy, a positive correlation was observed between FT3 and DKK1 (p = 0.003), whereas a negative correlation was found between TSH and DKK1 (p = 0.04). Correlation analysis demonstrated no association of the sclerostin and DKK1 with other bone remodeling biomarkers OC, β-CTX, or DPD. Also, no significant correlation between sclerostin or DKK1 and T-score or BMD of the lumbar spine, hip, and femoral neck was observed at both time points. Conclusion: Observed differences in sclerostin and DKK1 serum following GD treatment indicate involvement of Wnt inhibitors in the etiopathogenesis of bone loss associated with hyperthyroidism. Furthermore, both sclerostin and DKK1 are involved in the reversal of changes in bone metabolism following ATD therapy, thus presenting potentially valuable bone remodeling markers worth further investigation.
Collapse
|
26
|
Sharma-Ghimire P, Buchanan S, Bemben MG, Knehans A, Campbell J, Bemben DA. Sclerostin and Dickkopf-1 Characteristics According to Age and Physical Activity Levels in Premenopausal Women. J Clin Densitom 2022; 25:168-177. [PMID: 34391642 DOI: 10.1016/j.jocd.2021.07.008] [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: 02/09/2021] [Revised: 07/09/2021] [Accepted: 07/16/2021] [Indexed: 12/17/2022]
Abstract
We aimed to compare serum concentrations of sclerostin and DKK-1 in young (20-30 yrs, n = 25) and middle-aged (35-45 yrs, n = 25) premenopausal women and based on physical activity (PA) status. PA status was assessed by the International Physical Activity Questionnaire (low-moderate (≤ 2999 MET-min/week) and high (≥ 3000 MET-min/week). Serum sclerostin and DKK-1 levels were measured in fasting morning blood samples by ELISA. Areal bone mineral density (aBMD) was measured by DXA, and non-dominant tibia bone characteristics were assessed by pQCT. After adjusting for total body aBMD, middle-aged women had significantly (p < 0.001) higher (0.54 ± 0.01 ng/mL) serum sclerostin than young women (0.41 ± 0.01 ng/mL), and sclerostin was positively correlated with age (rs = 0.065, p ≤ 0.001) and total PA score (rs = 0.33, p = 0.021). Young women had higher left trochanter aBMD (p = 0.036) than middle-aged women and aBMD variables were higher (all p ≤ 0.043) in the high active group. Middle-aged women had higher 38% cortical vBMD than young women (p = 0.021), otherwise young women had higher values for pQCT variables (all p ≤ 0.036). Sclerostin showed significant correlations (r = 0.32 to 0.58, all p ≤ 0.026) with spine aBMD for the entire cohort and for each age group. Middle-aged women had significant correlations between sclerostin and hip aBMD sites (r = 0.043 to 0.56, all p ≤ 0.031). Sclerostin and cortical vBMD were positively correlated in the entire cohort (r = 0.35 to 0.50; both p < 0.013); split by age group, middle-aged women had positive correlations (r = 0.45 to 0.61 age and, all p ≤ 0.021) between sclerostin and pQCT variables. No significant differences for physical activity were observed for serum DKK-1 concentrations. Serum sclerostin concentrations were positively associated with age and bone characteristics in premenopausal women; however, these findings were not evident for circulating DKK-1. Further research is needed to elucidate the mechanisms for the discordant results in these Wnt inhibitors.
Collapse
Affiliation(s)
- Pragya Sharma-Ghimire
- Department of Physical Education and Exercise Science, Lander University, Greenwood, SC, USA.
| | - Samuel Buchanan
- Department of Health and Human Performance, The University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Michael G Bemben
- Department of Health and Exercise Science, University of Oklahoma, Norman, OK, USA
| | - Allen Knehans
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jason Campbell
- Department of Health and Exercise Science, University of Oklahoma, Norman, OK, USA
| | - Debra A Bemben
- Department of Health and Exercise Science, University of Oklahoma, Norman, OK, USA
| |
Collapse
|
27
|
Choi JUA, Kijas AW, Lauko J, Rowan AE. The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States. Front Cell Dev Biol 2022; 9:770143. [PMID: 35265628 PMCID: PMC8900535 DOI: 10.3389/fcell.2021.770143] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022] Open
Abstract
Bone homeostasis is a dynamic equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts. This process is primarily controlled by the most abundant and mechanosensitive bone cells, osteocytes, that reside individually, within chambers of porous hydroxyapatite bone matrix. Recent studies have unveiled additional functional roles for osteocytes in directly contributing to local matrix regulation as well as systemic roles through endocrine functions by communicating with distant organs such as the kidney. Osteocyte function is governed largely by both biochemical signaling and the mechanical stimuli exerted on bone. Mechanical stimulation is required to maintain bone health whilst aging and reduced level of loading are known to result in bone loss. To date, both in vivo and in vitro approaches have been established to answer important questions such as the effect of mechanical stimuli, the mechanosensors involved, and the mechanosensitive signaling pathways in osteocytes. However, our understanding of osteocyte mechanotransduction has been limited due to the technical challenges of working with these cells since they are individually embedded within the hard hydroxyapatite bone matrix. This review highlights the current knowledge of the osteocyte functional role in maintaining bone health and the key regulatory pathways of these mechanosensitive cells. Finally, we elaborate on the current therapeutic opportunities offered by existing treatments and the potential for targeting osteocyte-directed signaling.
Collapse
Affiliation(s)
- Jung Un Ally Choi
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Amanda W Kijas
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Jan Lauko
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Alan E Rowan
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| |
Collapse
|
28
|
Thomas S, Jaganathan BG. Signaling network regulating osteogenesis in mesenchymal stem cells. J Cell Commun Signal 2022; 16:47-61. [PMID: 34236594 PMCID: PMC8688675 DOI: 10.1007/s12079-021-00635-1] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/30/2021] [Indexed: 02/06/2023] Open
Abstract
Osteogenesis is an important developmental event that results in bone formation. Bone forming cells or osteoblasts develop from mesenchymal stem cells (MSCs) through a highly controlled process regulated by several signaling pathways. The osteogenic lineage commitment of MSCs is controlled by cell-cell interactions, paracrine factors, mechanical signals, hormones, and cytokines present in their niche, which activate a plethora of signaling molecules belonging to bone morphogenetic proteins, Wnt, Hedgehog, and Notch signaling. These signaling pathways individually as well as in coordination with other signaling molecules, regulate the osteogenic lineage commitment of MSCs by activating several osteo-lineage specific transcription factors. Here, we discuss the key signaling pathways that regulate osteogenic differentiation of MSCs and the cross-talk between them during osteogenic differentiation. We also discuss how these signaling pathways can be modified for therapy for bone repair and regeneration.
Collapse
Affiliation(s)
- Sachin Thomas
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
| |
Collapse
|
29
|
Terkawi MA, Matsumae G, Shimizu T, Takahashi D, Kadoya K, Iwasaki N. Interplay between Inflammation and Pathological Bone Resorption: Insights into Recent Mechanisms and Pathways in Related Diseases for Future Perspectives. Int J Mol Sci 2022; 23:1786. [PMID: 35163708 PMCID: PMC8836472 DOI: 10.3390/ijms23031786] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/01/2022] [Accepted: 02/03/2022] [Indexed: 02/01/2023] Open
Abstract
Bone is a mineralized and elastic connective tissue that provides fundamental functions in the human body, including mechanical support to the muscles and joints, protection of vital organs and storage of minerals. Bone is a metabolically active organ that undergoes continuous remodeling processes to maintain its architecture, shape, and function throughout life. One of the most important medical discoveries of recent decades has been that the immune system is involved in bone remodeling. Indeed, chronic inflammation has been recognized as the most significant factor influencing bone homeostasis, causing a shift in the bone remodeling process toward pathological bone resorption. Bone osteolytic diseases typified by excessive bone resorption account for one of the greatest causes of disability worldwide, with significant economic and public health burdens. From this perspective, we discuss the recent findings and discoveries highlighting the cellular and molecular mechanisms that regulate this process in the bone microenvironment, in addition to the current therapeutic strategies for the treatment of osteolytic bone diseases.
Collapse
Affiliation(s)
- M Alaa Terkawi
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; (G.M.); (T.S.); (D.T.); (K.K.); (N.I.)
| | - Gen Matsumae
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; (G.M.); (T.S.); (D.T.); (K.K.); (N.I.)
| | - Tomohiro Shimizu
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; (G.M.); (T.S.); (D.T.); (K.K.); (N.I.)
| | - Daisuke Takahashi
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; (G.M.); (T.S.); (D.T.); (K.K.); (N.I.)
| | - Ken Kadoya
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; (G.M.); (T.S.); (D.T.); (K.K.); (N.I.)
| | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo 060-8638, Japan; (G.M.); (T.S.); (D.T.); (K.K.); (N.I.)
| |
Collapse
|
30
|
Martínez-Gil N, Ugartondo N, Grinberg D, Balcells S. Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis. Genes (Basel) 2022; 13:genes13010138. [PMID: 35052478 PMCID: PMC8775112 DOI: 10.3390/genes13010138] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 12/11/2022] Open
Abstract
The Wnt pathway is involved in several processes essential for bone development and homeostasis. For proper functioning, the Wnt pathway is tightly regulated by numerous extracellular elements that act by both activating and inhibiting the pathway at different moments. This review aims to describe, summarize and update the findings regarding the extracellular modulators of the Wnt pathway, including co-receptors, ligands and inhibitors, in relation to bone homeostasis, with an emphasis on the animal models generated, the diseases associated with each gene and the bone processes in which each member is involved. The precise knowledge of all these elements will help us to identify possible targets that can be used as a therapeutic target for the treatment of bone diseases such as osteoporosis.
Collapse
|
31
|
Nagano K, Yamana K, Saito H, Kiviranta R, Pedroni AC, Raval D, Niehrs C, Gori F, Baron R. R-spondin 3 deletion induces Erk phosphorylation to enhance Wnt signaling and promote bone formation in the appendicular skeleton. eLife 2022; 11:84171. [PMID: 36321691 PMCID: PMC9681208 DOI: 10.7554/elife.84171] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 10/18/2022] [Indexed: 11/23/2022] Open
Abstract
Activation of Wnt signaling leads to high bone density. The R-spondin family of four secreted glycoproteins (Rspo1-4) amplifies Wnt signaling. In humans, RSPO3 variants are strongly associated with bone density. Here, we investigated the role of Rspo3 in skeletal homeostasis in mice. Using a comprehensive set of mouse genetic and mechanistic studies, we show that in the appendicular skeleton, Rspo3 haplo-insufficiency and Rspo3 targeted deletion in Runx2+ osteoprogenitors lead to an increase in trabecular bone mass, with increased number of osteoblasts and bone formation. In contrast and highlighting the complexity of Wnt signaling in the regulation of skeletal homeostasis, we show that Rspo3 deletion in osteoprogenitors results in the opposite phenotype in the axial skeleton, i.e., low vertebral trabecular bone mass. Mechanistically, Rspo3 deficiency impairs the inhibitory effect of Dkk1 on Wnt signaling activation and bone mass. We demonstrate that Rspo3 deficiency leads to activation of Erk signaling which in turn, stabilizes β-catenin and Wnt signaling activation. Our data demonstrate that Rspo3 haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling, to favor osteoblastogenesis, bone formation, and bone mass.
Collapse
Affiliation(s)
- Kenichi Nagano
- School of Dental Medicine, Harvard UniversityBostonUnited States
| | - Kei Yamana
- School of Dental Medicine, Harvard UniversityBostonUnited States
| | - Hiroaki Saito
- School of Dental Medicine, Harvard UniversityBostonUnited States
| | - Riku Kiviranta
- School of Dental Medicine, Harvard UniversityBostonUnited States
| | | | - Dhairya Raval
- School of Dental Medicine, Harvard UniversityBostonUnited States
| | - Christof Niehrs
- German Cancer Research Center, DKFZ-ZMBH AllianceHeidelbergGermany,Institute of Molecular Biology (IMB)MainzGermany
| | - Francesca Gori
- School of Dental Medicine, Harvard UniversityBostonUnited States
| | - Roland Baron
- School of Dental Medicine, Harvard UniversityBostonUnited States,Department of Medicine, Harvard Medical SchoolBostonUnited States,Endocrine Unit, Massachusetts General HospitalBostonUnited States
| |
Collapse
|
32
|
Aguirre JI, Castillo EJ, Kimmel DB. Biologic and pathologic aspects of osteocytes in the setting of medication-related osteonecrosis of the jaw (MRONJ). Bone 2021; 153:116168. [PMID: 34487892 PMCID: PMC8478908 DOI: 10.1016/j.bone.2021.116168] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/02/2021] [Accepted: 08/31/2021] [Indexed: 02/08/2023]
Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe, debilitating condition affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). Oral risk factors associated with the development of MRONJ include tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection). In bone tissues, osteocytes play a bidirectional role in which they not only act as the "receiver" of systemic signals from blood vessels, such as hormones and drugs, or local signals from the mineralized matrix as it is deformed, but they also play a critical role as "transmitter" of signals to the cells that execute bone modeling and remodeling (osteoclasts, osteoblasts and lining cells). When the survival capacity of osteocytes is overwhelmed, they can die. Osteocyte death has been associated with several pathological conditions. Whereas the causes and mechanisms of osteocyte death have been studied in conditions like osteonecrosis of the femoral head (ONFH), few studies of the causes and mechanisms of osteocyte death have been done in MRONJ. The three forms of cell death that affect most of the different cells in the body (apoptosis, autophagy, and necrosis) have been recognized in osteocytes. Notably, necroptosis, a form of regulated cell death with "a necrotic cell death phenotype," has also been identified as a form of cell death in osteocytes under certain pathologic conditions. Improving the understanding of osteocyte death in MRONJ may be critical for preventing disease and developing treatment approaches. In this review, we intend to provide insight into the biology of osteocytes, cell death, in general, and osteocyte death, in particular, and discuss hypothetical mechanisms involved in osteocyte death associated with MRONJ.
Collapse
Affiliation(s)
- J I Aguirre
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America.
| | - E J Castillo
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America.
| | - D B Kimmel
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America
| |
Collapse
|
33
|
Jang E, Ha J, Baek KH, Kang MI. Changes in Serum Dickkopf-1, RANK Ligand, Osteoprotegerin, and Bone Mineral Density after Allogeneic Hematopoietic Stem Cell Transplantation Treatment. Endocrinol Metab (Seoul) 2021; 36:1211-1218. [PMID: 34875817 PMCID: PMC8743595 DOI: 10.3803/enm.2021.1248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/01/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Dickkopf-1 (DKK1) regulates bone formation by inhibiting canonical Wnt/β-catenin pathway signaling, and indirectly enhances osteoclastic activity by altering the expression ratio of receptor activator of nuclear factor-κB ligand (RANKL) relative to osteoprotegerin (OPG). However, it is difficult to explain continued bone loss after allogeneic stem cell transplantation (allo-SCT) in terms of changes in only RANKL and OPG. Few studies have evaluated changes in DKK1 after allo-SCT. METHODS We prospectively enrolled 36 patients with hematologic malignancies who were scheduled for allo-SCT treatment. Serum DKK1, OPG, and RANKL levels were measured before (baseline), and at 1, 4, 12, 24, and 48 weeks after allo-SCT treatment. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry before (baseline) and 24 and 48 weeks after allo-SCT treatment. RESULTS After allo-SCT treatment, the DKK1 level decreased rapidly, returned to baseline during the first 4 weeks, and remained elevated for 48 weeks (P<0.0001 for changes observed over time). The serum RANKL/OPG ratio peaked at 4 weeks and then declined (P<0.001 for changes observed over time). BMD decreased relative to the baseline at all timepoints during the study period, and the lumbar spine in female patients had the largest decline (-11.3%±1.6% relative to the baseline at 48 weeks, P<0.05). CONCLUSION Serum DKK1 levels rapidly decreased at 1 week and then continued to increase for 48 weeks; bone mass decreased for 48 weeks following engraftment in patients treated with allo-SCT, suggesting that DKK1-mediated inhibition of osteoblast differentiation plays a role in bone loss in patients undergoing allo-SCT.
Collapse
Affiliation(s)
- Eunhee Jang
- Division of Endocrinology, Department of Internal Medicine, Mizmedi Hospital, Seoul, Korea
| | - Jeonghoon Ha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Hyun Baek
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Moo Il Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Corresponding author: Moo Il Kang Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2-2258-6006, Fax: +82-2-599-3589, E-mail:
| |
Collapse
|
34
|
Abstract
PURPOSE OF REVIEW In this review, we provide an overview of what is currently known about the impacts of mechanical stimuli on metastatic tumor-induced bone disease (TIBD). Further, we focus on the role of the osteocyte, the skeleton's primary mechanosensory cell, which is central to the skeleton's mechanoresponse, sensing and integrating local mechanical stimuli, and then controlling the downstream remodeling balance as appropriate. RECENT FINDINGS Exercise and controlled mechanical loading have anabolic effects on bone tissue in models of bone metastasis. They also have anti-tumorigenic properties, in part due to offsetting the vicious cycle of osteolytic bone loss as well as regulating inflammatory signals. The impacts of metastatic cancer on the mechanosensory function of osteocytes remains unclear. Increased mechanical stimuli are a potential method for mitigating TIBD.
Collapse
Affiliation(s)
- Blayne A Sarazin
- Department of Mechanical Engineering, University of Colorado, 427 UCB, Boulder, CO, 80309, USA
| | - Claire L Ihle
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Philip Owens
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Veterans Affairs, Research Service, Eastern Colorado Health Care System, Aurora, CO, 80045, USA
| | - Maureen E Lynch
- Department of Mechanical Engineering, University of Colorado, 427 UCB, Boulder, CO, 80309, USA.
- Biofrontiers Institute, University of Colorado, Boulder, CO, 80309, USA.
| |
Collapse
|
35
|
Romero-Sánchez C, Giraldo S, Heredia-P AM, De Avila J, Chila-Moreno L, Londoño J, Valle-Oñate R, Bello-Gualtero JM, Bautista-Molano W. Association of Serum and Crevicular Fluid Dickkopf-1 Levels with Disease Activity and Periodontitis in Patients with Early Rheumatoid Arthritis. Curr Rheumatol Rev 2021; 18:124-135. [PMID: 34784873 DOI: 10.2174/1573397117666211116105118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/30/2021] [Accepted: 08/10/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The aim of this study was to assess DKK-1 levels, in Gingival Crevicular Fluid (GCF) and serum, as a biomarker for bone loss and disease activity in periodontitis and early RA (eRA). METHODS In this cross-sectional study, we obtained serum and GCF from 10 interproximal sites (Distal Buccal I/S, Mesio Buccal I/S, Distal Palatal/Lingual, Mesio Palatal/Lingual) according to the highest degree of inflammation by a patient for 240 sites from eRA patients. Patients received a periodontal assessment, a radiographic evaluation, tomography of interproximal sites, and DKK1 levels were determined by ELISA. Comparisons were performed by the Mann-Whitney U test and analysis by Chi2 test, and a logistic regression model was applied. RESULTS The mean age was 46.33 ± 12.0 years, the Disease Activity Score (DAS-28-ESR) was 4.08 ± 1.4. Periodontitis was present in 65.2% of the patients, and 59.6% of these patients had bone loss in interproximal sites. Higher GCF-DKK1 levels were associated with serum-DKK1 (OR:2.41 IC95% 1.14-5.09, p=0.021) and were related with DAS28-ESR (p=0.001), Routine Assessment of Patient Index Data 3 (RAPID 3) (p=0.001), and tender joints (p=0.040). Foot bone erosion and juxta-articular osteopenia were associated with high levels of serum-DKK1 (p=0.009 and 0.001, respectively). Serum-DKK1 were associated with SDAI (OR: 2.38 IC95% 1.03-5.52, p=0.043), RAPID 3 (p=0.001), and rheumatoid factor (p=0.018). The GCF-DKK1 levels were associated with periodontal bone loss (p=0.011), periodontitis (p=0.070) and its severity (OR: 2.58 IC95% 2.28-7.28, p=0.001). Bone loss was more frequent in buccal sites (73.5%) and was associated with increased levels of DKK1 (p=0.033). CONCLUSION In the early stages of the eRA disease, serum and GCF-DKK1 could be a biomarker for clinical disease activity and periodontal and articular bone erosion.
Collapse
Affiliation(s)
- Consuelo Romero-Sánchez
- Cellular and Molecular Immunology Group/ INMUBO, School of Dentistry, Universidad El Bosque, Bogotá. Colombia
| | - Sebastián Giraldo
- Clinical Immunology Group, Rheumatology and Immunology Department Hospital Militar Central/School of Medicine, Universidad Militar Nueva Granada/, Bogotá. Colombia
| | - Ana María Heredia-P
- Cellular and Molecular Immunology Group/ INMUBO, School of Dentistry, Universidad El Bosque, Bogotá. Colombia
| | - Juliette De Avila
- Cellular and Molecular Immunology Group/ INMUBO, School of Dentistry, Universidad El Bosque, Bogotá. Colombia
| | - Lorena Chila-Moreno
- Cellular and Molecular Immunology Group/ INMUBO, School of Dentistry, Universidad El Bosque, Bogotá. Colombia
| | - John Londoño
- Spondyloarthropathy Group, Rheumatology Department, Hospital Militar Central/Universidad de La Sabana, Bogotá. Colombia
| | - Rafael Valle-Oñate
- Clinical Immunology Group, Rheumatology and Immunology Department Hospital Militar Central/School of Medicine, Universidad Militar Nueva Granada/, Bogotá. Colombia
| | - Juan Manuel Bello-Gualtero
- Clinical Immunology Group, Rheumatology and Immunology Department Hospital Militar Central/School of Medicine, Universidad Militar Nueva Granada/, Bogotá. Colombia
| | - Wilson Bautista-Molano
- Cellular and Molecular Immunology Group/ INMUBO, School of Dentistry, Universidad El Bosque, Bogotá. Colombia
| |
Collapse
|
36
|
Ding G, Lu W, Zhang Q, Li K, Zhou H, Wang F, Zhao C, Fan C, Wang J. ZBTB38 suppresses prostate cancer cell proliferation and migration via directly promoting DKK1 expression. Cell Death Dis 2021; 12:998. [PMID: 34697293 PMCID: PMC8546125 DOI: 10.1038/s41419-021-04278-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 12/24/2022]
Abstract
Prostate cancer is still one of the most common malignancies in men all around the world. The mechanism of how prostate cancer initiates and develops is still not clear. Here in this study, we show that tumor suppressor ZBTB38 could suppress the migration and proliferation of prostate cancer cells. We find lower ZBTB38 expression in prostate cancer tissues, which also strongly predicts a poorer prognosis of prostate cancer. ZBTB38 binds DKK1 (Dickkopf WNT signaling pathway inhibitor 1) locus and promotes DKK1 expression in prostate cancer cell lines. Consistently, reduction of DKK1 expression significantly restores ZBTB38-mediated suppression of migration and proliferation of prostate cancer cell lines. Mechanistically, we find that ZBTB38 primarily binds the promoters of target genes, and differentially regulates the expression of 1818 genes. We also identify PRKDC (protein kinase, DNA-activated, catalytic subunit) as a ZBTB38-interacting protein that could repress the function of ZBTB38 in suppressing migration and proliferation of prostate cancer cells. Taken together, our results indicate that ZBTB38 could repress cell migration and proliferation in prostate cancer via promoting DKK1 expression, and also provide evidence supporting ZBTB38 as a potential prognosis marker for prostate cancer.
Collapse
Affiliation(s)
- Guanxiong Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wei Lu
- School of Nursing, Suzhou Vocational Health College, Suzhou, China
| | - Qing Zhang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Kai Li
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Huihui Zhou
- Department of pathology, Affiliated Yuhuangding Hospital of Qingdao University, Qingdao, China
| | - Fei Wang
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Chunchun Zhao
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Caibin Fan
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Jianqing Wang
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China.
| |
Collapse
|
37
|
Zhao Y, Suo Y, Yang Z, Hao Y, Li W, Su Y, Shi Y, Gao Y, Song L, Yin X, Shi H. Inspiration for the prevention and treatment of neuropsychiatric disorders: New insight from the bone-brain-axis. Brain Res Bull 2021; 177:263-272. [PMID: 34678443 DOI: 10.1016/j.brainresbull.2021.10.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/09/2021] [Accepted: 10/15/2021] [Indexed: 11/30/2022]
Abstract
Bone is the main supporting structure of the body and the main organ involved in body movement and calcium and phosphorus metabolism. Recent studies have shown that bone is also a potential new endocrine organ that participates in the physiological and pathophysiological processes of the cardiovascular, digestive, and endocrine systems through various bioactive cytokines secreted by bone cells and bone marrow. Bone-derived active cytokines can also directly act on the central nervous system and regulate brain function and individual behavior. The bidirectional regulation of the bone-brain axis has gradually attracted attention in the field of neuroscience. This paper reviews the regulatory effects of bone-derived active cytokines and bone-derived cells on individual brain function and brain diseases, as well as the occurrence and development of related neuropsychiatric diseases. The central regulatory mechanism function is briefly introduced, which will broaden the scope for mechanistic research and help establish prevention and treatment strategies for neuropsychiatric diseases based on the bone-brain axis.
Collapse
Affiliation(s)
- Ye Zhao
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Yining Suo
- Child Health Department, Hebei Children's Hospital, Shijiazhuang 050031, China
| | - Zhenbang Yang
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Ying Hao
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Wenshuya Li
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Yujiao Su
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China
| | - Yun Shi
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China
| | - Yuan Gao
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China
| | - Li Song
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China
| | - Xi Yin
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Department of Functional Region of Diagnosis, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
| | - Haishui Shi
- Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang 050017, China.
| |
Collapse
|
38
|
Myeloma-Bone Interaction: A Vicious Cycle via TAK1-PIM2 Signaling. Cancers (Basel) 2021; 13:cancers13174441. [PMID: 34503251 PMCID: PMC8431187 DOI: 10.3390/cancers13174441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Myeloma cells interact with their ambient cells in the bone, such as bone marrow stromal cells, osteoclasts, and osteocytes, resulting in enhancement of osteoclastogenesis and inhibition of osteoblastogenesis while enhancing their growth and drug resistance. The activation of the TAK1–PIM2 signaling axis appears to be vital for this mutual interaction, posing it as an important therapeutic target to suppress tumor expansion and ameliorate bone destruction in multiple myeloma. Abstract Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM.
Collapse
|
39
|
Reamer-irrigator-aspirate versus bone marrow aspirate concentrate for osteoprogenitor cell retention and osteoinductive protein release on cancellous bone. J Orthop 2021; 27:13-16. [PMID: 34434001 DOI: 10.1016/j.jor.2021.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022] Open
Abstract
Bone defects often require operative intervention with the use of bone graft. Two sources of autologous bone graft include reamer-irrigator-aspirate (RIA) and bone marrow aspirate concentrate (BMC). Osteoprogenitor cells and osteoconductive proteins have been identified in both sources. This study collected samples of these cells and proteins from a canine model and cultured them on human cancellous allograft bone blocks. Findings suggest that BMC may be preferred for indications that allow for delivery via injection, saturation of the patient's tissues, or an implanted scaffold, whereas RIA may be preferred when the biologic augment is delivered as a scaffold or graft.
Collapse
|
40
|
Stuss M, Migdalska-Sek M, Brzezianska-Lasota E, Michalska-Kasiczak M, Bazela P, Sewerynek E. Assessment of Wnt pathway selected gene expression levels in peripheral blood mononuclear cells (PBMCs) of postmenopausal patients with low bone mass. Bosn J Basic Med Sci 2021; 21:461-470. [PMID: 33357212 PMCID: PMC8292866 DOI: 10.17305/bjbms.2020.5179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/17/2020] [Indexed: 12/17/2022] Open
Abstract
The purpose of the study was to assess the expression of selected genes of the Wnt pathway: APC, AXIN1, CTNNB1, DKK1, GSK3B, KREMEN1, SFRP1, and WNT1 in peripheral blood mononuclear cells (PBMC) of patients, selected in consideration of their bone mineral density (BMD), and the occurrence of low-energy fractures. The study involved 45 postmenopausal women, divided into four groups, according to BMD and fracture history. Measurements of laboratory parameters and RNA expression in PBMC cells were carried out in material, collected once at the inclusion visit. The densitometric examination was performed on all participants. In the analysis of the relative expression levels (RELs) of the studied genes in the entire population, we observed an overexpression for SFRP1 in 100% of samples and WNT1. In addition, the REL of DKK1, APC, and GSK3B genes were slightly elevated versus the calibrator. In contrast, CTNNB1 and AXIN1 presented with a slightly decreased RELs. Analysis did not show any significant differences among the groups in the relative gene expression levels (p < 0.05) of particular genes. However, we have observed quite numerous interesting correlations between the expression of the studied genes and BMD, the presence of fractures, and laboratory parameters, both in the whole studied population as well as in selected groups. In conclusion, the high level of CTNNB1 expression maintains normal BMD and/or protects against fractures. It also appears that the changes in expression levels of the Wnt pathway genes in PBMCs reflect the expected changes in bone tissue.
Collapse
Affiliation(s)
- Michal Stuss
- Department of Endocrine Disorders and Bone Metabolism, Chair of Endocrinology, Medical University of Lodz, Lodz, Poland; Outpatient Clinic of Osteoporosis, Regional Center of Menopause and Osteoporosis, Military Medical Academy Memorial Teaching Hospital of the Medical University of Lodz - Central Veterans' Hospital, Lodz, Poland
| | - Monika Migdalska-Sek
- Outpatient Clinic of Osteoporosis, Regional Center of Menopause and Osteoporosis, Military Medical Academy Memorial Teaching Hospital of the Medical University of Lodz - Central Veterans' Hospital, Lodz, Poland; Department of Biomedicine and Genetics, Chair of Biology and Medical Parasitology, Medical University of Lodz, Lodz, Poland
| | - Ewa Brzezianska-Lasota
- Department of Biomedicine and Genetics, Chair of Biology and Medical Parasitology, Medical University of Lodz, Lodz, Poland
| | - Marta Michalska-Kasiczak
- Department of Endocrine Disorders and Bone Metabolism, Chair of Endocrinology, Medical University of Lodz, Lodz, Poland
| | - Pawel Bazela
- Department of Endocrine Disorders and Bone Metabolism, Chair of Endocrinology, Medical University of Lodz, Lodz, Poland
| | - Ewa Sewerynek
- Department of Endocrine Disorders and Bone Metabolism, Chair of Endocrinology, Medical University of Lodz, Lodz, Poland; Outpatient Clinic of Osteoporosis, Regional Center of Menopause and Osteoporosis, Military Medical Academy Memorial Teaching Hospital of the Medical University of Lodz - Central Veterans' Hospital, Lodz, Poland
| |
Collapse
|
41
|
Long-Term Administration of Abacavir and Etravirine Impairs Semen Quality and Alters Redox System and Bone Metabolism in Growing Male Wistar Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5596090. [PMID: 34373766 PMCID: PMC8349296 DOI: 10.1155/2021/5596090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/24/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
Highly active antiretroviral therapy (HAART) is used in HIV-infected patients. Alongside the prolongation of patients' life, adverse side effects associated with long-term therapy are becoming an increasing problem. Therefore, optimizing of HAART is extremely important. The study is aimed at evaluating the toxicity of abacavir and etravirine in monotherapy on the reproductive system, liver, kidneys, and bones in young, sexually mature, male rats. Thirty-six 8-week-old male Wistar rats randomized into three 12-animal groups received either normal saline (control), abacavir 60 mg/kg (AB group), or etravirine 40 mg/kg (ET group) once daily for 16 weeks. Semen morphology, oxide-redox state parameters (MDA, SOD, catalase, GPx, glutathione, GSH/GSSG ratio) in tissue homogenates (testes, liver, kidneys), and serum samples were studied. In bones, microcomputed tomography and a four-point bending test were performed. Total sperm count, sperm concentration, motility, and sperm morphology did not differ significantly in AB or ET groups compared to the control. In the flow cytometry of semen, an increased percentage of cells with denatured DNA was noticed for both tested drugs. However, no significant changes of oxide-redox state in testicular homogenates were found, except of increased SOD activity in the AB-receiving group. Additionally, ET significantly altered catalase and GPx in the liver and SOD activity in kidneys. Abacavir decreased catalase in the liver and GSH levels in kidneys. AB caused significant changes to bone microarchitecture (bone volume fraction, trabecular number, connectivity density, total porosity) and increased Young's modulus. Etravirine had a greater impact on macrometric parameters of bones (tibial index, mid-tibial diameter, femur length). After 4 weeks in the ET group, a lower 1,25-dihydroxyvitamin D3 serum concentration was found. The results showed that abacavir and etravirine disturb oxidative stress. An increase in the percentage of sperms with chromatin damage suggests decreased fertility in rats receiving the studied drugs. Both drugs affected bone formation in growing rats. Additionally, etravirine disturbed vitamin D metabolism.
Collapse
|
42
|
Kimura H, Sada R, Takada N, Harada A, Doki Y, Eguchi H, Yamamoto H, Kikuchi A. The Dickkopf1 and FOXM1 positive feedback loop promotes tumor growth in pancreatic and esophageal cancers. Oncogene 2021; 40:4486-4502. [PMID: 34117362 PMCID: PMC8249240 DOI: 10.1038/s41388-021-01860-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/30/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
Dickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5'-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.
Collapse
Affiliation(s)
- Hirokazu Kimura
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Ryota Sada
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Naoki Takada
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Akikazu Harada
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hideki Yamamoto
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Akira Kikuchi
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.
| |
Collapse
|
43
|
Feizi S, Alemzadeh-Ansari M, Karimian F, Esfandiari H. Use of erythropoietin in ophthalmology: a review. Surv Ophthalmol 2021; 67:427-439. [PMID: 34157346 DOI: 10.1016/j.survophthal.2021.06.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 06/08/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022]
Abstract
Erythropoietin (EPO) is a glycoprotein hormone that regulates hematopoiesis in the human body. The presence of EPO and its receptors in different tissues indicates that this hormone has extramedullary effects in other tissues, including the eye. We focus on the biological roles of this hormone in the development and normal physiologic functions of the eye. Furthermore, we explore the role of EPO in the management of different ocular diseases - including diabetic retinopathy, retinopathy of prematurity, inherited retinal degeneration, branch and central retinal vein occlusion, retinal detachment, traumatic optic neuropathy, optic neuritis, methanol optic neuropathy, nonarteritic anterior ischemic optic neuropathy, glaucoma, and scleral necrosis.
Collapse
Affiliation(s)
- Sepehr Feizi
- Ophthalmic Research Center, Department of Ophthalmology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | | | - Farid Karimian
- Ophthalmic Research Center, Department of Ophthalmology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Esfandiari
- Department of Ophthalmology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| |
Collapse
|
44
|
Povoroznyuk VV, Dedukh NV, Bystrytska MA, Shapovalov VS. Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms. REGULATORY MECHANISMS IN BIOSYSTEMS 2021. [DOI: 10.15421/022130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This review provides a rationale for the cellular and molecular mechanisms of bone remodeling stages under physiological conditions and glucocorticoids (GCs) in excess. Remodeling is a synchronous process involving bone resorption and formation, proceeding through stages of: (1) resting bone, (2) activation, (3) bone resorption, (4) reversal, (5) formation, (6) termination. Bone remodeling is strictly controlled by local and systemic regulatory signaling molecules. This review presents current data on the interaction of osteoclasts, osteoblasts and osteocytes in bone remodeling and defines the role of osteoprogenitor cells located above the resorption area in the form of canopies and populating resorption cavities. The signaling pathways of proliferation, differentiation, viability, and cell death during remodeling are presented. The study of signaling pathways is critical to understanding bone remodeling under normal and pathological conditions. The main signaling pathways that control bone resorption and formation are RANK / RANKL / OPG; M-CSF – c-FMS; canonical and non-canonical signaling pathways Wnt; Notch; MARK; TGFβ / SMAD; ephrinB1/ephrinB2 – EphB4, TNFα – TNFβ, and Bim – Bax/Bak. Cytokines, growth factors, prostaglandins, parathyroid hormone, vitamin D, calcitonin, and estrogens also act as regulators of bone remodeling. The role of non-encoding microRNAs and long RNAs in the process of bone cell differentiation has been established. MicroRNAs affect many target genes, have both a repressive effect on bone formation and activate osteoblast differentiation in different ways. Excess of glucocorticoids negatively affects all stages of bone remodeling, disrupts molecular signaling, induces apoptosis of osteocytes and osteoblasts in different ways, and increases the life cycle of osteoclasts. Glucocorticoids disrupt the reversal stage, which is critical for the subsequent stages of remodeling. Negative effects of GCs on signaling molecules of the canonical Wingless (WNT)/β-catenin pathway and other signaling pathways impair osteoblastogenesis. Under the influence of excess glucocorticoids biosynthesis of biologically active growth factors is reduced, which leads to a decrease in the expression by osteoblasts of molecules that form the osteoid. Glucocorticoids stimulate the expression of mineralization inhibitor proteins, osteoid mineralization is delayed, which is accompanied by increased local matrix demineralization. Although many signaling pathways involved in bone resorption and formation have been discovered and described, the temporal and spatial mechanisms of their sequential turn-on and turn-off in cell proliferation and differentiation require additional research.
Collapse
|
45
|
Gerosa L, Lombardi G. Bone-to-Brain: A Round Trip in the Adaptation to Mechanical Stimuli. Front Physiol 2021; 12:623893. [PMID: 33995117 PMCID: PMC8120436 DOI: 10.3389/fphys.2021.623893] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Besides the classical ones (support/protection, hematopoiesis, storage for calcium, and phosphate) multiple roles emerged for bone tissue, definitively making it an organ. Particularly, the endocrine function, and in more general terms, the capability to sense and integrate different stimuli and to send signals to other tissues, has highlighted the importance of bone in homeostasis. Bone is highly innervated and hosts all nervous system branches; bone cells are sensitive to most of neurotransmitters, neuropeptides, and neurohormones that directly affect their metabolic activity and sensitivity to mechanical stimuli. Indeed, bone is the principal mechanosensitive organ. Thanks to the mechanosensing resident cells, and particularly osteocytes, mechanical stimulation induces metabolic responses in bone forming (osteoblasts) and bone resorbing (osteoclasts) cells that allow the adaptation of the affected bony segment to the changing environment. Once stimulated, bone cells express and secrete, or liberate from the entrapping matrix, several mediators (osteokines) that induce responses on distant targets. Brain is a target of some of these mediator [e.g., osteocalcin, lipocalin2, sclerostin, Dickkopf-related protein 1 (Dkk1), and fibroblast growth factor 23], as most of them can cross the blood-brain barrier. For others, a role in brain has been hypothesized, but not yet demonstrated. As exercise effectively modifies the release and the circulating levels of these osteokines, it has been hypothesized that some of the beneficial effects of exercise on brain functions may be associated to such a bone-to-brain communication. This hypothesis hides an interesting clinical clue: may well-addressed physical activities support the treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases?
Collapse
Affiliation(s)
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy.,Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
| |
Collapse
|
46
|
Lehmann J, Thiele S, Baschant U, Rachner TD, Niehrs C, Hofbauer LC, Rauner M. Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss. iScience 2021; 24:102224. [PMID: 33748710 PMCID: PMC7961106 DOI: 10.1016/j.isci.2021.102224] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 01/16/2021] [Accepted: 02/19/2021] [Indexed: 12/17/2022] Open
Abstract
The Wnt inhibitor Dickkopf-1 (DKK1) is a negative regulator of bone formation and bone mass and is dysregulated in various bone diseases. How DKK1 contributes to postmenopausal osteoporosis, however, remains poorly understood. Here, we show that mice lacking DKK1 in T cells are protected from ovariectomy-induced bone loss. Ovariectomy activated CD4+ and CD8+ T cells and increased their production of DKK1. Co-culture of activated T cells with osteoblasts inhibited Wnt signaling in osteoblasts, leading to impaired differentiation. Importantly, DKK1 expression in T cells also controlled physiological bone remodeling. T-cell-deficient Dkk1 knock-out mice had a higher bone mass with an increased bone formation rate and decreased numbers of osteoclasts compared with controls, a phenotype that was rescued by adoptive transfer of wild-type T cells. Thus, these findings highlight that T cells control bone remodeling in health and disease via their expression of DKK1.
Collapse
Affiliation(s)
- Juliane Lehmann
- Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Sylvia Thiele
- Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Ulrike Baschant
- Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Tilman D Rachner
- Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Christof Niehrs
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany.,Institute of Molecular Biology, Mainz, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.,Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| |
Collapse
|
47
|
Martínez-Gil N, Roca-Ayats N, Atalay N, Pineda-Moncusí M, Garcia-Giralt N, Van Hul W, Boudin E, Ovejero D, Mellibovsky L, Nogués X, Díez-Pérez A, Grinberg D, Balcells S. Functional Assessment of Coding and Regulatory Variants From the DKK1 Locus. JBMR Plus 2020; 4:e10423. [PMID: 33354644 PMCID: PMC7745885 DOI: 10.1002/jbm4.10423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 10/03/2020] [Indexed: 12/17/2022] Open
Abstract
The DKK1 gene encodes an extracellular inhibitor of the Wnt pathway with an important role in bone tissue development, bone homeostasis, and different critical aspects of bone biology. Several BMD genome‐wide association studies (GWASs) have consistently found association with SNPs in the DKK1 genomic region. For these reasons, it is important to assess the functionality of coding and regulatory variants in the gene. Here, we have studied the functionality of putative regulatory variants, previously found associated with BMD in different studies by others and ourselves, and also six missense variants present in the general population. Using a Wnt‐pathway‐specific luciferase reporter assay, we have determined that the variants p.Ala41Thr, p.Tyr74Phe, p.Arg120Leu, and p.Ser157Ile display a reduced DKK1 inhibitory capacity as compared with WT. This result agrees with the high‐bone‐mass (HBM) phenotype of two women from our cohort who carried mutations p.Tyr74Phe or p.Arg120Leu. On the other hand, by means of a circularized chromosome conformation capture‐ (4C‐) sequencing experiment, we have detected that the region containing 24 BMD‐GWA variants, located 350‐kb downstream of DKK1, interacts both with DKK1 and the LNCAROD (LncRNA‐activating regulator of DKK1, AKA LINC0148) in osteoblastic cells. In conclusion, we have shown that some rare coding variants are partial loss‐of‐function mutations that may lead to a HBM phenotype, whereas the common SNPs associated with BMD in GWASs belong to a putative long‐range regulatory region, through a yet unknown mechanism involving LNCAROD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Collapse
Affiliation(s)
- Núria Martínez-Gil
- Department of Genetics, Microbiology and Statistics, Faculty of Biology Universitat de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD) Barcelona Spain
| | - Neus Roca-Ayats
- Department of Genetics, Microbiology and Statistics, Faculty of Biology Universitat de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD) Barcelona Spain
| | - Nurgül Atalay
- Department of Genetics, Microbiology and Statistics, Faculty of Biology Universitat de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD) Barcelona Spain
| | - Marta Pineda-Moncusí
- Musculoskeletal Research Group, Hospital del Mar Medical Research Institute Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable, ISCIII Barcelona Spain
| | - Natàlia Garcia-Giralt
- Musculoskeletal Research Group, Hospital del Mar Medical Research Institute Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable, ISCIII Barcelona Spain
| | - Wim Van Hul
- Center of Medical Genetics University of Antwerp & University Hospital Antwerp Antwerp Belgium
| | - Eveline Boudin
- Center of Medical Genetics University of Antwerp & University Hospital Antwerp Antwerp Belgium
| | - Diana Ovejero
- Musculoskeletal Research Group, Hospital del Mar Medical Research Institute Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable, ISCIII Barcelona Spain
| | - Leonardo Mellibovsky
- Musculoskeletal Research Group, Hospital del Mar Medical Research Institute Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable, ISCIII Barcelona Spain
| | - Xavier Nogués
- Musculoskeletal Research Group, Hospital del Mar Medical Research Institute Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable, ISCIII Barcelona Spain
| | - Adolfo Díez-Pérez
- Musculoskeletal Research Group, Hospital del Mar Medical Research Institute Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable, ISCIII Barcelona Spain
| | - Daniel Grinberg
- Department of Genetics, Microbiology and Statistics, Faculty of Biology Universitat de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD) Barcelona Spain
| | - Susanna Balcells
- Department of Genetics, Microbiology and Statistics, Faculty of Biology Universitat de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD) Barcelona Spain
| |
Collapse
|
48
|
Iemura S, Kawao N, Akagi M, Kaji H. Role of Dkk2 in the Muscle/bone Interaction of Androgen-Deficient Mice. Exp Clin Endocrinol Diabetes 2020; 129:770-775. [PMID: 33352594 DOI: 10.1055/a-1331-7021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Androgen deficiency is known to cause both osteoporosis and sarcopenia. Myokines, humoral factors secreted from the skeletal muscles, have recently been getting attention as the key factors related to the interactions between muscle and bone. Dickkopf (Dkk) 2 is known as an inhibitor of canonical Wnt/β-catenin signaling, and Wnt/β-catenin signaling is crucial for the maintenance of muscle and bone. The present study was therefore performed to investigate the roles of Dkk2 in the alterations of muscle and bone of androgen-deficient mice with orchidectomy (ORX). ORX significantly enhanced Dkk2 mRNA levels, but not other Dkks and secreted frizzled related proteins, in the soleus muscles of mice. Moreover, ORX enhanced serum Dkk2 levels, but not Dkk2 mRNA levels in the tibial bone tissues, the white adipose tissues and liver of mice. In simple regression analyses, serum Dkk2 levels were negatively related to trabecular bone mineral density at the tibias in mice employed in the experiments. In vitro experiments, testosterone suppressed Dkk2 mRNA levels in mouse muscle C2C12 cells. In conclusion, we showed that androgen deficiency enhances Dkk2 expression and secretion in the muscles of mice. Dkk2 might be involved in androgen deficiency-induced muscle wasting and osteopenia as a myokine linking muscle to bone.
Collapse
Affiliation(s)
- Shunki Iemura
- Department of Orthopaedic Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan.,Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Masao Akagi
- Department of Orthopaedic Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osakasayama, Japan
| |
Collapse
|
49
|
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.
Collapse
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;
| |
Collapse
|
50
|
Association of Dickkopf-1 Polymorphisms With Radiological Damage and Periodontal Disease in Patients With Early Rheumatoid Arthritis. J Clin Rheumatol 2020; 26:S187-S194. [DOI: 10.1097/rhu.0000000000001391] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|