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Noorizadeh S, Tehranchi M, Taleghani F, Hakimiha N, Pourhajibagher M, Hodjat M. Effects of photobiomodulation therapy with 808 nm diode laser on the expression of RANKL and OPG genes in exosomes isolated from MG63 osteoblast-like cells: An in-vitro study. Photodiagnosis Photodyn Ther 2025; 53:104566. [PMID: 40122481 DOI: 10.1016/j.pdpdt.2025.104566] [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: 12/21/2024] [Revised: 03/10/2025] [Accepted: 03/21/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND AND AIM This study assessed the effects of 808 nm diode laser on the gene expression of receptor activator of nuclear factor kappa beta ligand (RANKL) and osteoprotegerin (OPG), key regulators of bone remodeling, in exosomes derived from osteoblast-like cells. MATERIALS AND METHODS The cultured MG63 cells were subjected to 808 nm diode laser irradiation at energy densities of 3 J/cm², 6 J/cm², and 9 J/cm², along with a control group with no intervention. The irradiation sessions were conducted twice, with a 24-hour interval between them. Next the exosomes from the target cells were isolated, and the mRNA levels of the RANKL and OPG genes were assessed using qPCR. RESULTS The OPG mRNA level in exosomes extracted from cells exposed to 9 J/cm² was found to be significantly elevated compared to both the control group and 6 J/cm². Conversely, the mRNA level of RANKL in group exposed to 9 J/cm² was significantly reduced in comparison to the control group and 6 J/cm². Additionally, the RANKL mRNA level in 6 J/cm² was also significantly lower than that observed in the control group and 3 J/cm². CONCLUSION Using 808 nm diode laser at an energy density of 9 J/cm² resulted in an upregulation of exosomal mRNA for OPG and a downregulation of RANKL. Photobiomodulation may enhance bone regeneration via exosomal signaling. Considering the promising clinical application of exosomes in bone regeneration, our results highlight the potential of photobiomodulation to manipulate exosomal content for therapeutic purposes.
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Affiliation(s)
- Sara Noorizadeh
- Department of Periodontics, Faculty of Dentistry, Shahed University, Tehran, Iran
| | - Maryam Tehranchi
- Department of Periodontics, Faculty of Dentistry, Shahed University, Tehran, Iran
| | - Ferial Taleghani
- Department of Periodontics, Faculty of Dentistry, Shahed University, Tehran, Iran
| | - Neda Hakimiha
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Pourhajibagher
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mahshid Hodjat
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Xu H, Zhou Z, Wen F, Sun H, Hou J. Inhibiting autophagy further promotes Ginkgolide B's anti-osteoclastogenesis ability. Bone 2025; 192:117348. [PMID: 39617111 DOI: 10.1016/j.bone.2024.117348] [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: 09/08/2024] [Revised: 11/18/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
Excessive osteoclast activity could cause skeletal diseases including osteoporosis. Additionally, autophagy plays an initial role in osteoclast differentiation and function. Ginkgolide B (GB), a key compound in Ginkgo biloba, improves bone mass and suppresses mature osteoclast formation in vitro. This study examines the role of GB role in regulating osteoclast formation via autophagy. Using murine bone marrow-derived macrophages in vitro, we explored GB's effects on autophagy and osteoclast formation. We also assessed bone loss prevention in an ovariectomized (OVX) mouse model using GB combined with an autophagy inhibitor. Tartrate-resistant acid phosphatase staining was used to observe osteoclast formation. Autophagy-related proteins and intracellular microtubule associated protein 1 light chain 3 beta puncta were observed using western blotting and immunofluorescence. The impact of GB on OVX mice was evaluated using micro-computed tomography and hematoxylin and eosin staining. GB directly promoted autophagy in osteoclast precursors (OCPs), but inhibited osteoclast differentiation by reducing receptor activator of nuclear factor kappa B ligand (RANKL)-induced autophagy. GB inhibits the phosphorylation of RANKL downstream signaling pathways, such as Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). Anisomycin (ANI), a JNK activator, reversed GB's inhibitory effects on RANKL-induced autophagy and osteoclastogenesis. Inhibiting autophagy using 3-Methyladenine (3-MA) or small interfering RNA significantly suppressed osteoclast differentiation both in vitro and in vivo. Our findings suggested that GB inhibits osteoclast formation by decreasing JNK phosphorylation and autophagy under RANKL stimulation. Interestingly, GB also directly promotes autophagy in OCPs. Thus, GB markedly reduces osteoclast differentiation and prevents bone loss, with its anti-osteoclastogenesis effect being enhanced by 3-MA. Accordingly, inhibiting GB-induced direct autophagy could further increase its therapeutic effect on bone disease resulting from excessive osteoclast activity.
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Affiliation(s)
- Haoying Xu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China; Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Zijie Zhou
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China; Department of Orthopedics, Orthopedic and Sports Medicine Center, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, China
| | - Fuli Wen
- Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, China
| | - Hong Sun
- Department of Pharmacy, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, China.
| | - Jianming Hou
- Department of Endocrinology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, China.
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Lanzolla G, Sabini E, Beigel K, Khan MP, Sherry Liu X, Wang D, Laslow B, Taylor D, Bellido T, Giaccia A, Schipani E. Pharmacological inhibition of HIF2 protects against bone loss in an experimental model of estrogen deficiency. Proc Natl Acad Sci U S A 2024; 121:e2416004121. [PMID: 39602268 PMCID: PMC11626196 DOI: 10.1073/pnas.2416004121] [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: 08/23/2024] [Accepted: 11/02/2024] [Indexed: 11/29/2024] Open
Abstract
Estrogen deficiency, which is linked to various pathological conditions such as primary ovarian insufficiency and postmenopausal osteoporosis, disrupts the delicate balance between bone formation and resorption. This imbalance leads to bone loss and an increased risk of fractures, primarily due to a significant reduction in trabecular bone mass. Trabecular osteoblasts, the cells responsible for bone formation within the trabecular compartment, originate from skeletal progenitors located in the bone marrow. The microenvironment of the bone marrow contains hypoxic (low oxygen) regions, and the hypoxia-inducible factor-2α (HIF2) plays a crucial role in cellular responses to these low-oxygen conditions. This study demonstrates that the loss of HIF2 in skeletal progenitors and their derivatives during development enhances trabecular bone mass by promoting bone formation. More importantly, PT2399, a small molecule that specifically inhibits HIF2, effectively prevents trabecular bone loss in ovariectomized adult mice, a model for estrogen-deficient bone loss. Both the genetic and pharmacological approaches result in an increase in osteoblast number, which is linked to the expansion of the pool of skeletal progenitor cells. This expansion either by loss or inhibition of HIF2 uncovers a pivotal mechanism for increasing osteoblast numbers and bone formation, resulting in greater trabecular bone mass.
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Affiliation(s)
- Giulia Lanzolla
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA19104
| | - Elena Sabini
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA19104
| | - Katherine Beigel
- Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Mohd Parvez Khan
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA19104
| | - Xiaowei Sherry Liu
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA19104
| | - Dian Wang
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA19104
| | - Brittany Laslow
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA19104
| | - Deanne Taylor
- Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Teresita Bellido
- Department of Physiology and Cell Biology, University of Arkansas, School of Medicine, Little Rock, AR72205
- Central Arkansas Veterans Healthcare System, John L. McClellan, Little Rock, AR72205
| | - Amato Giaccia
- Department of Oncology, University of Oxford, Division of Medical Sciences, OxfordOX37DQ, United Kingdom
| | - Ernestina Schipani
- Department of Orthopaedic Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA19104
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Lourenço ES, Rocha NRS, de Lima Barbosa R, Mello-Machado RC, de Souza Lima VH, Leite PEC, Pereira MR, Casado PL, Kawase T, Mourão CF, Alves GG. Investigating the Biological Efficacy of Albumin-Enriched Platelet-Rich Fibrin (Alb-PRF): A Study on Cytokine Dynamics and Osteoblast Behavior. Int J Mol Sci 2024; 25:11531. [PMID: 39519084 PMCID: PMC11547010 DOI: 10.3390/ijms252111531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/19/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
The development of effective biomaterials for tissue regeneration has led to the exploration of blood derivatives such as leucocyte- and platelet-rich fibrin (L-PRF). A novel variant, Albumin-Enriched Platelet-Rich Fibrin (Alb-PRF), has been introduced to improve structural stability and bioactivity, making it a promising candidate for bone regeneration. This study aimed to evaluate Alb-PRF's capacity for cytokine and growth factor release, along with its effects on the proliferation, differentiation, and mineralization of human osteoblasts in vitro. Alb-PRF membranes were analyzed using histological, scanning electron microscopy, and fluorescence microscopy techniques. Cytokine and growth factor release was quantified over seven days, and osteoinductive potential was evaluated with MG-63 osteoblast-like cells. Structural analysis showed Alb-PRF as a biphasic, highly cellularized material that releases lower levels of inflammatory cytokines and higher concentrations of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) compared to L-PRF. Alb-PRF exhibited higher early alkaline phosphatase activity and in vitro mineralization (p < 0.05) and significantly increased the OPG/RANKL mRNA ratio (p < 0.05). These results indicate that Alb-PRF has promising potential as a scaffold for bone repair, warranting further in vivo and clinical assessments to confirm its suitability for clinical applications.
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Affiliation(s)
- Emanuelle Stellet Lourenço
- Clinical Research Unit, Antonio Pedro Hospital, Fluminense Federal University, Niteroi 24033-900, Brazil; (E.S.L.); (N.R.S.R.); (R.d.L.B.); (R.C.M.-M.); (V.H.d.S.L.); (G.G.A.)
| | - Neilane Rodrigues Santiago Rocha
- Clinical Research Unit, Antonio Pedro Hospital, Fluminense Federal University, Niteroi 24033-900, Brazil; (E.S.L.); (N.R.S.R.); (R.d.L.B.); (R.C.M.-M.); (V.H.d.S.L.); (G.G.A.)
- Graduate Program in Science and Biotechnology, Fluminense Federal University, Niteroi 24210-201, Brazil; (P.E.C.L.); (M.R.P.)
| | - Renata de Lima Barbosa
- Clinical Research Unit, Antonio Pedro Hospital, Fluminense Federal University, Niteroi 24033-900, Brazil; (E.S.L.); (N.R.S.R.); (R.d.L.B.); (R.C.M.-M.); (V.H.d.S.L.); (G.G.A.)
- Graduate Program in Science and Biotechnology, Fluminense Federal University, Niteroi 24210-201, Brazil; (P.E.C.L.); (M.R.P.)
| | - Rafael Coutinho Mello-Machado
- Clinical Research Unit, Antonio Pedro Hospital, Fluminense Federal University, Niteroi 24033-900, Brazil; (E.S.L.); (N.R.S.R.); (R.d.L.B.); (R.C.M.-M.); (V.H.d.S.L.); (G.G.A.)
| | - Victor Hugo de Souza Lima
- Clinical Research Unit, Antonio Pedro Hospital, Fluminense Federal University, Niteroi 24033-900, Brazil; (E.S.L.); (N.R.S.R.); (R.d.L.B.); (R.C.M.-M.); (V.H.d.S.L.); (G.G.A.)
- Graduate Program in Science and Biotechnology, Fluminense Federal University, Niteroi 24210-201, Brazil; (P.E.C.L.); (M.R.P.)
| | - Paulo Emilio Correa Leite
- Graduate Program in Science and Biotechnology, Fluminense Federal University, Niteroi 24210-201, Brazil; (P.E.C.L.); (M.R.P.)
| | - Mariana Rodrigues Pereira
- Graduate Program in Science and Biotechnology, Fluminense Federal University, Niteroi 24210-201, Brazil; (P.E.C.L.); (M.R.P.)
| | - Priscila Ladeira Casado
- Department of Implant Dentistry, Dental School, Fluminense Federal University, Niteroi 24210-201, Brazil;
| | - Tomoyuki Kawase
- Division of Oral Bioengineering, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
| | - Carlos Fernando Mourão
- Department of Basic and Clinical Translational Sciences, Tufts University School of Dental Medicine, Boston, MA 02111, USA;
| | - Gutemberg Gomes Alves
- Clinical Research Unit, Antonio Pedro Hospital, Fluminense Federal University, Niteroi 24033-900, Brazil; (E.S.L.); (N.R.S.R.); (R.d.L.B.); (R.C.M.-M.); (V.H.d.S.L.); (G.G.A.)
- Graduate Program in Science and Biotechnology, Fluminense Federal University, Niteroi 24210-201, Brazil; (P.E.C.L.); (M.R.P.)
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Sims NA. Osteoclast-derived coupling factors: origins and state-of-play Louis V Avioli lecture, ASBMR 2023. J Bone Miner Res 2024; 39:1377-1385. [PMID: 38990205 PMCID: PMC11425696 DOI: 10.1093/jbmr/zjae110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/28/2024] [Accepted: 07/04/2024] [Indexed: 07/12/2024]
Abstract
Coupling, the mechanism that controls the sequence of events in bone remodeling, is a fundamental theory for understanding the way the skeleton changes throughout life. This review is an adapted version of the Louis V Avioli lecture, delivered at the Annual Scientific Meeting of the American Society of Bone and Mineral Research in 2023. It outlines the history of the coupling concept, details how coupling is thought to occur within trabecular and cortical bone, and describes its multiple contexts and the many mechanisms suggested to couple bone-forming osteoblasts to the prior action of osteoclasts on the same bone surface. These mechanisms include signals produced at each stage of the remodeling sequence (resorption, reversal, and formation), such as factors released by osteoclasts through their resorptive action and through protein synthesis, molecules deposited in the cement line during the reversal phase, and potential signals from osteocytes within the local bone environment. The review highlights two examples of coupling factors (Cardiotrophin 1 and EphrinB2:EphB4) to illustrate the limited data available, the need to integrate the many functions of these factors within the basic multicellular unit (BMU), and the multiple origins of these factors, including the other cell types present during the remodeling sequence (such as osteocytes, macrophages, endothelial cells, and T-cells).
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Affiliation(s)
- Natalie A Sims
- Bone Cell Biology and Diease Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria 3065, Australia
- Department of Medicine at St. Vincent’s Hospital Melbourne, The University of Melbourne, Fitzroy, Victoria 3065, Australia
- The Mary McKillop Institute for Health Research, Australian Catholic University, Fitzroy, Victoria 3065, Australia
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6
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Feng L, Lang Y, Feng Y, Tang X, Zhang Q, Xu H, Liu Y. Maternal F-53B exposure during pregnancy and lactation affects bone growth and development in male offspring. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 279:116501. [PMID: 38805831 DOI: 10.1016/j.ecoenv.2024.116501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 05/30/2024]
Abstract
6:2 Chlorinated polyfluoroalkyl ether sulfonate (F-53B) is a new type of perfluorinated and polyfluoroalkyl substance (PFAS) that is used extensively in industry and manufacturing. F-53B causes damage to multiple mammalian organs. However, the impacts of F-53B on bone are unknown. Maternal exposure to F-53B is of particular concern because of the vulnerability of the developing fetus and newborn to contaminants from the mother. The goal of this study was to examine the impacts of maternal F-53B exposure on bone growth and development in offspring and to explore its underlying mechanisms. Herein, C57BL/6 J mice were given free access to deionized water containing 0, 0.57, or 5.7 mg/L F-53B during pregnancy and lactation. F-53B exposure resulted in impaired liver function, decreased IGF-1 secretion, dysregulation of bone metabolism and disruption of the dynamic balance between osteoblasts and osteoclasts in male offspring. F-53B inhibits longitudinal bone growth and development and causes osteoporosis in male offspring. F-53B may affect the growth and development of offspring bone via the IGF-1/OPG/RANKL/CTSK signaling pathway. This study provides new insights for the study of short stature and bone injury caused by F-53B.
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Affiliation(s)
- Lihua Feng
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China
| | - Yuanyuan Lang
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China
| | - Yueying Feng
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China
| | - Xiaomin Tang
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China
| | - Qingqing Zhang
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China
| | - Hengyi Xu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, China
| | - Yang Liu
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China.
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Sheela S, Kheder W, Samsudin ABR. Investigating the influence of titanium particle size and concentration on osteogenic response of human osteoblasts - in vitro study. Biomater Investig Dent 2024; 11:40843. [PMID: 38903775 PMCID: PMC11187976 DOI: 10.2340/biid.v11.40843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 05/16/2024] [Indexed: 06/22/2024] Open
Abstract
Purpose The purpose of this study was to investigate the correlation between the size and concentration of titanium particles and the osteogenic response of human osteoblasts (HOB). Materials and Methods Different concentrations of titanium dioxide nano- and micro-particles were prepared and their biocompatibility on HOBs was analyzed using XTT assay. The changes in the actin cytoskeletal organization were studied by confocal laser scanning microscopy. The generation of intracellular reactive oxygen species (ROS) by HOBs after exposure to titanium dioxide particles was analyzed using ROS assay. Besides, the osteogenic potential represented by alkaline phosphatase activity, osteoprotegerin, macrophage colony stimulating factor levels, and biomineralization were analyzed. Results Short-term interaction of titanium dioxide nano- and micro-particles did not induce toxicity to HOBs. However, cells treated with 100 μg/mL titanium dioxide nano- and micro-particles demonstrated higher ROS generation compared to control. Besides, cells treated with 100 μg/mL titanium dioxide nanoparticles showed higher alkaline phosphatase activity, osteoprotegerin, macrophage colony stimulating factor levels and biomineralization compared to titanium dioxide microparticles. Conclusion Collectively, the study found titanium dioxide nanoparticles to be more biocompatible than microparticles providing an insight into the capability of nanostructures in supporting osteoblast differentiation and its plausibility in biomedical applications.
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Affiliation(s)
- Soumya Sheela
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Waad Kheder
- College of Dental Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - A B Rani Samsudin
- College of Dental Medicine, University of Sharjah, Sharjah, United Arab Emirates
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Henning P, Westerlund A, Horkeby K, Lionikaite V, Nilsson KH, Movérare-Skrtic S, Conaway HH, Lerner UH. Vitamin A enhanced periosteal osteoclastogenesis is associated with increased number of tissue-derived macrophages/osteoclast progenitors. J Biol Chem 2024; 300:107308. [PMID: 38657862 PMCID: PMC11163173 DOI: 10.1016/j.jbc.2024.107308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/27/2024] [Accepted: 04/15/2024] [Indexed: 04/26/2024] Open
Abstract
A deleterious effect of elevated levels of vitamin A on bone health has been reported in clinical studies. Mechanistic studies in rodents have shown that numbers of periosteal osteoclasts are increased, while endocortical osteoclasts are simultaneously decreased by vitamin A treatment. The present study investigated the in vitro and in vivo effect of all-trans retinoic acid (ATRA), the active metabolite of vitamin A, on periosteal osteoclast progenitors. Mouse calvarial bone cells were cultured in media containing ATRA, with or without the osteoclastogenic cytokine receptor activator of nuclear factor kappa B-ligand (RANKL), on plastic dishes or bone discs. Whereas ATRA did not stimulate osteoclast formation alone, the compound robustly potentiated the formation of RANKL-induced bone resorbing osteoclasts. This effect was due to stimulation by ATRA (half-maximal stimulation ∼3 nM) on the numbers of macrophages/osteoclast progenitors in the bone cell cultures, as assessed by mRNA and protein expression of several macrophage and osteoclast progenitor cell markers, such as macrophage colony-stimulating factor receptor, receptor activator of nuclear factor kappa B, F4/80, and CD11b, as well as by flow cytometry (FACS) analysis of CD11b+/F480+/Gr1- cells. The stimulation of macrophage numbers in the periosteal cell cultures was not mediated by increased macrophage colony-stimulating factor or interleukin-34. In contrast, ATRA did not enhance macrophages in bone marrow cell cultures. Importantly, ATRA treatment upregulated the mRNA expression of several macrophage-related genes in the periosteum of tibia in adult mice. These observations demonstrate a novel mechanism by which vitamin A enhances osteoclast formation specifically on periosteal surfaces.
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Affiliation(s)
- Petra Henning
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anna Westerlund
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Karin Horkeby
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Vikte Lionikaite
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Karin H Nilsson
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Sofia Movérare-Skrtic
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - H Herschel Conaway
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Ulf H Lerner
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
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Kavitha K, Navaneethan D, Balagurunathan R, Subramaniam RT, Shaik MR, Guru A. Exploring the biocompatibility and healing activity of actinobacterial-enhanced reduced nano-graphene oxide in in vitro and in vivo model and induce bone regeneration through modulation of OPG/RANKL/RUNX2/ALP pathways. Mol Biol Rep 2024; 51:702. [PMID: 38822942 DOI: 10.1007/s11033-024-09600-8] [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: 03/19/2024] [Accepted: 05/01/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND The development of cost-effective, simple, environment-friendly biographene is an area of interest. To accomplish environmentally safe, benign culturing that has advantages over other methods to reduce the graphene oxide (GO), extracellular metabolites from actinobacteria associated with mushrooms were used for the first time. METHODS Bactericidal effect of GO against methicillin-resistant Staphylococcus aureus, antioxidant activity, and hydroxyapatite-like bone layer formation, gene expression analysis and appropriate biodegradation of the microbe-mediated synthesis of graphene was studied. RESULTS Isolated extracellular contents Streptomyces achromogenes sub sp rubradiris reduced nano-GO to graphene (rGO), which was further examined by spectrometry and suggested an efficient conversion and significant reduction in the intensity of all oxygen-containing moieties and shifted crystalline peaks. Electron microscopic results also suggested the reduction of GO layer. In addition, absence of significant toxicity in MG-63 cell line, intentional free radical scavenging prowess, liver and kidney histopathology, and Wistar rat bone regeneration through modulation of OPG/RANKL/RUNX2/ALP pathways show the feasibility of the prepared nano GO. CONCLUSIONS The study demonstrates the successful synthesis of biographene from actinobacterial extracellular metabolites, its potential biomedical applications, and its promising role in addressing health and environmental concerns.
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Affiliation(s)
- K Kavitha
- Department of Biotechnology Paavai Engineering College, Pachal, Namakkal, Tamil Nadu, 637018, India.
- Center for Research and Development, K.S.Rangasamy College of Technology, Tiruchengode, Namakkal, 637215, India.
| | - D Navaneethan
- Department of Chemistry, J.K.K. Nataraja College of Arts and Science, Komarapalayam, Namakkal, Tamil Nadu, 638183, India
| | - R Balagurunathan
- Research and Development, Vivekanandha Educational Institutions, Elayampalayam, Tiruchengode, Namakkal, Tamil Nadu, 637 205, India.
| | - Ramesh T Subramaniam
- Department of Physics, Faculty of Science, Center for Ionics University of Malaya, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Mohammed Rafi Shaik
- Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh-11451, Saudi Arabia
| | - Ajay Guru
- Department of Cariology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, 600 077, India
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Chen W, Wang Q, Tao H, Lu L, Zhou J, Wang Q, Huang W, Yang X. Subchondral osteoclasts and osteoarthritis: new insights and potential therapeutic avenues. Acta Biochim Biophys Sin (Shanghai) 2024; 56:499-512. [PMID: 38439665 DOI: 10.3724/abbs.2024017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2024] Open
Abstract
Osteoarthritis (OA) is the most common joint disease, and good therapeutic results are often difficult to obtain due to its complex pathogenesis and diverse causative factors. After decades of research and exploration of OA, it has been progressively found that subchondral bone is essential for its pathogenesis, and pathological changes in subchondral bone can be observed even before cartilage lesions develop. Osteoclasts, the main cells regulating bone resorption, play a crucial role in the pathogenesis of subchondral bone. Subchondral osteoclasts regulate the homeostasis of subchondral bone through the secretion of degradative enzymes, immunomodulation, and cell signaling pathways. In OA, osteoclasts are overactivated by autophagy, ncRNAs, and Rankl/Rank/OPG signaling pathways. Excessive bone resorption disrupts the balance of bone remodeling, leading to increased subchondral bone loss, decreased bone mineral density and consequent structural damage to articular cartilage and joint pain. With increased understanding of bone biology and targeted therapies, researchers have found that the activity and function of subchondral osteoclasts are affected by multiple pathways. In this review, we summarize the roles and mechanisms of subchondral osteoclasts in OA, enumerate the latest advances in subchondral osteoclast-targeted therapy for OA, and look forward to the future trends of subchondral osteoclast-targeted therapies in clinical applications to fill the gaps in the current knowledge of OA treatment and to develop new therapeutic strategies.
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Affiliation(s)
- Wenlong Chen
- Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215000, China
- Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Qiufei Wang
- Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Huaqiang Tao
- Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Lingfeng Lu
- Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215000, China
- Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Jing Zhou
- Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215000, China
- Gusu School, Nanjing Medical University, Suzhou 215000, China
| | - Qiang Wang
- Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Wei Huang
- Department of Orthopaedics, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
| | - Xing Yang
- Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215000, China
- Gusu School, Nanjing Medical University, Suzhou 215000, China
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11
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Henning P, Kassem A, Westerlund A, Lundberg P, Engdahl C, Lionikaite V, Wikström P, Wu J, Li L, Lindholm C, de Souza PPC, Movérare-Skrtic S, Lerner UH. Toll-like receptor-2 induced inflammation causes local bone formation and activates canonical Wnt signaling. Front Immunol 2024; 15:1383113. [PMID: 38646530 PMCID: PMC11026618 DOI: 10.3389/fimmu.2024.1383113] [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: 02/06/2024] [Accepted: 03/11/2024] [Indexed: 04/23/2024] Open
Abstract
It is well established that inflammatory processes in the vicinity of bone often induce osteoclast formation and bone resorption. Effects of inflammatory processes on bone formation are less studied. Therefore, we investigated the effect of locally induced inflammation on bone formation. Toll-like receptor (TLR) 2 agonists LPS from Porphyromonas gingivalis and PAM2 were injected once subcutaneously above mouse calvarial bones. After five days, both agonists induced bone formation mainly at endocranial surfaces. The injection resulted in progressively increased calvarial thickness during 21 days. Excessive new bone formation was mainly observed separated from bone resorption cavities. Anti-RANKL did not affect the increase of bone formation. Inflammation caused increased bone formation rate due to increased mineralizing surfaces as assessed by dynamic histomorphometry. In areas close to new bone formation, an abundance of proliferating cells was observed as well as cells robustly stained for Runx2 and alkaline phosphatase. PAM2 increased the mRNA expression of Lrp5, Lrp6 and Wnt7b, and decreased the expression of Sost and Dkk1. In situ hybridization demonstrated decreased Sost mRNA expression in osteocytes present in old bone. An abundance of cells expressed Wnt7b in Runx2-positive osteoblasts and ß-catenin in areas with new bone formation. These data demonstrate that inflammation, not only induces osteoclastogenesis, but also locally activates canonical WNT signaling and stimulates new bone formation independent on bone resorption.
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Affiliation(s)
- Petra Henning
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Ali Kassem
- Department of Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Anna Westerlund
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Pernilla Lundberg
- Department of Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Cecilia Engdahl
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- Department of Rheumatology and Inflammation Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Vikte Lionikaite
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Pernilla Wikström
- Department of Medical Biosciences, Section of Pathology, Umeå University, Umeå, Sweden
| | - Jianyao Wu
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Lei Li
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Catharina Lindholm
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- Department of Rheumatology and Inflammation Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Pedro P. C. de Souza
- Innovation in Biomaterials Laboratory, Federal University of Goiás, Goiania, Brazil
| | - Sofia Movérare-Skrtic
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Ulf H. Lerner
- Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- Department of Molecular Periodontology, Umeå University, Umeå, Sweden
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12
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Li X, Chen W, Liu D, Chen P, Wang S, Li F, Chen Q, Lv S, Li F, Chen C, Guo S, Yuan W, Li P, Hu Z. Pathological progression of osteoarthritis: a perspective on subchondral bone. Front Med 2024; 18:237-257. [PMID: 38619691 DOI: 10.1007/s11684-024-1061-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/17/2024] [Indexed: 04/16/2024]
Abstract
Osteoarthritis (OA) is a degenerative bone disease associated with aging. The rising global aging population has led to a surge in OA cases, thereby imposing a significant socioeconomic burden. Researchers have been keenly investigating the mechanisms underlying OA. Previous studies have suggested that the disease starts with synovial inflammation and hyperplasia, advancing toward cartilage degradation. Ultimately, subchondral-bone collapse, sclerosis, and osteophyte formation occur. This progression is deemed as "top to bottom." However, recent research is challenging this perspective by indicating that initial changes occur in subchondral bone, precipitating cartilage breakdown. In this review, we elucidate the epidemiology of OA and present an in-depth overview of the subchondral bone's physiological state, functions, and the varied pathological shifts during OA progression. We also introduce the role of multifunctional signal pathways (including osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK), and chemokine (CXC motif) ligand 12 (CXCL12)/CXC motif chemokine receptor 4 (CXCR4)) in the pathology of subchondral bone and their role in the "bottom-up" progression of OA. Using vivid pattern maps and clinical images, this review highlights the crucial role of subchondral bone in driving OA progression, illuminating its interplay with the condition.
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Affiliation(s)
- Xuefei Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Wenhua Chen
- Research and Development Center of Chinese Medicine Resources and Biotechnology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dan Liu
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Pinghua Chen
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Shiyun Wang
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Fangfang Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Qian Chen
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Shunyi Lv
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Fangyu Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Chen Chen
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Suxia Guo
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Weina Yuan
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Pan Li
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Zhijun Hu
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
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13
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Henning P, Westerlund A, Movérare-Skrtic S, Lindholm C, Márquez-Méndez M, Nilsson S, Holmberg AR, Lerner UH. The novel cytotoxic polybisphosphonate osteodex decreases bone resorption by enhancing cell death of mature osteoclasts without affecting osteoclastogenesis of RANKL-stimulated mouse bone marrow macrophages. Invest New Drugs 2024; 42:207-220. [PMID: 38427117 PMCID: PMC10944397 DOI: 10.1007/s10637-024-01427-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/30/2024] [Indexed: 03/02/2024]
Abstract
It has previously been demonstrated that the polybisphosphonate osteodex (ODX) inhibits bone resorption in organ-cultured mouse calvarial bone. In this study, we further investigate the effects by ODX on osteoclast differentiation, formation, and function in several different bone organ and cell cultures. Zoledronic acid (ZOL) was used for comparison. In retinoid-stimulated mouse calvarial organ cultures, ODX and ZOL significantly reduced the numbers of periosteal osteoclasts without affecting Tnfsf11 or Tnfrsf11b mRNA expression. ODX and ZOL also drastically reduced the numbers of osteoclasts in cell cultures isolated from the calvarial bone and in vitamin D3-stimulated mouse crude bone marrow cell cultures. These data suggest that ODX can inhibit osteoclast formation by inhibiting the differentiation of osteoclast progenitor cells or by directly targeting mature osteoclasts. We therefore assessed if osteoclast formation in purified bone marrow macrophage cultures stimulated by RANKL was inhibited by ODX and ZOL and found that the initial formation of mature osteoclasts was not affected, but that the bisphosphonates enhanced cell death of mature osteoclasts. In agreement with these findings, ODX and ZOL did not affect the mRNA expression of the osteoclastic genes Acp5 and Ctsk and the osteoclastogenic transcription factor Nfatc1. When bone marrow macrophages were incubated on bone slices, ODX and ZOL inhibited RANKL-stimulated bone resorption. In conclusion, ODX does not inhibit osteoclast formation but inhibits osteoclastic bone resorption by decreasing osteoclast numbers through enhanced cell death of mature osteoclasts.
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Affiliation(s)
- Petra Henning
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Osteoporosis Centre, Sahlgrenska Academy at the University of Gothenburg, Vita Stråket 11, Gothenburg 41345, Sweden
| | - Anna Westerlund
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Osteoporosis Centre, Sahlgrenska Academy at the University of Gothenburg, Vita Stråket 11, Gothenburg 41345, Sweden
| | - Sofia Movérare-Skrtic
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Osteoporosis Centre, Sahlgrenska Academy at the University of Gothenburg, Vita Stråket 11, Gothenburg 41345, Sweden
| | - Catharina Lindholm
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Osteoporosis Centre, Sahlgrenska Academy at the University of Gothenburg, Vita Stråket 11, Gothenburg 41345, Sweden
| | | | - Sten Nilsson
- Department of Oncology and Pathology, Karolinska Institute, Stockholm SE-171 76, Sweden
| | - Anders R Holmberg
- Department of Oncology and Pathology, Karolinska Institute, Stockholm SE-171 76, Sweden
| | - Ulf H Lerner
- Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Osteoporosis Centre, Sahlgrenska Academy at the University of Gothenburg, Vita Stråket 11, Gothenburg 41345, Sweden.
- Molecular Periodontology, Faculty of Medicine, Umeå University, SE-901 87, Umeå, Sweden.
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14
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Dong B, Zhu J, Chen X, Jiang H, Deng Y, Xu L, Wang Y, Li S. The Emerging Role of Interleukin-(IL)-11/IL-11R in Bone Metabolism and Homeostasis: From Cytokine to Osteokine. Aging Dis 2023; 14:2113-2126. [PMID: 37199584 PMCID: PMC10676798 DOI: 10.14336/ad.2023.0306] [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: 01/03/2023] [Accepted: 03/06/2023] [Indexed: 05/19/2023] Open
Abstract
Interleukin-(IL)-11 is a cytokine involved in hematopoiesis, cancer metastasis, and inflammation. IL-11 belongs to the IL-6 cytokine family, binding to the complex of receptors glycoprotein gp130 and the ligand-specific-receptor subunits (IL-11Rα or their soluble counterpart sIL-11R). IL-11/IL-11R signaling enhances osteoblast differentiation and bone formation and mitigates osteoclast-induced bone resorption and cancer bone metastasis. Recent studies have shown that systemic and osteoblast/osteocyte-specific IL-11 deficiency leads to reduced bone mass and formation, but also adiposity, glucose intolerance, and insulin resistance. In humans, mutations of IL-11 and the receptor IL-11RA genes are associated with height reduction, osteoarthritis, and craniosynostosis. In this review, we describe the emerging role of IL-11/IL-11R signaling in bone metabolism by targeting osteoblasts, osteoclasts, osteocytes, and bone mineralization. Furthermore, IL-11 promotes osteogenesis and suppresses adipogenesis, thereby influencing the fate of osteoblast/adipocyte differentiation derived from pluripotent mesenchymal stem cells. We have newly identified IL-11 as a bone-derived cytokine that regulates bone metabolism and the link between bone and other organs. Thus, IL-11 is vital in bone homeostasis and could be considered a potential therapeutic strategy.
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Affiliation(s)
- Bingzi Dong
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jingjing Zhu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xian Chen
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongyuan Jiang
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yujie Deng
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lili Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yangang Wang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shufa Li
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
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15
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Kresnoadi U, Sari N, Laksono H. Socket preservation using a combination of propolis extract and bovine bone graft towards the expression of receptor activator of nuclear κB ligand and osteoprogerin. Folia Med (Plovdiv) 2023; 65:737-743. [PMID: 38351755 DOI: 10.3897/folmed.65.e95802] [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: 09/29/2022] [Accepted: 03/07/2023] [Indexed: 02/16/2024] Open
Abstract
AIM This study was undertaken to comprehend the effect of a combination of bovine bone graft (BBG) and propolis extract on the receptor activator of nuclear κB ligand (RANKL) and osteoprotegerin (OPG) expressions in post-extraction tooth sockets.
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Affiliation(s)
| | - Nila Sari
- Universitas Airlangga, Surabaya, Indonesia
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16
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Anuj A, Reuven N, Roberts SGE, Elson A. BASP1 down-regulates RANKL-induced osteoclastogenesis. Exp Cell Res 2023; 431:113758. [PMID: 37619639 DOI: 10.1016/j.yexcr.2023.113758] [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: 05/04/2023] [Revised: 07/03/2023] [Accepted: 08/21/2023] [Indexed: 08/26/2023]
Abstract
The cytokine RANKL (Receptor Activator of NFκB Ligand) is the key driver of differentiation of monocytes/macrophages to form multi-nucleated, bone-resorbing osteoclasts, a process that is accompanied by significant changes in gene expression. We show that exposure to RANKL rapidly down-regulates expression of Brain Acid Soluble Protein 1 (BASP1) in cultured primary mouse bone marrow macrophages (BMMs), and that this reduced expression is causally linked to the osteoclastogenic process in vitro. Knocking down BASP1 expression in BMMs or eliminating its expression in these cells or in RAW 264.7 cells enhanced RANKL-induced osteoclastogenesis, promoted cell-cell fusion, and generated cultures containing larger osteoclasts with increased mineral degrading abilities relative to controls. Expression of exogenous BASP1 in BMMs undergoing osteoclastogenic differentiation produced the opposite effects. Upon exposure to RANKL, primary mouse BMMs in which BASP1 had been knocked down exhibited increased expression of the key osteoclastogenic transcription factor Nfatc1and of its downstream target genes Dc-stamp, Ctsk, Itgb3, and Mmp9 relative to controls. The knock-down cells also exhibited increased sensitivity to the pro-osteoclastogenic effects of RANKL. We conclude that BASP1 is a negative regulator of RANKL-induced osteoclastogenesis, which down-regulates the pro-osteoclastogenic gene expression pattern induced by this cytokine. Decreased expression of BASP1 upon exposure of BMMs to RANKL removes a negative regulator of osteoclastogenesis and promotes this process.
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Affiliation(s)
- Anuj Anuj
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, 76100, Israel
| | - Nina Reuven
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, 76100, Israel
| | - Stefan G E Roberts
- School of Cellular & Molecular Medicine, University of Bristol, Bristol, BS8 1TD, United Kingdom
| | - Ari Elson
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, 76100, Israel.
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17
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Mariano LC, Grenho L, Fernandes MH, de Sousa Gomes P. Integrative tissue, cellular and molecular responsiveness of an innovative ex vivo model of the Staphylococcus aureus-mediated bone infection. FASEB J 2023; 37:e23166. [PMID: 37650876 DOI: 10.1096/fj.202300287rr] [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: 02/17/2023] [Revised: 07/21/2023] [Accepted: 08/14/2023] [Indexed: 09/01/2023]
Abstract
Osteomyelitis is a pathological condition of the bone, frequently associated with the presence of infectious agents - namely Staphylococcus aureus - that induce inflammation and tissue destruction. Recent advances in the understanding of its pathophysiology and the identification of innovative therapeutic approaches were gathered from experimental in vitro and in vivo systems. However, cell culture models offer limited representativeness of the cellular functionality and the cell-cell and cell-matrix interactions, further failing to mimic the three-dimensional tissue organization; and animal models allow for limited mechanistic assessment given the complex nature of systemic and paracrine regulatory systems and are endorsed with ethical constraints. Accordingly, this study aims at the establishment and assessment of a new ex vivo bone infection model, upon the organotypic culture of embryonic chicken femurs colonized with S. aureus, highlighting the model responsiveness at the molecular, cellular, and tissue levels. Upon infection with distinct bacterial inoculums, data reported an initial exponential bacterial growth, followed by diminished metabolic activity. At the tissue level, evidence of S. aureus-mediated tissue destruction was attained and demonstrated through distinct methodologies, conjoined with decreased osteoblastic/osteogenic and increased osteoclastic/osteoclastogenic functionalities-representative of the osteomyelitis clinical course. Overall, the establishment and characterization of an innovative bone tissue infection model that is simple, reproducible, easily manipulated, cost-effective, and simulates many features of human osteomyelitis, further allowing the maintenance of the bone tissue's three-dimensional morphology and cellular arrangement, was achieved. Model responsiveness was further demonstrated, showcasing the capability to improve the research pipeline in bone tissue infection-related research.
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Affiliation(s)
- Lorena Castro Mariano
- BoneLab-Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Porto, Portugal
- LAQV/REQUIMTE, University of Porto, Porto, Portugal
| | - Liliana Grenho
- BoneLab-Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Porto, Portugal
- LAQV/REQUIMTE, University of Porto, Porto, Portugal
| | - Maria Helena Fernandes
- BoneLab-Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Porto, Portugal
- LAQV/REQUIMTE, University of Porto, Porto, Portugal
| | - Pedro de Sousa Gomes
- BoneLab-Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Porto, Portugal
- LAQV/REQUIMTE, University of Porto, Porto, Portugal
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18
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Akyay OZ, Canturk Z, Selek A, Cetinarslan B, Tarkun İ, Cakmak Y, Baydemir C. The effects of exenatide and insulin glargine treatments on bone turnover markers and bone mineral density in postmenopausal patients with type 2 diabetes mellitus. Medicine (Baltimore) 2023; 102:e35394. [PMID: 37773814 PMCID: PMC10545322 DOI: 10.1097/md.0000000000035394] [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: 07/07/2023] [Accepted: 09/05/2023] [Indexed: 10/01/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) related bone fracture. The effects of glucagon-like peptide-1 receptor analogs for the treatment of T2DM on bone are controversial in human studies. This study aimed to compare the effects of GLP-1 receptor analogs exenatide and insulin glargine treatment on bone turnover marker levels and bone mineral density (BMD) in postmenopausal female patients with T2DM. Thirty female patients with T2DM who were naive to insulin and incretin-based treatments, with spontaneous postmenopause, were randomized to exenatide or insulin glargine arms and were followed up for 24 weeks. BMD was evaluated using dual-energy X-ray absorptiometry and bone turnover markers by serum enzyme-linked immunosorbent assay. The body mass index significantly decreased in the exenatide group compared to the glargine group (P < .001). Receptor activator of nuclear factor kappa-B (RANK) and RANK ligand (RANKL) levels were significantly decreased with exenatide treatment (P = .009 and P = .015, respectively). Osteoprotegerin (OPG) level significantly increased with exenatide treatment (P = .02). OPG, RANK, RANKL levels did not change with insulin glargine treatment. No statistically significant difference was found between the pre- and posttreatment BMD, alkaline phosphatase, bone-specific alkaline phosphatase, and type 1 crosslinked N-telopeptide levels in both treatment arms. Despite significant weight loss with exenatide treatment, BMD did not decrease, OPG increased, and the resorption markers of RANK and RANKL decreased, which may reflect early antiresorptive effects of exenatide via the OPG/RANK/RANKL pathway.
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Affiliation(s)
- Ozlem Zeynep Akyay
- University of Health Sciences Sanliurfa Mehmet Akif İnan Education and Research Hospital, Department of Endocrinology and Metabolism, Sanliurfa, Turkey
| | - Zeynep Canturk
- Kocaeli University School of Medicine, Department of Endocrinology and Metabolism, Kocaeli, Turkey
| | - Alev Selek
- Kocaeli University School of Medicine, Department of Endocrinology and Metabolism, Kocaeli, Turkey
| | - Berrin Cetinarslan
- Kocaeli University School of Medicine, Department of Endocrinology and Metabolism, Kocaeli, Turkey
| | - İlhan Tarkun
- Anadolu Medical Center, Department of Endocrinology and Metabolism, Kocaeli, Turkey
| | - Yagmur Cakmak
- Kocaeli University School of Medicine, Department of Oncology, Kocaeli, Turkey
| | - Canan Baydemir
- Kocaeli University School of Medicine, Department of Biostatistics and Medical Informatics, Kocaeli, Turkey
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19
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Tariq S, Tariq S, Abualhamael SA, Baig M, Malik AA, Shahzad M. Osteoprotegerin genetic polymorphisms and their influence on therapeutic response to ibandronate in postmenopausal osteoporotic females. PLoS One 2023; 18:e0291959. [PMID: 37751449 PMCID: PMC10521989 DOI: 10.1371/journal.pone.0291959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 09/10/2023] [Indexed: 09/28/2023] Open
Abstract
OBJECTIVES The present study investigated osteoprotegerin (OPG) genetic polymorphisms and their influence on the therapeutic response to ibandronate in postmenopausal osteoporotic females. METHODS This case-control study included 135 postmenopausal females (89 osteoporotic females and 46 non-osteoporotic females). Each osteoporotic patient received a monthly 150 mg ibandronate tablet for six months, and blood samples were taken before and after treatment. Bone mineral density (BMD) was measured using DEXA Scan. Three SNPs (A163G, T245G, and G1181C) of the OPG gene were selected for analysis. RESULTS Serum OPG levels were significantly lower in osteoporotic subjects than in the control group. The percentage changes in OPG levels in the osteoporotic group before and after treatment with ibandronate were significant (p < .001). After six months of therapy with ibandronate, the percentage changes in OPG levels with AA, TT, TC, GC, and GG genotypes were significant. Following six months of ibandronate treatment, the AA genotype of rs3134069, TT, TC genotypes of rs3102735, GG, and GC genotypes of rs2073618 SNP showed a significant increase in OPG levels. Age, BMI, and GC polymorphism (rs2073618 (G/C) G1181C) were inversely associated with low BMD. Adjusted odds ratios (OR) showed that BMI, GC, GG polymorphism (rs2073618 (G/C) G1181C) and TC polymorphism (rs3102735 (T/C) A163G) were inversely associated with low BMD. CONCLUSION The inverse association of rs2073618 and rs3102735 with low BMD indicates the protective role of these SNPs in our population. More research is needed to replicate these results in another cohort and to determine the molecular processes by which such SNPs may influence BMD.
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Affiliation(s)
- Saba Tariq
- Department of Pharmacology and Therapeutics, University Medical & Dental College, The University of Faisalabad, Faisalabad, Pakistan
- University of Birmingham, Birmingham, England, United Kingdom
| | - Sundus Tariq
- Department of Physiology, International School of Medicine, Istanbul Medipol University, Research Institute for Health Sciences and Technologies (SABITA), Istanbul, Turkey
| | | | - Mukhtiar Baig
- Department of Clinical Biochemistry, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmad Azam Malik
- Department of Family and Community Medicine, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muhammad Shahzad
- Department of Pharmacology, University of Health Sciences, Lahore, Pakistan
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20
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Qi Q, Xu Y, Sun H, Zhou J, Li L, Pan X, Wang J, Cao W, Sun Y, Wang L. Apolipoprotein E deficiency attenuated osteogenesis via down-regulating osterix. Drug Discov Ther 2023; 17:270-278. [PMID: 37587051 DOI: 10.5582/ddt.2023.01026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
Apolipoprotein E (ApoE), a ligand for low-density lipoprotein receptors, is strongly induced during osteogenesis and has a physiologic role in regulating osteoblast function, but the mechanisms of its action are still unclear. The study aims to elucidate the influence and molecular mechanisms of ApoE on bone formation. An ovariectomy-induced osteoporotic model were conducted in ApoE knockout (ApoE-/-) mice to study the effect of ApoE on the bone system. Bone quality were assessed through bone mineral density and histomorphometric analysis. To investigate the underlying role and mechanisms of ApoE during osteogenesis, primary osteoblasts from the calvariums of newborn ApoE-/- or wild-type (WT) mice were cultured in the osteoblastic differentiation medium in vitro for further research. Our animal experiment data showed that ApoE-/- mice exhibited bone loss, exacerbated by estrogen deprivation after ovariectomy. ApoE deficiency attenuated osteoblast activity and inhibited osteoblast osteogenesis, accompanied by decreased osterix expression. ApoE deficiency did not affect primary osteoblast viability and collagen-1 expression. Moreover, osteoprotegerin expression in ApoE-/- osteoblasts was reduced compared to WT controls. Our study demonstrated that ApoE gene deficiency contributed to bone loss and attenuated osteogenesis by down-regulating osterix expression.
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Affiliation(s)
- Qing Qi
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Yingping Xu
- Reproductive Medicine Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Hongmei Sun
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Jing Zhou
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Lisha Li
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Xinyao Pan
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Jing Wang
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Wenli Cao
- Reproductive Medicine Center of Zhoushan Maternal and Child Health Care Hospital, Zhoushan, Zhejiang, China
| | - Yan Sun
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Ling Wang
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
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21
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Lai Y, Guo Y, Liao C, Mao C, Liu J, Ren C, Yang W, Luo L, Chen W. Osteoclast differentiation and dynamic mRNA expression during mice embryonic palatal bone development. Sci Rep 2023; 13:15170. [PMID: 37704707 PMCID: PMC10499879 DOI: 10.1038/s41598-023-42423-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 09/10/2023] [Indexed: 09/15/2023] Open
Abstract
This study is the first to investigate the process of osteoclast (OCL) differentiation, its potential functions, and the associated mRNA and signalling pathways in embryonic palatal bone. Our findings suggest that OCLs are involved in bone remodelling, bone marrow cavity formation, and blood vessel formation in embryonic palatal bone. We observed TRAP-positive OCLs at embryonic day 16.5 (E16.5), E17.5, and E18.5 at the palatal process of the palate (PPP) and posterior and anterior parts of the palatal process of the maxilla (PPMXP and PPMXA, respectively), with OCL differentiation starting 2 days prior to TRAP positivity. By comparing the key periods of OCL differentiation between PPMX and PPP (E14.5, E15.5, and E16.5) using RNA-seq data of the palates, we found that the PI3K-AKT and MAPK signalling pathways were sequentially enriched, which may play critical roles in OCL survival and differentiation. Csf1r, Tnfrsff11a, Ctsk, Fos, Tyrobp, Fcgr3, and Spi1 were significantly upregulated, while Pik3r3, Tgfbr1, and Mapk3k7 were significantly downregulated, in both PPMX and PPP. Interestingly, Tnfrsff11b was upregulated in PPMX but downregulated in PPP, which may regulate the timing of OCL appearance. These results contribute to the limited knowledge regarding mRNA-specific steps in OCL differentiation in the embryonic palatal bone.
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Affiliation(s)
- Yongzhen Lai
- Department of Oral and Craniomaxillofacial Science, Fujian Medical University Union Hospital, No. 28, Xinquan Road, Fuzhou, 350001, Fujian, China
- Stomatological Key Laboratory of Fujian College and University, Fuzhou, China
| | - Yan Guo
- Stomatological Key Laboratory of Fujian College and University, Fuzhou, China
| | - Caiyu Liao
- Stomatological Key Laboratory of Fujian College and University, Fuzhou, China
| | - Chuanqing Mao
- Department of Oral and Craniomaxillofacial Science, Fujian Medical University Union Hospital, No. 28, Xinquan Road, Fuzhou, 350001, Fujian, China
| | - Jing Liu
- Department of Stomatology, Fujian Maternal and Child Health Hospital, No. 18 Dao Shan Road, Fuzhou, 350001, Fujian, China
| | - Chengyan Ren
- Stomatological Key Laboratory of Fujian College and University, Fuzhou, China
| | - Wen Yang
- Stomatological Key Laboratory of Fujian College and University, Fuzhou, China
| | - Lin Luo
- Stomatological Key Laboratory of Fujian College and University, Fuzhou, China
| | - Weihui Chen
- Department of Oral and Craniomaxillofacial Science, Fujian Medical University Union Hospital, No. 28, Xinquan Road, Fuzhou, 350001, Fujian, China.
- Stomatological Key Laboratory of Fujian College and University, Fuzhou, China.
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22
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Ran D, Zhou D, Liu G, Ma Y, Ali W, Yu R, Wang Q, Zhao H, Zhu J, Zou H, Liu Z. Reactive Oxygen Species Control Osteoblast Apoptosis through SIRT1/PGC-1α/P53 Lys382 Signaling, Mediating the Onset of Cd-Induced Osteoporosis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023. [PMID: 37023393 DOI: 10.1021/acs.jafc.2c08505] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
The imbalance between osteogenesis and osteoclastogenesis is a feature of bone metabolic disease. Cadmium (Cd) exposure causes human bone loss and osteoporosis (OP) through bioaccumulation of the food chain. However, the impact of Cd on bone tissues and the underlying molecular mechanisms are not well-characterized. In the current study, we found that the Cd concentration in bone tissues of OP patients was higher than normal subjects; meanwhile, the nuclear silent information regulator of transcription 1 (SIRT1) protein expression level was significantly decreased, which is a new star molecule to treat OP. It is further revealed that SIRT1 activation markedly reprograms bone metabolic and stress-response pathways that incline with osteoblast (OB) apoptosis. Suppressing reactive oxygen species (ROS) release with N-acetyl-l-cysteine (NAC) abolished Cd-induced reduction of SIRT1 protein, deacetylation of P53, OB apoptosis, and attenuated OP. Conversely, overexpression of SIRT1 suppressed Cd-induced ROS release. SIRT1 overexpression in vivo and in vitro dampened PGC-1α protein, acetylation of P53 at lysine 382, and caspase-dependent apoptosis. These results reveal that ROS/SIRT1 controls P53 acetylation and coordinates OB apoptosis involved in the onset of OP.
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Affiliation(s)
- Di Ran
- College of Veterinary Medicine, Southwest University, Chongqing 400715, People's Republic of China
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Dehui Zhou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Gang Liu
- Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, United States
| | - Yonggang Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Waseem Ali
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Rui Yu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Qinghua Wang
- College of Veterinary Medicine, Southwest University, Chongqing 400715, People's Republic of China
| | - Hongyan Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Jiaqiao Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People's Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, People's Republic of China
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23
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Williams DF. The plasticity of biocompatibility. Biomaterials 2023; 296:122077. [PMID: 36907003 DOI: 10.1016/j.biomaterials.2023.122077] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 02/19/2023] [Accepted: 03/02/2023] [Indexed: 03/11/2023]
Abstract
Biocompatibility concerns the phenomena that occur within the interactions between biomaterials and human patients, which ultimately control the performance of many facets of medical technology. It involves aspects of materials science, many different forms of engineering and nanotechnology, chemistry, biophysics, molecular and cellular biology, immunology, pathology and a myriad of clinical applications. It is not surprising that an overarching framework of mechanisms of biocompatibility has been difficult to elucidate and validate. This essay discusses one fundamental reason for this; we have tended to consider biocompatibility pathways as essentially linear sequences of events which follow well-understood processes of materials science and biology. The reality, however, is that the pathways may involve a great deal of plasticity, in which many additional idiosyncratic factors, including those of genetic, epigenetic and viral origin, exert influence, as do complex mechanical, physical and pharmacological variables. Plasticity is an inherent core feature of the performance of synthetic materials; here we follow the more recent biological applications of plasticity concepts into the sphere of biocompatibility pathways. A straightforward linear pathway may result in successful outcomes for many patients; we may describe this in terms of classic biocompatibility pathways. In other situations, which usually command much more attention because of their unsuccessful outcomes, these plasticity-driven processes follow alternative biocompatibility pathways; often, the variability in outcomes with identical technologies is due to biological plasticity rather than material or device deficiency.
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Affiliation(s)
- David F Williams
- Wake Forest Institute of Regenerative Medicine, Winston-Salem, North Carolina, USA.
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Molecular Basis beyond Interrelated Bone Resorption/Regeneration in Periodontal Diseases: A Concise Review. Int J Mol Sci 2023; 24:ijms24054599. [PMID: 36902030 PMCID: PMC10003253 DOI: 10.3390/ijms24054599] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/19/2023] [Accepted: 02/06/2023] [Indexed: 03/02/2023] Open
Abstract
Periodontitis is the sixth most common chronic inflammatory disease, destroying the tissues supporting the teeth. There are three distinct stages in periodontitis: infection, inflammation, and tissue destruction, where each stage has its own characteristics and hence its line of treatment. Illuminating the underlying mechanisms of alveolar bone loss is vital in the treatment of periodontitis to allow for subsequent reconstruction of the periodontium. Bone cells, including osteoclasts, osteoblasts, and bone marrow stromal cells, classically were thought to control bone destruction in periodontitis. Lately, osteocytes were found to assist in inflammation-related bone remodeling besides being able to initiate physiological bone remodeling. Furthermore, mesenchymal stem cells (MSCs) either transplanted or homed exhibit highly immunosuppressive properties, such as preventing monocytes/hematopoietic precursor differentiation and downregulating excessive release of inflammatory cytokines. In the early stages of bone regeneration, an acute inflammatory response is critical for the recruitment of MSCs, controlling their migration, and their differentiation. Later during bone remodeling, the interaction and balance between proinflammatory and anti-inflammatory cytokines could regulate MSC properties, resulting in either bone formation or bone resorption. This narrative review elaborates on the important interactions between inflammatory stimuli during periodontal diseases, bone cells, MSCs, and subsequent bone regeneration or bone resorption. Understanding these concepts will open up new possibilities for promoting bone regeneration and hindering bone loss caused by periodontal diseases.
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Zastulka A, Clichici S, Tomoaia-Cotisel M, Mocanu A, Roman C, Olteanu CD, Culic B, Mocan T. Recent Trends in Hydroxyapatite Supplementation for Osteoregenerative Purposes. MATERIALS (BASEL, SWITZERLAND) 2023; 16:1303. [PMID: 36770309 PMCID: PMC9919169 DOI: 10.3390/ma16031303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 06/18/2023]
Abstract
Bone regeneration has gained attention in the biomedical field, which has led to the development of materials and synthesis methods meant to improve osseointegration and cellular bone activity. The properties of hydroxyapatite, a type of calcium phosphate, have been researched to determine its advantages for bone tissue engineering, particularly its biocompatibility and ability to interact with bone cells. Recently, the advantages of utilizing nanomolecules of hydroxyapatite, combined with various substances, in order to enhance and combine their characteristics, have been reported in the literature. This review will outline the cellular and molecular roles of hydroxypatite, its interactions with bone cells, and its nano-combinations with various ions and natural products and their effects on bone growth, development, and bone repair.
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Affiliation(s)
- Ana Zastulka
- Physiology Department, Iuliu Hatieganu University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Simona Clichici
- Physiology Department, Iuliu Hatieganu University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Maria Tomoaia-Cotisel
- Department of Chemical Engineering, Faculty of Chemistry and Chemical Engineering, Research Center in Physical Chemistry, Babes-Bolyai University of Cluj-Napoca, 11 Arany Janos Str., 400028 Cluj-Napoca, Romania
- Academy of Romanian Scientists, 3 Ilfov Str., 050044 Bucharest, Romania
| | - Aurora Mocanu
- Department of Chemical Engineering, Faculty of Chemistry and Chemical Engineering, Research Center in Physical Chemistry, Babes-Bolyai University of Cluj-Napoca, 11 Arany Janos Str., 400028 Cluj-Napoca, Romania
| | - Cecilia Roman
- INCDO-INOE 2000, Research Institute for Analytical Instrumentation, 400296 Cluj-Napoca, Romania
| | - Cristian-Doru Olteanu
- Orthodontic Department, Iuliu Hatieganu University of Medicine and Pharmacy, 31 Avram Iancu Street, 400083 Cluj-Napoca, Romania
| | - Bogdan Culic
- Department of Prosthetic Dentistry and Dental Materials, Iuliu Hatieganu University of Medicine and Pharmacy, 32 Clinicilor Street, 400012 Cluj-Napoca, Romania
| | - Teodora Mocan
- Physiology Department, Iuliu Hatieganu University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
- Nanomedicine Department, Regional Institute of Gastroenterology and Hepatology Cluj-Napoca, 5 Constanta Street, 400158 Cluj-Napoca, Romania
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26
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Abdullameer MA, Abdulkareem AA. Diagnostic potential of salivary interleukin-17, RANKL, and OPG to differentiate between periodontal health and disease and discriminate stable and unstable periodontitis: A case-control study. Health Sci Rep 2023; 6:e1103. [PMID: 36778772 PMCID: PMC9900720 DOI: 10.1002/hsr2.1103] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/20/2023] [Accepted: 01/28/2023] [Indexed: 02/08/2023] Open
Abstract
Background and Aims Limitations of the conventional diagnostic techniques urged researchers to seek novel methods to predict, diagnose, and monitor periodontal disease. Use of the biomarkers available in oral fluids could be a revolutionary surrogate for the manual probing/diagnostic radiograph. Several salivary biomarkers have the potential to accurately discriminate periodontal health and disease. This study aimed to determine the diagnostic sensitivity and specificity of salivary interleukin (IL)-17, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), RANKL/OPG for differentiating (1) periodontal health from disease and (2) stable and unstable periodontitis. Methods Participants with periodontitis (n = 50) and gingivitis (n = 25), both diseases represented the cases, and subjects with healthy periodontium (n = 15) as a control were recruited for this study. Periodontitis cases were further equally subdivided into stable and unstable. Whole unstimulated salivary sample were collected from all participants. Periodontal parameters including bleeding on probing, probing pocket depth, clinical attachment loss, and number of missing teeth were recorded. The protein levels of salivary IL-17, RANKL, and OPG were determined by using enzyme-linked immunosorbent assays technique. Results Salivary IL-17, OPG, RANKL, and RANKL/OPG showed high sensitivity and specificity to differentiate periodontal health from gingivitis and periodontitis. Similar pattern was observed in discriminating stable and unstable periodontitis. Salivary IL-17 and RANKL showed a good accuracy to differentiate gingivitis from periodontitis. However, OPG and RANKL/OPG did not exhibit enough sensitivity and specificity to differentiate the latter conditions. Conclusion Salivary IL-17, RANKL, OPG, and RANKL/OPG system are potential candidates for differentiating periodontal health and disease and discriminate stable and unstable periodontitis.
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Affiliation(s)
- Marwa A. Abdullameer
- Department of HealthMinistry of HealthBaghdadIraq
- College of DentistryUniversity of BaghdadBaghdadIraq
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27
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Assem NZ, Pazmiño VFC, Caliente EA, Dalben GDS, Soares S, Santiago Júnior JF, de Almeida ALPF, de Almeida ALPF. Bone substitutes vs. autogenous bone graft for regeneration of the anterior maxillary alveolar process with horizontal bone resorption: systematic review. J ORAL IMPLANTOL 2022; 49:102-113. [PMID: 36913696 DOI: 10.1563/aaid-joi-d-22-00014] [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: 12/17/2021] [Revised: 07/26/2022] [Accepted: 08/20/2022] [Indexed: 12/12/2022]
Abstract
The objective of this systematic review was to identify the available scientific evidence on bone substitutes (BS) compared to autogenous bone grafts (ABG) for regeneration of horizontal bone resorption in the anterior maxillary alveolar process, aiming at rehabilitation with endosseous implants. This review was performed according to the PRISMA guidelines (2020) and registered in the database PROSPERO (CRD: 42017070574) . The databases searched were PUBMED/MEDLINE, EMBASE, SCOPUS, SCIENCE DIRECT, WEB OF SCIENCE, and CENTRAL COCHRANE, in the English language. The Australian National Health and Medical Research Council (NHMRC) and Cochrane Risk of Bias Tool were used to assess the study's quality and risk of bias. 544 papers were found. After the selection process, six studies were selected for review. A total of 182 patients were followed for a period of 6 to 48 months. The mean age of patients was 46.46 years, 152 implants were installed in the anterior region. Two studies achieved a reduced graft and implant failure rate, while the remaining four studies had no losses. It may be concluded that both the use of ABG and some BS are viable alternatives for the rehabilitation with implants in individuals with anterior horizontal bone loss. However, additional RCTs are warranted due to the limited number of papers.
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Affiliation(s)
- Naida Zanini Assem
- Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | | | - Eliana Aparecida Caliente
- Postgraduate Student at the Department of Dentistry, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Gisele da Silva Dalben
- Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, São Paulo, Brazil
| | - Simone Soares
- Department of Prosthodontics and Periodontics, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Joel Ferreira Santiago Júnior
- Sacred Heart University - Bauru Assistant Professor Health Sciences 10-50 Irmã Arminda BRAZIL Bauru São Paulo 17011160 551421077112
| | - Ana Lúcia Pompéia Fraga de Almeida
- Associate Professor, Department of Prosthodontics and Periodontics, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
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28
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Granata V, Possetti V, Parente R, Bottazzi B, Inforzato A, Sobacchi C. The osteoblast secretome in Staphylococcus aureus osteomyelitis. Front Immunol 2022; 13:1048505. [PMID: 36483565 PMCID: PMC9723341 DOI: 10.3389/fimmu.2022.1048505] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/03/2022] [Indexed: 11/23/2022] Open
Abstract
Osteomyelitis (OM) is an infectious disease of the bone predominantly caused by the opportunistic bacterium Staphylococcus aureus (S. aureus). Typically established upon hematogenous spread of the pathogen to the musculoskeletal system or contamination of the bone after fracture or surgery, osteomyelitis has a complex pathogenesis with a critical involvement of both osteal and immune components. Colonization of the bone by S. aureus is traditionally proposed to induce functional inhibition and/or apoptosis of osteoblasts, alteration of the RANKL/OPG ratio in the bone microenvironment and activation of osteoclasts; all together, these events locally subvert tissue homeostasis causing pathological bone loss. However, this paradigm has been challenged in recent years, in fact osteoblasts are emerging as active players in the induction and orientation of the immune reaction that mounts in the bone during an infection. The interaction with immune cells has been mostly ascribed to osteoblast-derived soluble mediators that add on and synergize with those contributed by professional immune cells. In this respect, several preclinical and clinical observations indicate that osteomyelitis is accompanied by alterations in the local and (sometimes) systemic levels of both pro-inflammatory (e.g., IL-6, IL-1α, TNF-α, IL-1β) and anti-inflammatory (e.g., TGF-β1) cytokines. Here we revisit the role of osteoblasts in bacterial OM, with a focus on their secretome and its crosstalk with cellular and molecular components of the bone microenvironment and immune system.
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Affiliation(s)
- Valentina Granata
- IRCCS Humanitas Research Hospital, Rozzano, Italy,Milan Unit, National Research Council - Institute for Genetic and Biomedical Research (CNR-IRGB), Milan, Italy
| | - Valentina Possetti
- IRCCS Humanitas Research Hospital, Rozzano, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | | | | | - Antonio Inforzato
- IRCCS Humanitas Research Hospital, Rozzano, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Cristina Sobacchi
- IRCCS Humanitas Research Hospital, Rozzano, Italy,Milan Unit, National Research Council - Institute for Genetic and Biomedical Research (CNR-IRGB), Milan, Italy,*Correspondence: Cristina Sobacchi,
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Elson A, Anuj A, Barnea-Zohar M, Reuven N. The origins and formation of bone-resorbing osteoclasts. Bone 2022; 164:116538. [PMID: 36028118 DOI: 10.1016/j.bone.2022.116538] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 02/07/2023]
Abstract
Osteoclasts (OCLs) are hematopoietic cells whose physiological function is to degrade bone. OCLs are key players in the processes that determine and maintain the mass, shape, and physical properties of bone. OCLs adhere to bone tightly and degrade its matrix by secreting protons and proteases onto the underlying surface. The combination of low pH and proteases degrades the mineral and protein components of the matrix and forms a resorption pit; the degraded material is internalized by the cell and then secreted into the circulation. Insufficient or excessive activity of OCLs can lead to significant changes in bone and either cause or exacerbate symptoms of diseases, as in osteoporosis, osteopetrosis, and cancer-induced bone lysis. OCLs are derived from monocyte-macrophage precursor cells whose origins are in two distinct embryonic cell lineages - erythromyeloid progenitor cells of the yolk sac, and hematopoietic stem cells. OCLs are formed in a multi-stage process that is induced by the cytokines M-CSF and RANKL, during which the cells differentiate, fuse to form multi-nucleated cells, and then differentiate further to become mature, bone-resorbing OCLs. Recent studies indicate that OCLs can undergo fission in vivo to generate smaller cells, called "osteomorphs", that can be "re-cycled" by fusing with other cells to form new OCLs. In this review we describe OCLs and discuss their cellular origins and the cellular and molecular events that drive osteoclastogenesis.
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Affiliation(s)
- Ari Elson
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
| | - Anuj Anuj
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel
| | - Maayan Barnea-Zohar
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel
| | - Nina Reuven
- Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel
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Yang Y, Cheng R, Liu J, Fang J, Wang X, Cui Y, Zhang P, Du B. Linarin Protects against Cadmium-Induced Osteoporosis Via Reducing Oxidative Stress and Inflammation and Altering RANK/RANKL/OPG Pathway. Biol Trace Elem Res 2022; 200:3688-3700. [PMID: 34674107 DOI: 10.1007/s12011-021-02967-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022]
Abstract
Cadmium (Cd) contamination in the environment is a major public health concern since it has been linked to osteoporosis and other bone deformities. Linarin is a flavonoid glycoside, and it can promote osteoblastogenesis. This research aimed to investigate the potential role of linarin against Cd-exposed bone deformations in mice model. In our research, male mice were randomly allocated into four groups: control, Cd-exposed, and Cd + linarin (20 and 40mg/kg/bw, respectively). Linarin prevented body weight loss, increased serum calcium (Ca) and phosphorus (P), and bone alkaline phosphatase (BAP) levels in Cd-exposed groups. Furthermore, linarin treatment at 20 and 40mg/kg/bw significantly decreased RANK and OPG, resulting in an increase in RANKL mRNA levels and protein distribution in the bone of Cd-exposed mice. In addition, the bone of Cd-exposed mice administered with linarin showed higher TRAP, NFATc1, MMP9, and RUNX2 mRNA levels and protein distribution. Linarin significantly decreased oxidative stress in Cd-exposed mice bone by decreasing MDA, a lipid peroxidation product. Moreover, linarin protects Cd-exposed mice antioxidant enzymes by increasing bone SOD, CAT, and GPx levels. Besides, linarin suppresses alterations in the inflammatory system, i.e., NF-κB p65/IKKβ, by reducing NF-κB p65, IKKβ, IL-6, and TNF-α in the bone of Cd-exposed animals. This study concluded that linarin has potential to cure osteoporosis in Cd-exposed mice by reducing oxidative stress and inflammation and modulating the RANK/RANKL/OPG pathway.
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Affiliation(s)
- Yating Yang
- Xi'an Jiao Tong University, Xi'an, Shaanxi, 710049, China
- Department of Geriatrics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China
| | - Ruining Cheng
- Department of Geriatrics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China
| | - Jingyun Liu
- Department of Geriatrics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China
| | - Jing Fang
- Department of Geriatrics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China
| | - Xiaojing Wang
- Department of Geriatrics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China
| | - Yingxue Cui
- Department of Geriatrics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China
| | - Pan Zhang
- Department of Geriatrics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China
| | - Bin Du
- Xi'an Jiao Tong University, Xi'an, Shaanxi, 710049, China.
- Department of Orthopaedics, Xi'an Ninth Hospital, No. 151, East Section of South Second Ring Road, Beilin District, Xi'an, Shaanxi, 710054, China.
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Jiang J, Röper L, Alageel S, Dornseifer U, Schilling AF, Hadjipanayi E, Machens HG, Moog P. Hypoxia Preconditioned Serum (HPS) Promotes Osteoblast Proliferation, Migration and Matrix Deposition. Biomedicines 2022; 10:biomedicines10071631. [PMID: 35884936 PMCID: PMC9313157 DOI: 10.3390/biomedicines10071631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/21/2022] Open
Abstract
Interest in discovering new methods of employing natural growth factor preparations to promote bone fracture healing is becoming increasingly popular in the field of regenerative medicine. In this study, we were able to demonstrate the osteogenic potential of hypoxia preconditioned serum (HPS) on human osteoblasts in vitro. Human osteoblasts were stimulated with two HPS concentrations (10% and 40%) and subsequently analyzed at time points of days 2 and 4. In comparison to controls, a time- and dose-dependent (up to 14.2× higher) proliferation of osteoblasts was observed after 4 days of HPS-40% stimulation with lower lactate dehydrogenase (LDH)-levels detected than controls, indicating the absence of cytotoxic/stress effects of HPS on human osteoblasts. With regards to cell migration, it was found to be significantly faster with HPS-10% application after 72 h in comparison to controls. Further osteogenic response to HPS treatment was evaluated by employing culture supernatant analysis, which exhibited significant upregulation of OPG (Osteoprotegerin) with higher dosage (HPS-10% vs. HPS-40%) and longer duration (2 d vs. 4 d) of HPS stimulation. There was no detection of anti-osteogenic sRANKL (soluble Receptor Activator of NF-κB Ligand) after 4 days of HPS stimulation. In addition, ALP (alkaline phosphatase)-enzyme activity, was found to be upregulated, dose-dependently, after 4 days of HPS-40% application. When assessing ossification through Alizarin-Red staining, HPS dose-dependently achieved greater (up to 2.8× higher) extracellular deposition of calcium-phosphate with HPS-40% in comparison to controls. These findings indicate that HPS holds the potential to accelerate bone regeneration by osteogenic promotion of human osteoblasts.
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Affiliation(s)
- Jun Jiang
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (L.R.); (S.A.); (E.H.)
| | - Lynn Röper
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (L.R.); (S.A.); (E.H.)
| | - Sarah Alageel
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (L.R.); (S.A.); (E.H.)
| | - Ulf Dornseifer
- Department of Plastic, Reconstructive and Aesthetic Surgery, Isar Klinikum, D-80331 Munich, Germany;
| | - Arndt F. Schilling
- Department of Trauma Surgery, Orthopedics and Plastic Surgery, Universitätsmedizin Göttingen, D-37075 Göttingen, Germany;
| | - Ektoras Hadjipanayi
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (L.R.); (S.A.); (E.H.)
| | - Hans-Günther Machens
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (L.R.); (S.A.); (E.H.)
- Correspondence: (H.-G.M.); (P.M.)
| | - Philipp Moog
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (L.R.); (S.A.); (E.H.)
- Correspondence: (H.-G.M.); (P.M.)
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Ateeq H, Zia A, Husain Q, Khan MS, Ahmad M. Effect of inflammation on bones in diabetic patients with periodontitis via RANKL/OPG system-A review. J Diabetes Metab Disord 2022; 21:1003-1009. [PMID: 35673491 PMCID: PMC9167386 DOI: 10.1007/s40200-021-00960-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/14/2021] [Indexed: 01/31/2023]
Abstract
Purpose Diabetes mellitus and periodontitis are inflammatory diseases, the severity of inflammation results in the progression and persistence of both the disorders and affects bones. Diabetic complications aggravate in diabetic subjects having periodontitis; similarly, diabetic patients are more prone to developing gingivitis and periodontitis. Periodontal and diabetic inflammation disturbs bone homeostasis, which possibly involves both innate and adaptive immune responses. The pathogenic processes that link the two diseases are the focus of much research and it is likely that upregulated inflammation arising from each condition adversely affects the other. RANKL/OPG pathway plays a prominent role in periodontal and diabetic inflammation and bone resorption. Method This review article summarises the literature on the link between inflammatory cytokines and the prevalence of disturbed bone homeostasis in diabetic patients with periodontitis. An extensive search was done in PubMed, Scopus, Medline and Google Scholar databases between April 2003 and May 2021. Result A total of 27 articles, including pilot studies, case-control studies, cross-sectional studies, cohort studies, randomized control trials, longitudinal studies, descriptive studies and experimental studies, were included in our literature review. Conclusion Since RANKL/OPG are cytokines and have immune responses, regulating these cytokines expression will help control diabetes, periodontitis and bone homeostasis. The growing evidence of bone loss and increased fracture risk in diabetic patients with periodontitis makes it imperative that health professionals carry out planned treatment focusing on monitoring oral health in diabetic patients; bone markers should also be evaluated in patients with chronic periodontitis with an impaired glycemic state.
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Affiliation(s)
- Hira Ateeq
- Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh-202002, India
- Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh-202002, India
| | - Afaf Zia
- Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh-202002, India
| | - Qayyum Husain
- Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh-202002, India
| | - Mohd Sajid Khan
- Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh-202002, India
| | - Mohd Ahmad
- Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh-202002, India
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Sirisereephap K, Maekawa T, Tamura H, Hiyoshi T, Domon H, Isono T, Terao Y, Maeda T, Tabeta K. Osteoimmunology in Periodontitis: Local Proteins and Compounds to Alleviate Periodontitis. Int J Mol Sci 2022; 23:5540. [PMID: 35628348 PMCID: PMC9146968 DOI: 10.3390/ijms23105540] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/13/2022] [Accepted: 05/14/2022] [Indexed: 01/25/2023] Open
Abstract
Periodontitis is one of the most common oral diseases resulting in gingival inflammation and tooth loss. Growing evidence indicates that it results from dysbiosis of the oral microbiome, which interferes with the host immune system, leading to bone destruction. Immune cells activate periodontal ligament cells to express the receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) and promote osteoclast activity. Osteocytes have active roles in periodontitis progression in the bone matrix. Local proteins are involved in bone regeneration through functional immunological plasticity. Here, we discuss the current knowledge of cellular and molecular mechanisms in periodontitis, the roles of local proteins, and promising synthetic compounds generating a periodontal regeneration effect. It is anticipated that this may lead to a better perception of periodontitis pathophysiology.
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Affiliation(s)
- Kridtapat Sirisereephap
- Division of Periodontology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (K.S.); (H.T.); (K.T.)
- Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (T.H.); (T.M.)
- Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Tomoki Maekawa
- Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (T.H.); (T.M.)
| | - Hikaru Tamura
- Division of Periodontology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (K.S.); (H.T.); (K.T.)
| | - Takumi Hiyoshi
- Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (T.H.); (T.M.)
| | - Hisanori Domon
- Division of Microbiology and Infectious Disease, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (H.D.); (T.I.); (Y.T.)
| | - Toshihito Isono
- Division of Microbiology and Infectious Disease, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (H.D.); (T.I.); (Y.T.)
| | - Yutaka Terao
- Division of Microbiology and Infectious Disease, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (H.D.); (T.I.); (Y.T.)
| | - Takeyasu Maeda
- Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (T.H.); (T.M.)
| | - Koichi Tabeta
- Division of Periodontology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan; (K.S.); (H.T.); (K.T.)
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Commensal gut bacterium critically regulates alveolar bone homeostasis. J Transl Med 2022; 102:363-375. [PMID: 34934182 PMCID: PMC8967765 DOI: 10.1038/s41374-021-00697-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/28/2022] Open
Abstract
The alveolar bone is a unique osseous tissue due to the presence of the teeth and the proximity of commensal oral microbes. Commensal microbe effects on alveolar bone homeostasis have been attributed to the oral microbiota, yet the impact of commensal gut microbes is unknown. Study purpose was to elucidate whether commensal gut microbes regulate osteoimmune mechanisms and skeletal homeostasis in alveolar bone. Male C57BL/6T germfree (GF) littermate mice were maintained as GF or monoassociated with segmented filamentous bacteria (SFB), a commensal gut bacterium. SFB has been shown to elicit broad immune response effects, including the induction of TH17/IL17A immunity, which impacts the development and homeostasis of host tissues. SFB colonized the gut, but not oral cavity, and increased IL17A levels in the ileum and serum. SFB had catabolic effects on alveolar bone and non-oral skeletal sites, which was attributed to enhanced osteoclastogenesis. The alveolar bone marrow of SFB vs. GF mice had increased dendritic cells, activated helper T-cells, TH1 cells, TH17 cells, and upregulated Tnf. Primary osteoblast cultures from SFB and GF mice were stimulated with vehicle-control, IL17A, or TNF to elucidate osteoblast-derived signaling factors contributing to the pro-osteoclastic phenotype in SFB mice. Treatment of RAW264.7 osteoclastic cells with supernatants from vehicle-stimulated SFB vs. GF osteoblasts recapitulated the osteoclast phenotype found in vivo. Supernatants from TNF-stimulated osteoblasts normalized RAW264.7 osteoclast endpoints across SFB and GF cultures, which was dependent on the induction of CXCL1 and CCL2. This report reveals that commensal gut microbes have the capacity to regulate osteoimmune processes in alveolar bone. Outcomes from this investigation challenge the current paradigm that alveolar bone health and homeostasis is strictly regulated by oral microbes.
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de Souza PPC, Henning P, Lerner UH. Stimulation of Osteoclast Formation by Oncostatin M and the Role of WNT16 as a Negative Feedback Regulator. Int J Mol Sci 2022; 23:3287. [PMID: 35328707 PMCID: PMC8953253 DOI: 10.3390/ijms23063287] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/09/2022] [Accepted: 03/15/2022] [Indexed: 02/05/2023] Open
Abstract
Oncostatin M (OSM), which belongs to the IL-6 family of cytokines, is the most potent and effective stimulator of osteoclast formation in this family, as assessed by different in vitro assays. Osteoclastogenesis induced by the IL-6 type of cytokines is mediated by the induction and paracrine stimulation of the osteoclastogenic cytokine receptor activator of nuclear factor κ-B ligand (RANKL), expressed on osteoblast cell membranes and targeting the receptor activator of nuclear factor κ-B (RANK) on osteoclast progenitor cells. The potent effect of OSM on osteoclastogenesis is due to an unusually robust induction of RANKL in osteoblasts through the OSM receptor (OSMR), mediated by a JAK-STAT/MAPK signaling pathway and by unique recruitment of the adapter protein Shc1 to the OSMR. Gene deletion of Osmr in mice results in decreased numbers of osteoclasts and enhanced trabecular bone caused by increased trabecular thickness, indicating that OSM may play a role in physiological regulation of bone remodeling. However, increased amounts of OSM, either through administration of recombinant protein or of adenoviral vectors expressing Osm, results in enhanced bone mass due to increased bone formation without any clear sign of increased osteoclast numbers, a finding which can be reconciled by cell culture experiments demonstrating that OSM can induce osteoblast differentiation and stimulate mineralization of bone nodules in such cultures. Thus, in vitro studies and gene deletion experiments show that OSM is a stimulator of osteoclast formation, whereas administration of OSM to mice shows that OSM is not a strong stimulator of osteoclastogenesis in vivo when administered to adult animals. These observations could be explained by our recent finding showing that OSM is a potent stimulator of the osteoclastogenesis inhibitor WNT16, acting in a negative feedback loop to reduce OSM-induced osteoclast formation.
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Affiliation(s)
- Pedro P. C. de Souza
- The Innovation in Biomaterials Laboratory, School of Dentistry, Federal University of Goiás, Goiânia 74690-900, Brazil;
| | - Petra Henning
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden;
| | - Ulf H. Lerner
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden;
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Rodrigues J, Sarmento B, Pereira CL. Osteosarcoma tumor microenvironment: the key for the successful development of biologically relevant 3D in vitro models. IN VITRO MODELS 2022; 1:5-27. [PMID: 39872973 PMCID: PMC11756501 DOI: 10.1007/s44164-022-00008-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 01/09/2022] [Accepted: 01/09/2022] [Indexed: 01/30/2025]
Abstract
Osteosarcoma (OS) is the most common primary bone cancer in children and young adults. This type of cancer is characterized by a high mortality rate, especially for patients with resistant lung metastases. Given its low incidence, high genetic heterogeneity, the lack of effective targets, and poor availability of relevant in vitro and in vivo models to study the tumor progression and the metastatic cascade, the pathophysiology of OS is still poorly understood and the translation of novel drugs into the market has become stagnant. Due to the importance of the tumor microenvironment (TME) in the development of metastases and the growing interest in targeting TME-specific pathways for novel therapeutics in cancer, models that closely represent these interactions are crucial for a better understanding of cancer-related events. In OS research, most studies rely on oversimplified two-dimensional (2D) assays and complex animal models that do not faithfully recapitulate OS development and progression. In turn, three-dimensional (3D) models are able to mimic not only the physical 3D environment in which cancer cells grow but also involve interactions with the TME, including its extracellular matrix, and thus are promising tools for drug screening studies. In this review, the existing and innovative OS in vitro 3D models are highlighted, focusing on how the TME is crucial to develop effective platforms for OS tumor and metastasis modeling in a physiologically relevant context. Graphical abstract
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Affiliation(s)
- João Rodrigues
- Instituto de Investigação E Inovação Em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, 4150-180 Porto, Portugal
- Faculdade de Engenharia da Universidade Do Porto (FEUP), University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
| | - Bruno Sarmento
- Instituto de Investigação E Inovação Em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- CESPU, Instituto de Investigação E Formação Avançada Em Ciências E Tecnologias da Saúde, Rua Central da Gandra 1317, 4585-116 Gandra, Portugal
| | - Catarina Leite Pereira
- Instituto de Investigação E Inovação Em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
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Melatonin Attenuates RANKL-Induced Osteoclastogenesis via Inhibition of Atp6v0d2 and DC-STAMP through MAPK and NFATc1 Signaling Pathways. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27020501. [PMID: 35056817 PMCID: PMC8781594 DOI: 10.3390/molecules27020501] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 12/27/2022]
Abstract
Melatonin is a hormone secreted by the pineal gland that is involved in the biorhythm of reproductive activities. The present study investigated the inhibitory effects of melatonin on osteoclastogenesis in RAW 264.7 cells according to changes in V-ATPase and the corresponding inhibition of the MAPK and NFATc1 signaling processes. Methods: the cytotoxic effect of melatonin was investigated by MTT assay. Osteoclast differentiation and gene expression of osteoclast-related factors were confirmed via TRAP staining, pit formation assay, immunofluorescence imaging, western blot, and real-time PCR. Results: melatonin was found to inactivate the p38 and JNK of MAP kinase in RAW264.7 cells treated with RANKL and treated with a combination RANKL and melatonin for 1, 3, and 5 days. The melatonin treatment group showed a reduction in osteoclastogenesis transcription factors and ATP6v0d2 gene expression. Conclusions: melatonin inhibits osteoclast differentiation and cell fusion by inhibiting the expression of Atp6v0d2 through the inactivation of MAPK and NFATc1 signaling in RANKL-stimulated RAW264.7 macrophages. The findings of the present study suggest that melatonin could be a suitable therapy for bone loss and imply a potential role of melatonin in bone health.
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Ma Q, Wang S, Xie Z, Shen Y, Zheng B, Jiang C, Yuan P, Yu C, Li L, Zhao X, Chen J, Qin A, Fan S, Jie Z. The SFRP1 Inhibitor WAY-316606 Attenuates Osteoclastogenesis Through Dual Modulation of Canonical Wnt Signaling. J Bone Miner Res 2022; 37:152-166. [PMID: 34490916 DOI: 10.1002/jbmr.4435] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 08/17/2021] [Accepted: 08/29/2021] [Indexed: 11/07/2022]
Abstract
Osteoporosis, a noteworthy age-related disease induced by imbalanced osteogenesis and osteoclastogenesis, is a serious economic burden on both individuals and society. Small molecule drugs with dual effects on both bone resorption and mineralization are pressingly needed. Secreted frizzled-related protein 1 (SFRP1), a well-known extracellular repressor of canonical Wnt signaling, has been reported to regulate osteogenesis. Global SFRP1 knockout mice show significantly elevated bone mass. Although osteoclasts (OCs) express and secrete SFRP1, the role of SFRP1 produced by OCs in osteoclastogenesis and osteoporosis remains unclear. In this work, the levels of SFRP1 were found to be increased in patients with osteoporosis compared with healthy controls. Pharmacological inhibition of SFRP1 by WAY-316606 (WAY)- attenuated osteoclastogenesis and bone resorption in vitro. The expressions of OC-specific genes were suppressed by the SFRP1 inhibitor, WAY. Mechanistically, both extracellular and intracellular SFRP1 could block activation of the canonical Wnt signaling pathway, and WAY reverse the silent status of canonical Wnt through dual effects, leading to osteoclastogenesis inhibition and osteogenesis promotion. Severe osteopenia was observed in the ovariectomized (OVX) mouse model, and WAY treatment effectively improved the OVX-induced osteoporosis. In summary, this work found that SFRP1 supports OC differentiation and function, which could be attenuated by WAY through dual modulation of canonical Wnt signaling, suggesting its therapeutic potential. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Qingliang Ma
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Shiyu Wang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Ziang Xie
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Yang Shen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Bingjie Zheng
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Chao Jiang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Putao Yuan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Congcong Yu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Liangping Li
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Xiangde Zhao
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Junxin Chen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - An Qin
- Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shunwu Fan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Zhiwei Jie
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
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Williams DF. Biocompatibility pathways and mechanisms for bioactive materials: The bioactivity zone. Bioact Mater 2021; 10:306-322. [PMID: 34901548 PMCID: PMC8636667 DOI: 10.1016/j.bioactmat.2021.08.014] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 08/07/2021] [Indexed: 12/14/2022] Open
Abstract
This essay analyzes the scientific evidence that forms the basis of bioactive materials, covering the fundamental understanding of bioactivity phenomena and correlation with the mechanisms of biocompatibility of biomaterials. This is a detailed assessment of performance in areas such as bone-induction, cell adhesion, immunomodulation, thrombogenicity and antimicrobial behavior. Bioactivity is the modulation of biological activity by characteristics of the interfacial region that incorporates the material surface and the immediate local host tissue. Although the term ‘bioactive material’ is widely used and has a well understood general meaning, it would be useful now to concentrate on this interfacial region, considered as ‘the bioactivity zone’. Bioactivity phenomena are either due to topographical/micromechanical characteristics, or to biologically active species that are presented in the bioactivity zone. Examples of topographical/micromechanical effects are the modulation of the osteoblast – osteoclast balance, nanotopographical regulation of cell adhesion, and bactericidal nanostructures. Regulation of bioactivity by biologically active species include their influence, especially of metal ions, on signaling pathways in bone formation, the role of cell adhesion molecules and bioactive peptides in cell attachment, macrophage polarization by immunoregulatory molecules and antimicrobial peptides. While much experimental data exists to demonstrate the potential of such phenomena, there are considerable barriers to their effective clinical translation. This essay shows that there is solid scientific evidence of the existence of bioactivity mechanisms that are associated with some types of biomaterials, especially when the material is modified in a manner designed to specifically induce that activity.
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Affiliation(s)
- David F Williams
- Wake Forest Institute of Regenerative Medicine, 391 Technology Way. Winston-Salem, North Carolina, 27101, USA
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40
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Pan X, Cen X, Zhang B, Pei F, Huang W, Huang X, Zhao Z. Circular RNAs as potential regulators in bone remodeling: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1505. [PMID: 34805367 PMCID: PMC8573438 DOI: 10.21037/atm-21-2114] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 08/20/2021] [Indexed: 02/05/2023]
Abstract
Objective In this review, we focus on the recent progress of circular ribonucleic acids (circRNAs)-related molecular mechanisms in the processes of osteogenesis and osteoclastogenesis, and explore their roles in the development of bone-remodeling disorders. Background The well-coupled bone-formation and bone-resorption processes are vital in bone remodeling. Once the balance is disrupted, bone-remodeling disorders (e.g., osteoporosis and osteopetrosis) occur, severely affecting patients’ quality of life. CircRNAs, the newly discovered members of the non-coding RNA family, have been reported to act as key checkpoints of various signaling pathways that influence osteoblasts and osteoclasts functions, thus regulating the physiological and pathological processes of bone homeostasis. Methods Three English and three Chinese databases [i.e., PubMed, Embase, MEDLINE (via Ovid), Chinese Biomedical Literature, China National Knowledge Infrastructure, and VIP databases] were searched to June 2021 without language restrictions. Studies exploring the roles of circRNAs in key bone remodeling mediators, such as Smad-dependent bone morphogenetic protein (BMP)/transforming growth factor beta (TGF-β), Wnts, runt-related transcription factor (RUNX), forkhead boxes (FOXs), colony-stimulating factor 1 (CSF-1), receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG), and circRNA-related bone-remodeling disorders, were included. Conclusions Many circRNAs have been shown to promote osteogenesis and facilitate osteoclast differentiation via diverse mechanisms, and thus modulate the process of bone homeostasis. The imbalance or impairment of these two parts causes diseases, such as osteoporosis, and osteonecrosis of the femoral head, which are also closely correlated to the aberrant presence of circRNAs. Current evidence provides us with promising diagnosis and treatment methods for some bone homeostasis disorders.
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Affiliation(s)
- Xuefeng Pan
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiao Cen
- Department of Temporomandibular Joint, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Zhang
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fang Pei
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wei Huang
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xinqi Huang
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhihe Zhao
- Department of Orthodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Khosla S, Samakkarnthai P, Monroe DG, Farr JN. Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus. Nat Rev Endocrinol 2021; 17:685-697. [PMID: 34518671 PMCID: PMC8605611 DOI: 10.1038/s41574-021-00555-5] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 02/08/2023]
Abstract
Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM). In addition, these patients sustain fractures despite having higher levels of areal bone mineral density, as measured by dual-energy X-ray absorptiometry, than individuals without T2DM. Thus, additional factors such as alterations in bone quality could have important roles in mediating skeletal fragility in patients with T2DM. Although the pathogenesis of increased fracture risk in T2DM is multifactorial, impairments in bone material properties and increases in cortical porosity have emerged as two key skeletal abnormalities that contribute to skeletal fragility in patients with T2DM. In addition, indices of bone formation are uniformly reduced in patients with T2DM, with evidence from mouse studies published over the past few years linking this abnormality to accelerated skeletal ageing, specifically cellular senescence. In this Review, we highlight the latest advances in our understanding of the mechanisms of skeletal fragility in patients with T2DM and suggest potential novel therapeutic approaches to address this problem.
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Affiliation(s)
- Sundeep Khosla
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
| | - Parinya Samakkarnthai
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
- Division of Endocrinology, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand
| | - David G Monroe
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Joshua N Farr
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
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Cheng W, Xu X, Lang Y, Cheng Z, Rizwan M, Tang X, Xie L, Liu Y, Xu H, Liu Y. Anatase and Rutile TiO 2 Nanoparticles Lead Effective Bone Damage in Young Rat Model via the IGF-1 Signaling Pathway. Int J Nanomedicine 2021; 16:7233-7247. [PMID: 34737562 PMCID: PMC8558833 DOI: 10.2147/ijn.s333632] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/09/2021] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To evaluate the effects of anatase and rutile TiO2 nanoparticles (NPs) on the growth and development of bones in young rats and explore their possible mechanisms. METHODS Three-week-old male rats were orally administered anatase TiO2 NPs and rutile TiO2 NPs for 28 days. The indicators of rat growth and development, liver function, bone metabolism, and insulin-like growth factor-1 (IGF-1) levels were evaluated. Micro-computed tomography (micro-CT) and immunohistochemistry were used to evaluate the tibia. RESULTS No significant differences were observed among growth and development indicators in young rats. Significant differences were found in IGF-1 levels, phosphorus levels, and liver function. Micro-CT revealed osteoporosis in the bones. The micro-CT data supported the same result. Bone immunohistochemistry results showed that the expression of osteoprotegerin (OPG) was decreased and the expression of receptor activator of nuclear factor-κB ligand (RANKL) and cathepsin K (CTSK) was increased. CONCLUSION This study demonstrated that TiO2 NPs can damage bones via the IGF-1/OPG/RANKL/CTSK pathway in young rats. Furthermore, rutile TiO2 NPs damaged the bones more seriously than anatase TiO2 NPs.
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Affiliation(s)
- Wenshu Cheng
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Xinyue Xu
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Yuanyuan Lang
- Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Zugen Cheng
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Mohammad Rizwan
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Xiaomin Tang
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Lixin Xie
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Yanling Liu
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
| | - Hengyi Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi Province, 330047, People’s Republic of China
| | - Yang Liu
- Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China
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Forsyth RG, Krenács T, Athanasou N, Hogendoorn PCW. Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis. Cancers (Basel) 2021; 13:5119. [PMID: 34680268 PMCID: PMC8534144 DOI: 10.3390/cancers13205119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/14/2022] Open
Abstract
Giant cell tumour of bone (GCTB) is a rare and intriguing primary bone neoplasm. Worrisome clinical features are its local destructive behaviour, its high tendency to recur after surgical therapy and its ability to create so-called benign lung metastases (lung 'plugs'). GCTB displays a complex and difficult-to-understand cell biological behaviour because of its heterogenous morphology. Recently, a driver mutation in histone H3.3 was found. This mutation is highly conserved in GCTB but can also be detected in glioblastoma. Denosumab was recently introduced as an extra option of medical treatment next to traditional surgical and in rare cases, radiotherapy. Despite these new insights, many 'old' questions about the key features of GCTB remain unanswered, such as the presence of telomeric associations (TAs), the reactivation of hTERT, and its slight genomic instability. This review summarises the recent relevant literature of histone H3.3 in relation to the GCTB-specific G34W mutation and pays specific attention to the G34W mutation in relation to the development of TAs, genomic instability, and the characteristic morphology of GCTB. As pieces of an etiogenetic puzzle, this review tries fitting all these molecular features and the unique H3.3 G34W mutation together in GCTB.
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Affiliation(s)
- Ramses G. Forsyth
- Department of Pathology, University Hospital Brussels (UZB), Laarbeeklaan 101, 1090 Brussels, Belgium;
- Labaratorium for Experimental Pathology (EXPA), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllöi ut 26, 1085 Budapest, Hungary;
| | - Nicholas Athanasou
- Department of Histopathology, Nuffield Orthopaedic Centre, University of Oxford, NDORMS, Oxford OX3 7HE, UK;
| | - Pancras C. W. Hogendoorn
- Department of Pathology, University Hospital Brussels (UZB), Laarbeeklaan 101, 1090 Brussels, Belgium;
- Labaratorium for Experimental Pathology (EXPA), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllöi ut 26, 1085 Budapest, Hungary;
- Department of Histopathology, Nuffield Orthopaedic Centre, University of Oxford, NDORMS, Oxford OX3 7HE, UK;
- Department of Pathology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2300 RC Leiden, The Netherlands
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Karanth DS, Martin ML, Holliday LS. Plasma Membrane Receptors Involved in the Binding and Response of Osteoclasts to Noncellular Components of the Bone. Int J Mol Sci 2021; 22:ijms221810097. [PMID: 34576260 PMCID: PMC8466431 DOI: 10.3390/ijms221810097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 12/21/2022] Open
Abstract
Osteoclasts differentiate from hematopoietic cells and resorb the bone in response to various signals, some of which are received directly from noncellular elements of the bone. In vitro, adherence to the bone triggers the reduction of cell–cell fusion events between osteoclasts and the activation of osteoclasts to form unusual dynamic cytoskeletal and membrane structures that are required for degrading the bone. Integrins on the surface of osteoclasts are known to receive regulatory signals from the bone matrix. Regulation of the availability of these signals is accomplished by enzymatic alterations of the bone matrix by protease activity and phosphorylation/dephosphorylation events. Other membrane receptors are present in osteoclasts and may interact with as yet unidentified signals in the bone. Bone mineral has been shown to have regulatory effects on osteoclasts, and osteoclast activity is also directly modulated by mechanical stress. As understanding of how osteoclasts and other bone cells interact with the bone has emerged, increasingly sophisticated efforts have been made to create bone biomimetics that reproduce both the structural properties of the bone and the bone’s ability to regulate osteoclasts and other bone cells. A more complete understanding of the interactions between osteoclasts and the bone may lead to new strategies for the treatment of bone diseases and the production of bone biomimetics to repair defects.
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Affiliation(s)
- Divakar S. Karanth
- Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (D.S.K.); (M.L.M.)
| | - Macey L. Martin
- Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (D.S.K.); (M.L.M.)
| | - Lexie S. Holliday
- Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (D.S.K.); (M.L.M.)
- Department of Anatomy & Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
- Correspondence:
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Insights into the Cellular and Molecular Mechanisms That Govern the Fracture-Healing Process: A Narrative Review. J Clin Med 2021; 10:jcm10163554. [PMID: 34441849 PMCID: PMC8397080 DOI: 10.3390/jcm10163554] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 12/28/2022] Open
Abstract
Fracture-healing is a complex multi-stage process that usually progresses flawlessly, resulting in restoration of bone architecture and function. Regrettably, however, a considerable number of fractures fail to heal, resulting in delayed unions or non-unions. This may significantly impact several aspects of a patient’s life. Not surprisingly, in the past few years, a substantial amount of research and number of clinical studies have been designed, aiming at shedding light into the cellular and molecular mechanisms that regulate fracture-healing. Herein, we present the current knowledge on the pathobiology of the fracture-healing process. In addition, the role of skeletal cells and the impact of marrow adipose tissue on bone repair is discussed. Unveiling the pathogenetic mechanisms that govern the fracture-healing process may lead to the development of novel, smarter, and more effective therapeutic strategies for the treatment of fractures, especially of those with large bone defects.
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Isojima T, Sims NA. Cortical bone development, maintenance and porosity: genetic alterations in humans and mice influencing chondrocytes, osteoclasts, osteoblasts and osteocytes. Cell Mol Life Sci 2021; 78:5755-5773. [PMID: 34196732 PMCID: PMC11073036 DOI: 10.1007/s00018-021-03884-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/06/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
Cortical bone structure is a crucial determinant of bone strength, yet for many years studies of novel genes and cell signalling pathways regulating bone strength have focused on the control of trabecular bone mass. Here we focus on mechanisms responsible for cortical bone development, growth, and degeneration, and describe some recently described genetic-driven modifications in humans and mice that reveal how these processes may be controlled. We start with embryonic osteogenesis of preliminary bone structures preceding the cortex and describe how this structure consolidates then matures to a dense, vascularised cortex containing an increasing proportion of lamellar bone. These processes include modelling-induced, and load-dependent, asymmetric cortical expansion, which enables the cortex's transition from a highly porous woven structure to a consolidated and thickened highly mineralised lamellar bone structure, infiltrated by vascular channels. Sex-specific differences emerge during this process. With aging, the process of consolidation reverses: cortical pores enlarge, leading to greater cortical porosity, trabecularisation and loss of bone strength. Each process requires co-ordination between bone formation, bone mineralisation, vascularisation, and bone resorption, with a need for locational-, spatial- and cell-specific signalling pathways to mediate this co-ordination. We will discuss these processes, and a number of cell-signalling pathways identified in both murine and human genetic studies to regulate cortical bone mass, including signalling through gp130, STAT3, PTHR1, WNT16, NOTCH, NOTUM and sFRP4.
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Affiliation(s)
- Tsuyoshi Isojima
- St. Vincent's Institute of Medical Research, 9 Princes St, Fitzroy, VIC, 3122, Australia
- Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, 9 Princes St, Fitzroy, VIC, 3122, Australia.
- Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia.
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Influences of the IL-6 cytokine family on bone structure and function. Cytokine 2021; 146:155655. [PMID: 34332274 DOI: 10.1016/j.cyto.2021.155655] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 01/12/2023]
Abstract
The IL-6 family of cytokines comprises a large group of cytokines that all act via the formation of a signaling complex that includes the glycoprotein 130 (gp130) receptor. Despite this, many of these cytokines have unique roles that regulate the activity of bone forming osteoblasts, bone resorbing osteoclasts, bone-resident osteocytes, and cartilage cells (chondrocytes). These include specific functions in craniofacial development, longitudinal bone growth, and the maintenance of trabecular and cortical bone structure, and have been implicated in musculoskeletal pathologies such as craniosynostosis, osteoporosis, rheumatoid arthritis, osteoarthritis, and heterotopic ossifications. This review will work systematically through each member of this family and provide an overview and an update on the expression patterns and functions of each of these cytokines in the skeleton, as well as their negative feedback pathways, particularly suppressor of cytokine signaling 3 (SOCS3). The specific cytokines described are interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine factor 1 (CLCF1), neuropoietin, humanin and interleukin 27 (IL-27).
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Chen W, Xian G, Gu M, Pan B, Wu X, Ye Y, Zheng L, Zhang Z, Sheng P. Autophagy inhibitors 3-MA and LY294002 repress osteoclastogenesis and titanium particle-stimulated osteolysis. Biomater Sci 2021; 9:4922-4935. [PMID: 34052845 DOI: 10.1039/d1bm00691f] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Aseptic loosening caused by peri-implant osteolysis (PIO) is a common complication after joint replacement, and there is still no better treatment than revision surgery. The wear particle-induced inflammation response, especially subsequent osteoclastic bone resorption, is responsible for PIO. As the importance of wear particles in inducing autophagy in cells around the prosthesis in PIO has been discovered, this might be a central process underlying aseptic loosening. However, the role of autophagy induced by wear particles in osteoclastogenesis during PIO remains unclear. In this study, we investigated the role of autophagy in osteoclastogenesis and verified it in a mouse calvarial osteolysis model. We found that osteoclasts were increased in the interface membranes of patients with aseptic loosening. In vitro, knocking down the Atg5 gene or using autophagy inhibitors (3-MA, LY294002) to inhibit autophagy was found to repress osteoclastogenesis and decrease expression of the osteoclast-related genes TRAP, cathepsin K, and matrix metalloprotein 9 (MMP-9) with or without titanium (Ti) particles. In vivo, 3-MA and LY294002 repressed Ti particle-stimulated osteolysis and osteoclastogenesis and reduced expression of the pro-inflammatory factors TNF-α, IL-1β, and IL-6. Our results suggest that 3-MA and LY294002 might be the potential medicines to prevent and treat PIO and aseptic loosening.
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Affiliation(s)
- Weishen Chen
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Guoyan Xian
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Minghui Gu
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Baiqi Pan
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Xiaoyu Wu
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Yongyu Ye
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Linli Zheng
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Ziji Zhang
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Puyi Sheng
- Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China. and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
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Li L, Zhou J, Xu Y, Huang Z, Zhang N, Qiu X, Wang L. C-C chemokine receptor type 6 modulates the biological function of osteoblastogenesis by altering the expression levels of Osterix and OPG/RANKL. Biosci Trends 2021; 15:240-248. [PMID: 34248133 DOI: 10.5582/bst.2021.01199] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Circulating inflammatory factors affect osteoblast and osteoclast formation and activity in osteoporosis. Estrogen affects the migration of Th17 cells via the C-C chemokine receptor type 6 (CCR6) and C-C chemokine ligand 20 (CCL20) signaling pathways to modulate bone metabolism; however, it is unclear whether and how CCR6 modulates bone homeostasis. In the present study, CCR6 knockout (CCR6-/-) mice were selected to investigate the effects of CCR6 in the regulation of homeostasis of osteoblasts and osteoclasts. Primary osteoblasts were isolated from the calvarium of newborn CCR6-/- or wild-type mice, followed by osteoblastic differentiation culture in vitro. CCR6 deletion reduced osteoblast activity in terms of alkaline phosphatase (ALP) activity and inhibited osteoblast mineralization according to the results of Alizarin Red S staining, whereas it did not affect the proliferation of osteoblasts. CCR6 deletion inhibited Osterix mRNA expression in osteoblasts during the late stage of mineralization in vitro, while it did not affect mRNA expression levels of runt-related transcription factor 2 (Runx2) and Collagen-1. The ratio of osteoprotegerin (OPG) /receptor activator of nuclear factor κ-Β ligand (RANKL) mRNA level in osteoblasts was decreased by CCR6 deficiency in the culture treated with 1,25(OH)2D3/PGE2, while there was no effect observed in the normal culture environment. The results provide novel insights, such as that CCR6 deletion suppresses osteoblast differentiation by downregulating the expression levels of the transcription factor Osterix, and indirectly promotes osteoclast production by increasing transcription of RANKL. This may be one of the mechanisms via which CCR6 deletion regulates bone metabolism.
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Affiliation(s)
- Lisha Li
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Jing Zhou
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Yingping Xu
- Reproductive Medicine Centre, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Zengshu Huang
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Na Zhang
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Xuemin Qiu
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Ling Wang
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
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Effects of photobiomodulation on bone remodeling in an osteoblast-osteoclast co-culture system. Lasers Med Sci 2021; 37:1049-1059. [PMID: 34142255 DOI: 10.1007/s10103-021-03352-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/07/2021] [Indexed: 10/21/2022]
Abstract
The general bone anabolic effect of photobiomodulation (PBM) is largely accepted. As a result, PBM therapy is expected to be beneficial in the medical fields of dentistry and bone healing. However, most of the previous in vitro studies on PBM and bone metabolism were performed with single-cell cultures of osteoclast-lineage cells or osteoblast-lineage cells. In the present study, the bone-modulating effects of PBM were evaluated in an in vitro osteoblast/osteoclast co-culture system. Mouse bone marrow-derived macrophages (BMMs) and mouse calvarial pre-osteoblasts cells were purified and used as precursor cells for osteoclasts and osteoblasts, respectively. The PBM effects on single-cell culture of osteoclasts or osteoblasts as well as co-culture were examined by 1.2 J/cm2 low-level Ga-Al-As laser (λ = 808 ± 3 nm, 80 mW, and 80 mA; spot size, 1cm2; NDLux, Seoul, Korea) irradiation for 30 s at daily intervals throughout culture period. At the end of culture, the osteoclast differentiation and osteoblast differentiation were assessed by TRAP staining and ALP staining, respectively. The expressions of osteoclastogenic cytokines were evaluated by RT-PCR and Western blot analyses. Under the single-cell culture condition, PBM enhanced osteoblast differentiation but had minor effects on osteoclast differentiation. However, in the co-culture condition, its osteoblastogenic effect was maintained, and osteoclast differentiation was substantially reduced. Subsequent RT-PCR analyses and western blot results revealed marked reduction in receptor activator of NF-κB ligand (RANKL) expression and elevation in osteoprotegerin (OPG) expression by PBM in co-cultured cells. More importantly, these alterations in RANKL/OPG levels were not observed under the single-cell culture conditions. Our results highlight the different effects of PBM on bone cells based on culture conditions. Further, our findings suggest the indirect anti-osteoclastogenic effect of PBM, which is accompanied by a decrease in RANKL expression and an increase in OPG expression.
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