1
|
Ginesin O, Coyac BR, Doppelt‐Flikshtain O, Mayer Y, Gabay E, Berg T, Bar‐On Y, Zigdon‐Giladi H. Macrophage Depletion Reduces Bone Loss and Alters Inflammatory Responses: A Mouse Peri-Implantitis Model. J Clin Periodontol 2025; 52:898-906. [PMID: 40234094 PMCID: PMC12082783 DOI: 10.1111/jcpe.14120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/24/2024] [Accepted: 12/24/2024] [Indexed: 04/17/2025]
Abstract
AIM To evaluate the impact of macrophage depletion on bone loss and inflammatory responses in a mouse model of peri-implantitis, assessing macrophage depletion potential as a therapeutic strategy. MATERIALS AND METHODS Using 6-week-old male C57BL/6 mice, peri-implantitis was induced by placing a silk ligature around osteointegrated dental implants. Mice were divided into three groups: Healthy control (Healthy group); peri-implantitis with liposomal phosphate-buffered saline (PBS group); and peri-implantitis with liposomal clodronate for macrophage depletion (CLOD group). Two weeks after ligature placement, micro-CT, histological and real-time PCR analyses were performed to assess bone density, leukocyte infiltration and cytokine levels. RESULTS The CLOD group showed a significantly higher bone-to-implant contact (74%) and bone volume relative to total volume (79%) compared to the PBS group (53% and 54%, respectively) and Healthy group (64% and 66%, respectively). Histological analysis revealed significantly reduced leukocyte and macrophage counts in the CLOD group. Additionally, TNF-α and IL-10 levels were significantly decreased in the CLOD group compared with the PBS group. CONCLUSION Macrophage depletion effectively reduces bone loss and inflammation in peri-implantitis. This study highlights targeting macrophages as a promising approach for managing peri-implantitis, although further research is needed to optimize therapeutic strategies.
Collapse
Affiliation(s)
- Ofir Ginesin
- Department of PeriodontologySchool of Graduate Dentistry, Rambam Health Care CampusHaifaIsrael
- Laboratory for Bone RepairCRIR Institute, Rambam Health Care CampusHaifaIsrael
- Rappaport Faculty of MedicineTechnion – Israeli Institute of TechnologyHaifaIsrael
| | - Benjamin R. Coyac
- Department of PeriodontologySchool of Graduate Dentistry, Rambam Health Care CampusHaifaIsrael
- Craniofacial Ossification Laboratory, Department of Oral BiologyGoldschleger School of Dental Medicine, Faculty of Medical and Health Sciences, Tel Aviv UniversityTel Aviv‐YafoIsrael
| | - Ofri Doppelt‐Flikshtain
- Laboratory for Bone RepairCRIR Institute, Rambam Health Care CampusHaifaIsrael
- Rappaport Faculty of MedicineTechnion – Israeli Institute of TechnologyHaifaIsrael
| | - Yaniv Mayer
- Department of PeriodontologySchool of Graduate Dentistry, Rambam Health Care CampusHaifaIsrael
- Rappaport Faculty of MedicineTechnion – Israeli Institute of TechnologyHaifaIsrael
| | - Eran Gabay
- Department of PeriodontologySchool of Graduate Dentistry, Rambam Health Care CampusHaifaIsrael
- Rappaport Faculty of MedicineTechnion – Israeli Institute of TechnologyHaifaIsrael
| | - Tal Berg
- Laboratory for Bone RepairCRIR Institute, Rambam Health Care CampusHaifaIsrael
- Rappaport Faculty of MedicineTechnion – Israeli Institute of TechnologyHaifaIsrael
| | - Yotam Bar‐On
- Department of ImmunologyRappaport Faculty of Medicine, Technion – Israeli Institute of TechnologyHaifaIsrael
| | - Hadar Zigdon‐Giladi
- Department of PeriodontologySchool of Graduate Dentistry, Rambam Health Care CampusHaifaIsrael
- Laboratory for Bone RepairCRIR Institute, Rambam Health Care CampusHaifaIsrael
- Rappaport Faculty of MedicineTechnion – Israeli Institute of TechnologyHaifaIsrael
| |
Collapse
|
2
|
Sheng K, Bisson DG, Saran N, Bourdages J, Coluni C, Upshaw K, Tiedemann K, Komarova SV, Ouellet JA, Haglund L. The TLR-M-CSF axis is implicated in increased bone turnover and curve progression in adolescent idiopathic scoliosis. Arthritis Res Ther 2025; 27:68. [PMID: 40165259 PMCID: PMC11956469 DOI: 10.1186/s13075-025-03535-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 03/12/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Facet joint osteoarthritis (OA) is prevalent in patients with adolescent idiopathic scoliosis (AIS). The most pronounced OA presents above and below the curve's apex where the intervertebral rotation is the greatest. This indicates that facet joint OA is implicated and potentially contributes to AIS progression. OA impacts both cartilage and bone and we have previously demonstrated an association between lower bone quality and more severe OA in AIS facet joints. This study aimed to further investigate the molecular mechanisms underlying cartilage-bone crosstalk in the facet joints of patients with AIS. METHODS Unbiased deep RNA sequencing was performed to compare gene expression in facet joint chondrocytes of age-matched AIS patients and non-scoliotic individuals. Differentially expressed genes of interest were validated through qPCR and ELISA in a larger sample cohort. Key regulatory pathways involved in cartilage-bone crosstalk were identified through bioinformatic analysis. Functional studies were conducted by treating chondrocytes with TLR2 and TLR4 agonists, collecting conditioned media, and administering it to an in vitro osteoclastogenesis model. The expression of M-CSF, a key regulatory factor influencing osteoclast proliferation, was measured in individual facet joint cartilage samples at different spinal levels and correlated with cartilage morphological grade and 3D structural parameters extracted from spine reconstruction. RESULTS One thousand four hundred twenty six upregulated genes were detected, and gene ontology analysis revealed a significant enrichment of the TLR pathway, and bone-regulating biological processes in AIS chondrocytes. TLR activation of AIS chondrocytes induced expression of bone-regulating factors, including M-CSF, a key regulator of osteoclast proliferation. Furthermore, secreted factors from AIS chondrocytes enhanced osteoclast proliferation and maturation, with a stronger effect observed following TLR pre-activation. Clinically, M-CSF expression was found to correlate strongly with increased OA severity and a greater degree of intervertebral axial rotation. CONCLUSIONS Together, our findings suggest that the TLR-M-CSF axis is implicated in osteoclastogenesis, resulting in increased bone turnover and may contribute to curve progression in AIS patients.
Collapse
Affiliation(s)
- Kai Sheng
- Shriners Hospital for Children, Montreal, QC, Canada
- Department of Surgery, Orthopaedic Research Laboratory, Mcgill University, Montreal, QC, Canada
| | - Daniel G Bisson
- Shriners Hospital for Children, Montreal, QC, Canada
- Department of Surgery, Orthopaedic Research Laboratory, Mcgill University, Montreal, QC, Canada
| | - Neil Saran
- Shriners Hospital for Children, Montreal, QC, Canada
| | | | | | - Kirby Upshaw
- Shriners Hospital for Children, Montreal, QC, Canada
- Mcgill University Health Centre, Montreal, QC, Canada
| | | | | | | | - Lisbet Haglund
- Shriners Hospital for Children, Montreal, QC, Canada.
- Department of Surgery, Orthopaedic Research Laboratory, Mcgill University, Montreal, QC, Canada.
| |
Collapse
|
3
|
Wang Z, Zhang W, Liu Z, Huang D, Kang H, Wang J, Jiang G, Gao A. Gut microbiota dysbiosis involved in decabromodiphenyl ether-induced bone homeostasis disorder through inflammaging. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 368:125710. [PMID: 39837379 DOI: 10.1016/j.envpol.2025.125710] [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: 07/29/2024] [Revised: 01/06/2025] [Accepted: 01/16/2025] [Indexed: 01/23/2025]
Abstract
BDE-209 has a causal relationship with adverse health outcomes. However, research on its effect on bone homeostasis is relatively lacking. This study examined the relationship between BDE-209 exposure and bone health, as well as the underlying mechanisms, using both in vitro and in vivo models. In animal studies, female SD rats were administered BDE-209 for 60 days. Bone mineral density, bone microstructure, gut microbiota, and inflammaging markers were measured. Furtherly, THP-1 cell-derived macrophages were treated with a culture medium containing population-relevant dose of BDE-209 or sodium butyrate. The expression of M1 macrophage markers, osteoclast markers, and inflammatory cytokines was measured. Then macrophages were induced by osteoclast conditioned medium to evaluate the effect of BDE-209 on their differentiation into osteoclasts. Results showed reduced humeral bone density, enhanced osteoclast activity, upregulation of IL-1β, TNF-α, IL-6, and activation of PGC-1α/NAD+/cGAS-STING in the exposed group. 16s sequencing revealed that BDE-209 disrupts the abundance of the gut microbiota, notably a reduction in Lachnospiraceae. In vitro, BDE-209 can stimulate macrophages to differentiate more osteoclasts and activate the cGAS-STING pathway, while sodium butyrate can inhibit these effects. This study reveals that gut microbiota dysbiosis is involved in BDE-209-induced bone homeostasis disorder through inflammatory aging and sodium butyrate can mitigate this effect. Overall, this study provides research data for the precaution and treatment of osteoporosis associated with BDE-209 exposure.
Collapse
Affiliation(s)
- Ziyan Wang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China
| | - Wei Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Ziyan Liu
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Danyang Huang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Huiwen Kang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Jingyu Wang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Guangyu Jiang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China
| | - Ai Gao
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, China.
| |
Collapse
|
4
|
Steemers E, Talbi WMI, Hogervorst JMA, Schoenmaker T, de Vries TJ. IL-1 Receptor Antagonist Anakinra Inhibits the Effect of IL-1β- Mediated Osteoclast Formation by Periodontal Ligament Fibroblasts. BIOLOGY 2025; 14:250. [PMID: 40136507 PMCID: PMC11939651 DOI: 10.3390/biology14030250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/10/2025] [Accepted: 02/28/2025] [Indexed: 03/27/2025]
Abstract
Rheumatoid arthritis and periodontitis are comorbidities that share mutual pathways. IL-1β is a pro-inflammatory cytokine that plays a crucial role in both diseases. One of the treatment options for rheumatoid arthritis is the use of an IL-1 receptor antagonist (IL-1RA) such as anakinra. Anakinra tempers the disease by decreasing bone resorption and it could possibly stimulate bone formation. Here, we investigate the effect of anakinra in a periodontal disease setting on osteoclastogenesis by co-culturing periodontal ligament fibroblasts (PDLFs) and peripheral blood mononuclear cells (PBMCs) that contain monocytes, a source of osteoclast precursors, as well as by culturing PBMCs alone. The effect of anakinra on PDLF-mediated osteogenesis was studied under mineralization conditions. To mimic a chronic infection such as that prevalent in periodontitis, 10 ng/mL of IL-1β was added either alone or with 10 µg/mL of anakinra. Osteoclastogenesis experiments were performed using co-cultures of PDLF and PBMCs and PBMCs only. Osteoclastogenesis was determined through the formation of multinucleated cells in co-cultures of PDLF and PBMCs, as well as PBMCs alone, at day 21, and gene expression through qPCR at day 14. Osteogenesis was determined by measuring alkaline phosphatase activity (ALP) per cell at day 14. Anakinra is effective in downregulating IL-1β mediated leukocyte clustering and osteoclastogenesis in the co-cultures of both PDLF and PMBCs and PBMCs alone. Gene expression analysis shows that IL-1β increases the expression of the osteoclastogenic marker RANKL and its own expression. This higher expression of IL-1β at the RNA level is reduced by anakinra. Moreover, IL-1β downregulates OPG expression, which is upregulated by anakinra. No effects of anakinra on osteogenesis were seen. Clinically, these findings suggest that anakinra could have a beneficial systemic effect on periodontal breakdown in rheumatoid arthritis patients taking anakinra.
Collapse
Affiliation(s)
- Elizabeth Steemers
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LH Amsterdam, The Netherlands; (E.S.); (W.M.I.T.); (T.S.)
| | - Wael M. I. Talbi
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LH Amsterdam, The Netherlands; (E.S.); (W.M.I.T.); (T.S.)
| | - Jolanda M. A. Hogervorst
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LH Amsterdam, The Netherlands;
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LH Amsterdam, The Netherlands; (E.S.); (W.M.I.T.); (T.S.)
| | - Teun J. de Vries
- Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit, Gustav Mahlerlaan 3004, 1081 LH Amsterdam, The Netherlands; (E.S.); (W.M.I.T.); (T.S.)
| |
Collapse
|
5
|
Zhu M, Xu M, Bertheloot D, Brom VC, Sieberath A, Salber J, Welle K, Burger C, Wirtz DC, Wang S, Schildberg FA. Arcyriaflavin A Alleviates Osteoporosis by Suppressing RANKL-Induced Osteoclastogenesis. Int J Mol Sci 2025; 26:2141. [PMID: 40076762 PMCID: PMC11899857 DOI: 10.3390/ijms26052141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Osteoclasts (OCs) are important therapeutic targets in the treatment of osteoporosis. The aim of this study was to explore a novel therapeutic approach for osteoporosis using Arcyriaflavin A (ArcyA), a natural compound derived from the marine invertebrate Eudistoma sp. We systematically evaluated the effects of ArcyA on OC differentiation and function in mouse models using molecular biology assays, cellular function analyses and in vivo animal experiments. We also evaluated the efficacy of ArcyA in human cells. The TRAP staining results provide the first clear evidence of the drug's inhibitory effect, whereby the administration of ArcyA led to a significant reduction in TRAP-positive cells compared to the control group at concentrations that were non-toxic to bone marrow macrophages. Meanwhile, a significant reduction in the number of multinucleated giant cells with more than ten nuclei was observed. Furthermore, similar TRAP staining results were reproduced in human OCs, suggesting that ArcyA has the same effect on OCs derived from human PBMCs. At the molecular level, ArcyA treatment resulted in the downregulation of genes relevant to OC differentiation (NFATc1, cFos and TNFrsf11α), fusion and survival (DCstamp and ATP6v0d2) and resorption function (CTSK, MMP9, integrin β3 and ACP5). A western blot analysis of the corresponding proteins (NFATc1, cFos, CTSK and integrin β3) further confirmed the PCR results. Furthermore, ArcyA-treated OCs produced significantly fewer resorption pits, indicating suppressed bone resorption activity. Consistent with this, in vivo experiments using an ovariectomy (OVX)-induced osteoporosis mouse model showed that ArcyA treatment significantly alleviated bone loss. Mice in the treatment groups had higher BV/TV values, and this therapeutic effect was enhanced in a dose-dependent manner. In addition, our research also showed that IκB could be a potential target for the inhibitory effect of ArcyA. In conclusion, these findings suggest that ArcyA has significant therapeutic potential for the treatment of osteoporosis by inhibiting osteoclastogenesis and bone resorption. Further studies are warranted to explore its clinical applications.
Collapse
Affiliation(s)
- Mengbo Zhu
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Mingwei Xu
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan 030013, China (S.W.)
| | - Damien Bertheloot
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Victoria C. Brom
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Alexander Sieberath
- Department of Experimental Surgery, Centre for Clinical Research, Ruhr-Universität Bochum, 44780 Bochum, Germany
| | - Jochen Salber
- Department of Experimental Surgery, Centre for Clinical Research, Ruhr-Universität Bochum, 44780 Bochum, Germany
- Department of Surgery, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, 44892 Bochum, Germany
| | - Kristian Welle
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Christof Burger
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Dieter C. Wirtz
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Shaowei Wang
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan 030013, China (S.W.)
| | - Frank A. Schildberg
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| |
Collapse
|
6
|
Huang SE, Hu KF, Lin MX, Tseng CJ, Wu BN, Dai ZK, Hsu JH, Yeh JL. Xanthine Derivative KMUP-3 Alleviates Periodontal Bone Resorption by Inhibiting Osteoclastogenesis and Macrophage Pyroptosis. J Periodontal Res 2025. [PMID: 40007249 DOI: 10.1111/jre.13393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/16/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025]
Abstract
AIM This study investigated the function effects of KMUP-3, a self-developed synthetic xanthine-based derivative, in suppressing Porphyromonas gingivalis (Pg-LPS)-aggravated osteoclastogenesis and pyroptosis as a potential treatment for periodontitis. METHODS In vitro, the effects of Pg-LPS and KMUP-3 on osteoclast formation and macrophage pyroptosis were investigated using the receptor activator of nuclear factor-κB ligand (RANKL)-primed RAW264.7 macrophages. In vivo, the therapeutic effects of KMUP-3 were evaluated in a model of experimental periodontitis induced by gingival ligature placement. RESULTS We reveal that KMUP-3 suppressed osteoclastogenesis, inducible nitric oxide synthase activation, and reduced nitric oxide production enhanced by Pg-LPS in RANKL-primed RAW264.7 cells while also decreasing TLR4/NF-κB p65 pathway activation and decreased pro-inflammatory cytokine production; moreover, Pg-LPS promoted NLRP3 activation and exacerbated pyroptosis induction effects that were abolished by KMUP-3. Finally, KMUP-3 ameliorated alveolar bone loss and IL-1β levels in the gingival crevicular fluid in the rat ligature periodontitis model. CONCLUSIONS Our study demonstrated that KMUP-3 attenuates Pg-LPS-enhanced osteoclastogenesis and macrophage pyroptosis. Notably, KMUP-3 alleviates alveolar bone loss in experimental periodontitis rats and thus suggests its certain role in safeguarding against periodontal bone resorption.
Collapse
Affiliation(s)
- Shang-En Huang
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kai-Fang Hu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Dentistry, Division of Periodontics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Meng-Xuan Lin
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Jiunn Tseng
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Bin-Nan Wu
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zen-Kong Dai
- Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jong-Hau Hsu
- Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jwu-Lai Yeh
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| |
Collapse
|
7
|
Ji C, Chen Y, Si M, Chen X. The impact of biocorrosion and titanium ions release on peri-implantitis. Clin Oral Investig 2025; 29:155. [PMID: 39998661 DOI: 10.1007/s00784-025-06186-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 01/20/2025] [Indexed: 02/27/2025]
Abstract
OBJECTIVES Biofilm accumulation is considered the primary cause of peri-implant inflammation. Still, metallosis caused by an increased concentration of titanium ions at the site of peri-implantitis site cannot be ignored. Whether titanium ions alone or in concert with bacterial biofilm trigger inflammation and bone destruction in peri-implant tissues remains unproven. MATERIALS AND METHODS Articles were retrieved from PubMed/Medline, Web of Science. All studies focusing on titanium ions release in peri-implant reactions were included and evaluated. RESULTS Titanium implants are considered non-inert and may release titanium ions in the intraoral microenvironment, the most important of which is the acidic environment created by bacterial biofilms. Although the correlation between titanium ion release and the incidence or progression of peri-implantitis is controversial, several studies have confirmed the potential role of titanium ions. Diffusion or entry of titanium ions into the circulation may be a scavenging effect on local titanium ions but can cause systemic adverse effects. However, existing measures are not yet able to balance reducing biocorrosion and maintaining osteogenic results, and the exploration of new materials requires long-term clinical data. CONCLUSIONS Titanium ions have potential impacts on peri-implant tissue and systemic circulation. Titanium ions are closely associated with bacterial biofilms in the occurrence and development of periimplantitis. The preventive strategies for the release and action of titanium ions remain to be explored. CLINICAL RELEVANCE Our findings may provide the hope of shedding light on the pathogenesis of peri-implantitis and its treatment.
Collapse
Affiliation(s)
- Chonghao Ji
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, China
| | - Yaqian Chen
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, China
| | - Misi Si
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, China.
| | - Xiaoyan Chen
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, China.
| |
Collapse
|
8
|
Wang C, Liu A, Zhao Z, Ying T, Deng S, Jian Z, Zhang X, Yi C, Li D. Application and progress of 3D printed biomaterials in osteoporosis. Front Bioeng Biotechnol 2025; 13:1541746. [PMID: 39968010 PMCID: PMC11832546 DOI: 10.3389/fbioe.2025.1541746] [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: 12/08/2024] [Accepted: 01/17/2025] [Indexed: 02/20/2025] Open
Abstract
Osteoporosis results from a disruption in skeletal homeostasis caused by an imbalance between bone resorption and bone formation. Conventional treatments, such as pharmaceutical drugs and hormone replacement therapy, often yield suboptimal results and are frequently associated with side effects. Recently, biomaterial-based approaches have gained attention as promising alternatives for managing osteoporosis. This review summarizes the current advancements in 3D-printed biomaterials designed for osteoporosis treatment. The benefits of biomaterial-based approaches compared to traditional systemic drug therapies are discussed. These 3D-printed materials can be broadly categorized based on their functionalities, including promoting osteogenesis, reducing inflammation, exhibiting antioxidant properties, and inhibiting osteoclast activity. 3D printing has the advantages of speed, precision, personalization, etc. It is able to satisfy the requirements of irregular geometry, differentiated composition, and multilayered structure of articular osteochondral scaffolds with boundary layer structure. The limitations of existing biomaterials are critically analyzed and future directions for biomaterial-based therapies are considered.
Collapse
Affiliation(s)
- Chenxu Wang
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Department of Orthopedics, The First Affiliated Hospital of Henan University, Kaifeng, China
| | - Aiguo Liu
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Department of Orthopedics, The First Affiliated Hospital of Henan University, Kaifeng, China
| | - Ziwen Zhao
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Ting Ying
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Shuang Deng
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Zhen Jian
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Xu Zhang
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Chengqing Yi
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Dejian Li
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| |
Collapse
|
9
|
Liu H, Sun C, Jiang Y, Gao R, Ying Q, Li X, Liu H, Guo J, Li M. Eldecalcitol alleviates diabetic periodontitis by regulating macrophage efferocytosis and polarization via SOCE machinery. Int Immunopharmacol 2025; 146:113894. [PMID: 39729922 DOI: 10.1016/j.intimp.2024.113894] [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: 09/18/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 12/29/2024]
Abstract
Diabetes exacerbates the occurrence and severity of periodontitis, the pathogenesis of diabetic periodontitis (DPD) is influenced by the delayed resolution of inflammation. Eldecalcitol (ED-71) has shown promise in preventing bone loss in DPD. We herein aimed to investigate the role of ED-71 in the inflammatory regression phase of DPD and elucidate the underlying mechanisms. Type-2 diabetes was induced by streptozotocin injection in Wistar rats, and to explore the in vivo effect of ED-71 on macrophage efferocytosis, periodontitis was induced by ligation combined with lipopolysaccharide. Alveolar bone destruction was assessed using micro-computed tomography, hematoxylin-eosin, immunohistochemistry, and tartrate-resistant acid phosphatase staining. Immunofluorescence staining and flow cytometry detected neutrophils, apoptotic cells, and macrophage polarization in periodontal tissue. Additionally, flow cytometry, real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to examine macrophage efferocytosis and changes in store-operated calcium entry (SOCE). We found that rats with diabetes exhibited more severe alveolar bone destruction and increased neutrophil aggregates in periodontal tissue. Following the ED-71 administration, alveolar bone loss significantly decreased, and the immune microenvironment of periodontal tissue tended to suppress inflammation. Macrophages stimulated with high glucose experienced disruption of SOCE machinery, leading to the inhibition of efferocytosis in vitro. ED-71 demonstrated the ability to restore macrophage efferocytosis by correcting SOCE, and preventing sustained inflammatory damage to periodontal tissue. In conclusion, diabetes impairs macrophage efferocytosis and M2 polarization in periodontitis rats, resulting in the delayed resolution of inflammation. ED-71 could attenuate alveolar bone loss by mitigating macrophage via SOCE machinery in DPD.
Collapse
Affiliation(s)
- Hongrui Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Changyun Sun
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Yujun Jiang
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Ruihan Gao
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Qiaohui Ying
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Xiaolin Li
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Hongrui Liu
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China; Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Jie Guo
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.
| | - Minqi Li
- Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No.44-1 Wenhua Road West, 250012, Jinan, Shandong, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China; School of Clinical Medicine, Jining Medical University, Jining, China; Institute of Oral Basic Research, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University.
| |
Collapse
|
10
|
Zheng B, Yu P, Liu H, Liang Y. Anti-Osteoporosis Is Imperative in Prevention of Progress of Ankylosing Spondylitis. Int J Gen Med 2025; 18:291-297. [PMID: 39850326 PMCID: PMC11756905 DOI: 10.2147/ijgm.s509296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 01/14/2025] [Indexed: 01/25/2025] Open
Abstract
Background Ankylosing spondylitis (AS) is a chronic autoimmune disease that affects the spine and peripheral joints, often leading to kyphosis, joint stiffness, and even ankylosis. Sagittal parameters, such as total thoracic kyphosis (TTK), thoracic kyphosis (TK), major thoracic kyphosis (MTK), and thoracolumbar kyphosis (TLK), are crucial indices for evaluating spinal alignment in AS patients and can reflect disease progression. This study aims to explore the relationship between bone mineral density (BMD), sagittal parameters, and joint ankylosis in AS patients. Methods A retrospective study was conducted on 147 AS patients. Participants were divided into three groups based on cervical and hip joint mobility. BMD was measured using quantitative computed tomography (QCT). Sagittal parameters (TTK, TK, MTK, TLK) were assessed using X-rays. Ordinal multinomial logistic regression and Spearman correlation analyses were performed to identify factors influencing joint stiffness. Results Significant differences in age, BMD, and sagittal parameters (TTK, TK, MTK, TLK) were observed among the groups. Ordinal logistic revealed that BMD (Estimate = 0.012) was negatively correlated with joint stiffness, while TTK (Estimate = 0.020) and TLK (Estimate = 0.030) were positively correlated. Age, TK, and MTK do not have a significant impact on joint stiffness. Spearman analysis showed no correlation between BMD and sagittal parameters (TTK and TLK). Besides, TTK and TLK were correlated. Conclusion In AS patients, BMD is an independent protective factor against joint stiffness, whereas sagittal parameters (TTK and TLK) contribute to increased joint stiffness. These findings highlight the importance of monitoring both bone mineral density and key sagittal parameters in clinical practice. Early anti-osteoporosis treatment, alongside interventions targeting abnormal spinal alignment, may help preserve joint mobility and potentially prevent progression to joint ankylosis.
Collapse
Affiliation(s)
- Bin Zheng
- Spine Surgery, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Panfeng Yu
- Spine Surgery, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Haiying Liu
- Spine Surgery, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Yan Liang
- Spine Surgery, Peking University People’s Hospital, Beijing, People’s Republic of China
| |
Collapse
|
11
|
Burgan J, Rahmati M, Lee M, Saiz AM. Innate immune response to bone fracture healing. Bone 2025; 190:117327. [PMID: 39522707 DOI: 10.1016/j.bone.2024.117327] [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: 09/10/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
The field of osteoimmunology has primarily focused on fracture healing in isolated musculoskeletal injuries. The innate immune system is the initial response to fracture, with inflammatory macrophages, cytokines, and neutrophils arriving first at the fracture hematoma, followed by an anti-inflammatory phase to begin the process of new bone formation. This review aims to first discuss the current literature and knowledge gaps on the immune responses governing single fracture healing by encompassing the individual role of macrophages, neutrophils, cytokines, mesenchymal stem cells, bone cells, and other immune cells. This paper discusses the interactive effects of these cellular responses underscoring the field of osteoimmunology. The critical role of the metabolic environment in guiding the immune system properties will be highlighted along with some effective therapeutics for fracture healing in the context of osteoimmunology. However, compared to isolated fractures, which frequently heal well, long bone fractures in over 30 % of polytrauma patients exhibit impaired healing. Clinical evidence suggests there may be distinct physiologic and inflammatory pathways altered in polytrauma resulting in nonunion. Nonunion is associated with worse patient outcomes and increased societal healthcare costs. The dysregulated immunomodulatory/inflammatory response seen in polytrauma may lead to this increased nonunion rate. This paper will investigate the differences in immune response between isolated and polytrauma fractures. Finally, future directions for fracture studies are explored with consideration of the emerging roles of newly discovered immune cell functions in fracture healing, the existing challenges and conflicting results in the field, the translational potential of these studies in clinic, and the more complex nature of polytrauma fractures that can alter cell functions in different tissues.
Collapse
Affiliation(s)
- Jane Burgan
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maryam Rahmati
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, PO Box 1109, Blindern, NO-0317 Oslo, Norway
| | - Mark Lee
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA
| | - Augustine Mark Saiz
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA.
| |
Collapse
|
12
|
Lin S, Moreinos D, Mavridou AM, Novak R, Rotstein I, Abbott PV. The role of infection in signalling root resorption: A narrative review. Int Endod J 2024; 57:1727-1744. [PMID: 39291291 DOI: 10.1111/iej.14132] [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: 12/12/2023] [Revised: 06/11/2024] [Accepted: 07/26/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Root resorption consists of complex, multistep processes that involve cell signalling caused by inflammation and stromal cells, which promotes the secretion of receptor activator of nuclear factor κB ligand/ macrophage-colony stimulating factor (RANKL/M-CSF) resulting in a resorptive process. OBJECTIVE The aim of this narrative review was to analyse the literature related to root resorption resulting from microbial infection and to comparing it with non-microbial infection. METHODS An electronic literature search was performed using the PubMed database and applying keywords of articles published in English. Eligible papers were reviewed to reveal the descriptions of bone and root resorption processes. The abstracts were searched manually to identify articles about infection-stimulating bone and root resorption. RESULTS Three main types of root resorption were identified, two associated with primary bacterial infection and one secondary to bacterial infection. These include external inflammatory resorption, internal inflammatory resorption and external cervical (invasive) resorption. DISCUSSION The magnitude of cytokine involvement that promotes resorption and M-CSF/RANKL production depends on multiple factors, including pathogen virulence, site of infection and host genetic factors that activate the inflammation at the infection site. Two mechanisms activate the resorption mechanisms-the canonical and non-canonical pathways that can activate clastic cells independently of the RANKL/RANK canonical pathways. CONCLUSIONS Two pathways of root resorption co-exist in the body. When resorption is caused by infection, chronic inflammation due to bacterial infection prolongs the secretions of pro-inflammatory cytokines that intensify root and bone resorption. The second pathway is bacterial independent of the non-infection root resorption that is part of the wound healing process, which is limited in time due to its innate ability.
Collapse
Affiliation(s)
- S Lin
- The Israeli National Center for Trauma & Emergency Medicine Research, Gertner Institute, Tel Hashomer, Israel
- Department of Endodontics, Rambam Health Care Campus, Haifa, Israel
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - D Moreinos
- Endodontic Department, Galilee Medical Center, Nahariya, Israel
| | - A M Mavridou
- Department of Endodontology, National and Kapodistrian University of Athens, Athens, Greece
| | - R Novak
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
- Orthopedic Oncology Unit, Department of Orthopedic, Rambam Health Care Campus, Haifa, Israel
| | - I Rotstein
- University of Southern California, Los Angeles, California, USA
| | - P V Abbott
- UWA Dental School, The University of Western Australia, Nedlands, Western Australia, Australia
| |
Collapse
|
13
|
Shehabeldin M, Kobyra J, Cho Y, Gao J, Chong R, Tabib T, Lafyatis R, Little SR, Sfeir C. Local Controlled Delivery of IL-4 Decreases Inflammatory Bone Loss in a Murine Model of Periodontal Disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:1635-1643. [PMID: 39465979 DOI: 10.4049/jimmunol.2400332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 09/16/2024] [Indexed: 10/29/2024]
Abstract
Chronic inflammatory diseases are a leading global health problem. In many of these diseases, the consistent presence of systemic low-grade inflammation induces tissue damage. This is true in conditions such as diabetes, arthritis, and autoimmune disorders, where an overactive and uncontrolled host immune response is a major driver of immunopathology. Central to this overactive and destructive host response are macrophages, the major phagocytic cells within the innate immune system. These cells exhibit a dual role in both host defense against invading pathogens and promotion of tissue repair during inflammation resolution. Those unique characteristics make macrophages an excellent target for therapeutic interventions in many chronic inflammatory conditions. Using periodontal disease as a model of chronic inflammation, we sought to assess the feasibility of using a controlled drug delivery strategy to target macrophages within the oral cavity. To that end, IL-4 was encapsulated within a biodegradable polymer carrier and locally delivered into the inflamed periodontal tissues. Our data indicate that local sustained delivery of IL-4 decreased inflammatory bone loss and promoted bone gain in the diseased mouse periodontium. Those effects correlated with a shift of local macrophage population toward a prorepair phenotype. Using single-cell RNA sequencing technology, we found that IL-4 delivery reversed several proinflammatory pathways associated with tissue destructive macrophages. Together, our data suggest that sustained delivery of IL-4 may be a viable therapeutic option for chronic diseases characterized by immune-mediated tissue damage.
Collapse
Affiliation(s)
- Mostafa Shehabeldin
- Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, PA
- Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA
- Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Julie Kobyra
- Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA
| | - Yejin Cho
- Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Jin Gao
- Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, PA
| | - Rong Chong
- Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, PA
| | - Tracy Tabib
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA
| | - Robert Lafyatis
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA
| | - Steven R Little
- Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Charles Sfeir
- Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, PA
- Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA
- Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA
| |
Collapse
|
14
|
Visarnta S, Ratisoontorn C, Panichuttra A, Sinpitaksakul P, Chantarangsu S, Dhanuthai K. Macrophage polarization in human periapical lesions in relation to histopathological diagnosis, clinical features and lesion volume: An ex vivo study. Int Endod J 2024; 57:1829-1847. [PMID: 39222032 DOI: 10.1111/iej.14138] [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: 12/19/2023] [Revised: 07/25/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024]
Abstract
AIM To evaluate M1 and M2 macrophage polarization in radicular cysts and periapical granulomas through an immunohistochemical analysis and the correlation between macrophage polarization and histopathological diagnosis, clinical characteristics and lesion volume using cone-beam computed tomography. METHODOLOGY Periapical biopsies diagnosed as radicular cysts (n = 52) and periapical granulomas (n = 51) were analysed by immunohistochemical method. Teeth with periapical lesion with no history of root canal treatment (primary lesion) and lesions persistent to root canal treatment (persistent lesions) were included. Pathological diagnosis, patients' age, gender and clinical characteristics were obtained from treatment records. A cone-beam computed tomographic periapical volume index (CBCTPAVI) score was assigned to each periapical lesion based on the volume of the lesion. Immuno-expressions of CD68 and CD163 were quantified. The CD68/CD163 ratio was adopted to represent M1 or M2 macrophage polarization. Mann-Whitney U test was used to determine the different CD68/CD163 ratio between groups of radicular cyst and periapical granuloma. Spearman's correlation test was performed to assess the correlation between the CD68/CD163 ratio and lesion volume and CBCTPAVI score. RESULTS Radicular cysts and periapical granulomas had CD68/CD163 median of 2.05 (IQR = 1.33) and 1.26 (IQR = 0.81), respectively. A significantly higher CD68/CD163 ratio was observed in radicular cysts (p < .001). In contrast, periapical granulomas had significantly lower median of CD68/CD163 ratio. Larger lesions had a higher median of CD68/CD163 ratio, while smaller lesions had lower median of CD68/CD163 ratio (p = .007, rs = .262). CD68/CD163 ratio was significantly correlated with the CBCTPAVI score in the overall periapical lesions (p = .002, rs = .306). The higher CD68/CD163 ratio in larger lesions indicated a higher degree of M1 polarization compared to smaller lesions. Regarding the pathological diagnosis, there was a significant positive correlation between CBCTPAVI score and CD68/CD163 ratio in periapical granulomas (p < .001, rs = .453), whereas the negative correlation was observed for radicular cysts (p < .001, rs = -.471). CONCLUSIONS Periapical granulomas are characterized by a M2-dominant macrophage polarization, while radicular cysts have significantly higher M1 macrophages. The higher degree of M1 macrophage polarization was significantly correlated with larger volume and higher CBCTPAVI scores of overall periapical lesion and periapical granuloma.
Collapse
Affiliation(s)
- Supanant Visarnta
- Section of Endodontics, Department of Operative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Chootima Ratisoontorn
- Section of Endodontics, Department of Operative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Anchana Panichuttra
- Section of Endodontics, Department of Operative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Phonkit Sinpitaksakul
- Department of Radiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Soranun Chantarangsu
- Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Kittipong Dhanuthai
- Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
15
|
Yang Y, Chen Q, Zhong W. The role of cytokines in the pathogenesis of SAPHO syndrome. Front Immunol 2024; 15:1427784. [PMID: 39286247 PMCID: PMC11402674 DOI: 10.3389/fimmu.2024.1427784] [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: 05/04/2024] [Accepted: 07/09/2024] [Indexed: 09/19/2024] Open
Abstract
SAPHO syndrome is a complex inflammatory disorder affecting the skin and bones, characterized by osteomyelitis, acne, and pustulosis. Cytokines play a pivotal role in the pathogenesis of SAPHO syndrome, especially in inflammatory responses and immune regulation. This article reviews the cytokines involved in the pathogenesis of SAPHO syndrome, such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IL-10, and transforming growth factor-β (TGF-β), and discusses their potential as intervention points for treatment. These findings elucidate the intricate immune regulatory network of SAPHO syndrome and provide a theoretical foundation for the development of new targeted therapeutic strategies.
Collapse
Affiliation(s)
- Yi Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, China
| | - Qianzhu Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, China
| | - Weiyang Zhong
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, China
| |
Collapse
|
16
|
Wänman M, Betnér S, Esberg A, Holm CK, Isehed C, Holmlund A, Palmqvist P, Lövgren A, Lindquist S, Hänström L, Lerner UH, Kindstedt E, Lundberg P. The PerioGene North Study Uncovers Serum Proteins Related to Periodontitis. J Dent Res 2024; 103:999-1007. [PMID: 39101637 PMCID: PMC11402264 DOI: 10.1177/00220345241263320] [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: 08/06/2024] Open
Abstract
The sequalae of periodontitis include irreversible degradation of tooth-supporting structures and circulatory spread of inflammatory mediators. However, the serum protein profile in periodontitis is not well described, which is partly attributable to the limited number of studies based on large and well-characterized periodontitis cohorts. This study aims to identify novel, circulating inflammation-related proteins associated with periodontitis within the PerioGene North case-control study, which includes 478 cases with severe periodontitis and 509 periodontally healthy controls. The serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and a panel of 45 inflammation-related proteins were analyzed using targeted proteomics. A distinguishable serum protein profile was evident in periodontitis cases. The protein pattern could separate cases from controls with a sensitivity of 0.81 and specificity of 0.81 (area under the curve = 0.87). Adjusted levels for hs-CRP and 24 of the 45 proteins were different between cases and controls. High levels of hs-CRP and matrix metalloproteinase-12, and low levels of epidermal growth factor (EGF) and oxidized low-density lipoprotein receptor 1 (OLR-1) were detected among the cases. Furthermore, the levels of C-C motif chemokine-19, granulocyte colony-stimulating factor-3 (CSF-3), interleukin-7 (IL-7), and hs-CRP were significantly higher in cases with a high degree of gingival inflammation. The levels of CSF-3 and tumor necrosis factor ligand superfamily member-10 TNFSF-10 were higher in cases with many deep periodontal pockets. The PerioGene North study includes detailed clinical periodontal data and uncovers a distinct serum protein profile in periodontitis. The findings of lower EGF and OLR-1 among the cases are highlighted, as this has not been presented before. The role of EGF and OLR-1 in periodontitis pathogenesis and as possible future biomarkers should be further explored.
Collapse
Affiliation(s)
- M Wänman
- Department of Odontology, Umeå University, Section for Molecular Periodontology, Umeå, Sweden
| | - S Betnér
- Northern Registry Centre, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - A Esberg
- Department of Odontology, Umeå University, Umeå, Sweden
| | - C K Holm
- Department of Odontology, Umeå University, Section for Molecular Periodontology, Umeå, Sweden
| | - C Isehed
- Gävle County Hospital, Department of Periodontology, Public Dental Health County Council of Gävleborg, Gävle, Sweden
- Center for Research and Development Uppsala University/Region Gävleborg, Gävle, Sweden
| | - A Holmlund
- Gävle County Hospital, Department of Periodontology, Public Dental Health County Council of Gävleborg, Gävle, Sweden
- Center for Research and Development Uppsala University/Region Gävleborg, Gävle, Sweden
| | - P Palmqvist
- Department of Periodontology, County Council of Västerbotten, Umeå, Sweden
| | - A Lövgren
- Department of Odontology, Umeå University, Section for Clinical Oral Physiology, Umeå, Sweden
| | - S Lindquist
- Department of Odontology, Umeå University, Section for Molecular Periodontology, Umeå, Sweden
- Lipum AB, Umeå, Sweden
| | - L Hänström
- Department of Odontology, Umeå University, Section for Molecular Periodontology, Umeå, Sweden
| | - U H Lerner
- Department of Odontology, Umeå University, Section for Molecular Periodontology, Umeå, Sweden
- Sahlgrenska Ostoporosis 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
| | - E Kindstedt
- Department of Odontology, Umeå University, Section for Molecular Periodontology, Umeå, Sweden
| | - P Lundberg
- Department of Odontology, Umeå University, Section for Molecular Periodontology, Umeå, Sweden
| |
Collapse
|
17
|
Zhang Z, Wu W, Li M, Du L, Li J, Yin X, Zhang W. Mesenchymal stem cell–derived extracellular vesicles: A novel nanoimmunoregulatory tool in musculoskeletal diseases. NANO TODAY 2024; 57:102343. [DOI: 10.1016/j.nantod.2024.102343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
18
|
Dyab A, Emnegard A, Wänman M, Sjöström F, Kindstedt E. Human gingival fibroblasts are a source of B cell-activating factor during periodontal inflammation. J Periodontol 2024; 95:673-681. [PMID: 38088123 DOI: 10.1002/jper.23-0543] [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: 09/17/2023] [Revised: 11/20/2023] [Accepted: 11/20/2023] [Indexed: 07/24/2024]
Abstract
BACKGROUND Host-modulating therapy is a possible treatment for individuals that respond poorly to conventional periodontal therapy. B cells, abundant in periodontitis lesions, require the cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) for survival and maturation. Although mRNA levels of BAFF and APRIL are increased in tissue from periodontitis lesions, it is unknown if periodontal resident cells express BAFF and/or APRIL during periodontal inflammation. In this study, we aim to analyze the expression of BAFF and APRIL in human gingival fibroblasts after stimulation with proinflammatory cytokines. Furthermore, we perform protein analysis in tissues and serum from periodontitis patients and healthy controls. METHODS Human gingival fibroblasts were cultured and stimulated with the proinflammatory cytokines' tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). The mRNA expression of BAFF and APRIL was analyzed by real-time quantitative polymerase chain reaction (qPCR), and the protein was detected in tissue sections using immune staining. Serum levels of BAFF were analyzed with enzyme-linked immunosorbent assay (ELISA). RESULTS In gingival fibroblasts, TNF-α upregulated BAFF mRNA, but APRIL was unaffected. IL-1β affected neither BAFF nor APRIL expression. BAFF protein was detected in the oral epithelium and in cells of the underlying connective tissue in periodontitis tissue, and BAFF protein was increased in the serum of periodontitis patients. CONCLUSION Periodontal resident cells express BAFF during periodontal inflammation and participate in providing a favorable milieu for the survival and action of B cells.
Collapse
Affiliation(s)
- Ahed Dyab
- Department of Odontology, Section for Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Ava Emnegard
- Department of Odontology, Section for Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Magnus Wänman
- Department of Odontology, Section for Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Filippa Sjöström
- Department of Odontology, Section for Molecular Periodontology, Umeå University, Umeå, Sweden
| | - Elin Kindstedt
- Department of Odontology, Section for Molecular Periodontology, Umeå University, Umeå, Sweden
- Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM), Umeå University, Umeå, Sweden
| |
Collapse
|
19
|
Idrus E, Harsono TS, Lestari W, Suniarti DF. Fusobacterium nucleatum mechanism of action in alveolar bone destruction: Scoping review. J Indian Soc Periodontol 2024; 28:290-296. [PMID: 39742069 PMCID: PMC11684578 DOI: 10.4103/jisp.jisp_269_23] [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: 05/27/2023] [Accepted: 08/30/2024] [Indexed: 01/03/2025] Open
Abstract
Fusobacterium nucleatum is implicated in periodontitis, a chronic inflammatory disease that destroys the periodontal tissue and alveolar bone due to host-microbe dysbiosis. This study focuses on understanding how F. nucleatum contributes to bone destruction in periodontitis. The literature search was conducted using PubMed and Scopus databases based on Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines by entering preselected keyword combinations of inclusion and exclusion criteria. Qualifying literature was evaluated based on four inclusion criteria: research articles, published in English, within the last ten years, and available in full text. The literature search yielded five articles exploring the mechanism of bone resorption by F. nucleatum. It was found that the bacteria increases the production of inflammatory mediators, such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha, C-C motif chemokine ligand (CCL) 2, CCL20, and C-X-C motif chemokine ligand 1, which leads to the destruction of alveolar bone. During infection, biomechanical stress also raises levels of prostaglandin E2 and cyclooxygenase-2. The elevated levels of inflammatory mediators and enzymes generate an imbalance in the receptor activator of nuclear factor kappa-B ligand to osteoprotegerin ratio, hindering osteogenic differentiation and heightening bone destruction. In conclusion, F. nucleatum infection promotes alveolar bone destruction by inducing inflammatory responses and inhibiting osteogenic differentiation stimulated by biomechanical loading. More research is essential to explore the connection between F. nucleatum virulence and its alveolar bone degradation mechanisms.
Collapse
Affiliation(s)
- Erik Idrus
- Department of Oral Biology, Faculty of Dentistry, Universitas Indonesia, Jakarta Pusat, Indonesia
| | - Tashya Shania Harsono
- Department of Oral Biology, Dentistry Study Program, Faculty of Dentistry, Universitas Indonesia, Jakarta Pusat, Indonesia
| | - Widya Lestari
- Department of Fundamental Dental and Medical Sciences, Kulliyyah of Dentistry, International Islamic University Malaysia, Kuantan, Pahang, Malaysia
| | - Dewi Fatma Suniarti
- Department of Oral Biology, Faculty of Dentistry, Universitas Indonesia, Jakarta Pusat, Indonesia
| |
Collapse
|
20
|
Mou K, Chan SMH, Vlahos R. Musculoskeletal crosstalk in chronic obstructive pulmonary disease and comorbidities: Emerging roles and therapeutic potentials. Pharmacol Ther 2024; 257:108635. [PMID: 38508342 DOI: 10.1016/j.pharmthera.2024.108635] [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: 11/06/2023] [Revised: 02/13/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a multifaceted respiratory disorder characterized by progressive airflow limitation and systemic implications. It has become increasingly apparent that COPD exerts its influence far beyond the respiratory system, extending its impact to various organ systems. Among these, the musculoskeletal system emerges as a central player in both the pathogenesis and management of COPD and its associated comorbidities. Muscle dysfunction and osteoporosis are prevalent musculoskeletal disorders in COPD patients, leading to a substantial decline in exercise capacity and overall health. These manifestations are influenced by systemic inflammation, oxidative stress, and hormonal imbalances, all hallmarks of COPD. Recent research has uncovered an intricate interplay between COPD and musculoskeletal comorbidities, suggesting that muscle and bone tissues may cross-communicate through the release of signalling molecules, known as "myokines" and "osteokines". We explored this dynamic relationship, with a particular focus on the role of the immune system in mediating the cross-communication between muscle and bone in COPD. Moreover, we delved into existing and emerging therapeutic strategies for managing musculoskeletal disorders in COPD. It underscores the development of personalized treatment approaches that target both the respiratory and musculoskeletal aspects of COPD, offering the promise of improved well-being and quality of life for individuals grappling with this complex condition. This comprehensive review underscores the significance of recognizing the profound impact of COPD on the musculoskeletal system and its comorbidities. By unravelling the intricate connections between these systems and exploring innovative treatment avenues, we can aspire to enhance the overall care and outcomes for COPD patients, ultimately offering hope for improved health and well-being.
Collapse
Affiliation(s)
- Kevin Mou
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Stanley M H Chan
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Ross Vlahos
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
| |
Collapse
|
21
|
Kainat R, Ahmed I, Alolaywi AM, Waheed H, Sultan ZK, Moin SF. Assessment of Salivary MMP-8 and IL-1β for the Diagnosis of Periodontal Diseases in Pakistani Population. Eur J Dent 2024; 18:672-679. [PMID: 38086426 PMCID: PMC11132764 DOI: 10.1055/s-0043-1772779] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2024] Open
Abstract
OBJECTIVE Clinical methods use the subjective diagnosis of periodontal diseases by visual observation that could result in differences and variability of diagnosis. The addition of specific markers could aid in the accurate diagnosis of the local population. The objective of the study was to target two of the major proteins for possible significance in such an approach. MATERIALS AND METHODS Unstimulated saliva samples were collected from 60 participants aged between 18 and 70 years. Three groups each with twenty participants were recruited into periodontitis, gingivitis, and healthy control. STATISTICAL ANALYSIS The samples were analyzed using human enzyme-linked immunosorbent assay kits for matrix metalloproteinase-8 (MMP-8) and interleukin-1β (IL-1β). RESULTS SPSS version 20 was used to analyze the result. Posthoc analysis by Tukey's test revealed that MMP-8 levels were higher in gingivitis and periodontitis groups as compared with healthy controls. The test also revealed that IL-1β levels were higher in the periodontitis group compared with the healthy control and gingivitis group. Additionally, one-way analysis of variance analysis showed a significant effect on probing depth in gingivitis and periodontitis patients. The mean age of periodontitis group was significantly higher than other groups. CONCLUSION Salivary biomarkers may provide useful diagnostic information and could be utilized as tests for periodontal disease screening, prognosis, and prediction.
Collapse
Affiliation(s)
- Rida Kainat
- Department of Biochemistry, Baqai Medical University, Karachi, Pakistan
| | - Iftikhar Ahmed
- Department of Biochemistry, Baqai Medical University, Karachi, Pakistan
| | | | - Humera Waheed
- Dow College of Biotechnology, Dow University of Health Sciences, Karachi, Pakistan
| | - Zohaib Khurshid Sultan
- Department of Prosthodontics and Dental Implantology, College of Dentistry, King Faisal University, Al-Ahsa, Saudia Arabia
- Department of Anatomy, Faculty of Dentistry, Center of Excellence for Regenerative Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Syed Faraz Moin
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, Pakistan
| |
Collapse
|
22
|
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.
Collapse
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
| |
Collapse
|
23
|
Chen Y, Yang C, Deng Z, Xiang T, Ni Q, Xu J, Sun D, Luo F. Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism. J Pineal Res 2024; 76:e12954. [PMID: 38618998 DOI: 10.1111/jpi.12954] [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: 03/03/2024] [Revised: 03/22/2024] [Accepted: 03/29/2024] [Indexed: 04/16/2024]
Abstract
Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.
Collapse
Affiliation(s)
- Yueqi Chen
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
- Department of Orthopedics, Chinese PLA 76th Army Corps Hospital, Beijing, Xining, China
| | - Chuan Yang
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
- Department of Biomedical Materials Science, Third Military Medical University, Chongqing, China
| | - Zihan Deng
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Tingwen Xiang
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qingrong Ni
- Department of Dermatology, Air Force Medical Center, Fourth Military Medical University, Beijing, China
| | - Jianzhong Xu
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Dong Sun
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Fei Luo
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| |
Collapse
|
24
|
Li C, Liu Y, Deng M, Li J, Li S, Li X, Zuo Y, Shen C, Wang Y. Comparison of the therapeutic effects of mesenchymal stem cells derived from human dental pulp (DP), adipose tissue (AD), placental amniotic membrane (PM), and umbilical cord (UC) on postmenopausal osteoporosis. Front Pharmacol 2024; 15:1349199. [PMID: 38601464 PMCID: PMC11004311 DOI: 10.3389/fphar.2024.1349199] [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: 12/04/2023] [Accepted: 03/18/2024] [Indexed: 04/12/2024] Open
Abstract
Background: Osteoporosis is a systemic bone disease characterized by bone loss and microstructural degeneration. Recent preclinical and clinical trials have further demonstrated that the transplantation of mesenchymal stem cells (MSCs) derived from human adipose tissue (AD), dental pulp (DP), placental amniotic membrane (AM), and umbilical cord (UC) tissues can serve as an effective form of cell therapy for osteoporosis. However, MSC-mediated osteoimmunology and the ability of these cells to regulate osteoclast-osteoblast differentiation varies markedly among different types of MSCs. Methods: In this study, we investigated whether transplanted allogeneic MSCs derived from AD, DP, AM, and UC tissues were able to prevent osteoporosis in an ovariectomy (OVX)-induced mouse model of osteoporosis. The homing and immunomodulatory ability of these cells as well as their effects on osteoblastogenesis and the maintenance of bone formation were compared for four types of MSCs to determine the ideal source of MSCs for the cell therapy-based treatment of OVX-induced osteoporosis. The bone formation and bone resorption ability of these four types of MSCs were analyzed using micro-computed tomography analyses and histological staining. In addition, cytokine array-based analyses of serological markers and bioluminescence imaging assays were employed to evaluate cell survival and homing efficiency. Immune regulation was determined by flow cytometer assay to reflect the mechanisms of osteoporosis treatment. Conclusion: These analyses demonstrated that MSCs isolated from different tissues have the capacity to treat osteoporosis when transplanted in vivo. Importantly, DP-MSCs infusion was able to maintain trabecular bone mass more efficiently with corresponding improvements in trabecular bone volume, mineral density, number, and separation. Among the tested MSC types, DP-MSCs were also found to exhibit greater immunoregulatory capabilities, regulating the Th17/Treg and M1/M2 ratios. These data thus suggest that DP-MSCs may represent an effective tool for the treatment of osteoporosis.
Collapse
Affiliation(s)
- Chuncai Li
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Hospital of Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yincong Liu
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingxing Deng
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jun Li
- Sichuan Provincial Cells Tissue Bank, Chengdu, China
| | - Shengqi Li
- Sichuan Provincial Cells Tissue Bank, Chengdu, China
| | - Xiaoyu Li
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuling Zuo
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Hospital of Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chongyang Shen
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yichao Wang
- Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
25
|
Soliman E, Ohrndorf S, Zehairy M, Matrawy K, Alhadidy A, Abdelati A. Osteopontin, osteoprotegerin and musculoskeletal ultrasound findings in first-degree relatives of rheumatoid arthritis: potential markers of preclinical disease. BMC Musculoskelet Disord 2024; 25:195. [PMID: 38443806 PMCID: PMC10913638 DOI: 10.1186/s12891-024-07291-7] [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: 04/28/2023] [Accepted: 02/19/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients are known to have increased risk of developing the disease. The detection of altered bone metabolism in FDRs could be a predictor of the disease. Musculoskeletal ultrasound (MSUS) is known for its ability to detect subclinical joint inflammation in RA, but changes in FDRs are not yet described. We aimed to study serum Osteopontin (OPN) and Osteoprotegerin (OPG) levels in FDRs of RA patients as markers of altered bone metabolism in relation to clinical, laboratory and musculoskeletal ultrasound (MSUS) findings. METHODS Fifty-five individuals were included, 20 had definite RA, 25 were first degree relatives (FDRs) of RA patients, and 10 healthy controls. Clinical evaluation for joint swelling/tenderness was performed for all. ESR, CRP, rheumatoid factor (RF), anti-citrullinated antibodies (ACPA), OPN, OPG, and Musculoskeletal ultrasound (MSUS) by the US7 score were evaluated. RESULTS Osteoprotegerin was significantly higher in RA (143.89 pg/ml ± 365.47) than in FDRs (22.23 pg/ml ± 65.73; p = 0.009) and controls (6.20 pg/ml ± 12.43; p = 0.003). OPN was also higher in RA (3.66 ng/ml ± 4.20) than in FDRs (1.97 ng/ml ± 1.04) and controls (2.81 ng/ml ± 1.31), though not significant (p = 0.102). Eight of 25 FDRs (32%) had arthralgia without clinical arthritis and 17/25 (68%) were asymptomatic. FDRs with arthralgia had significantly higher ESR and CRP levels than asymptomatic FDRs (9.82 mm/h ± 4.13; p = 0.003, and 3.93 mg/l ± 3.58; p = 0.003). Osteoprotegerin was higher in FDRs than in controls, and also in those with arthralgia (51.55 pg/ml ± 114.68) than in those without (8.44 pg/ml ± 9.67), though without significant difference. OPN was higher in FDRs with arthralgia (2.09 ng/ml ± 1.19) than in asymptomatic (1.70 ng/ml ± 0.55), also without significant difference. Pathologic findings by US7 were detected in 10/25 (40%) FDRs, of which three (12%) had arthralgia and seven (28%) were asymptomatic. CONCLUSIONS The raised OPG and lower OPN in FDRs than in controls reflect an altered bone metabolism which could precede clinical disease phase. OPN and OPG could serve as markers of altered preclinical bone metabolism in FDRs of RA. US7 score might be a useful screening tool to identify 'at-risk' individuals.
Collapse
Affiliation(s)
- Eiman Soliman
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Sarah Ohrndorf
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, 10117, Berlin, Germany
| | - Magdy Zehairy
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Khaled Matrawy
- Radiodiagnosis Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Abeer Alhadidy
- Clinical Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Abeer Abdelati
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| |
Collapse
|
26
|
Insua A, Galindo-Moreno P, Miron RJ, Wang HL, Monje A. Emerging factors affecting peri-implant bone metabolism. Periodontol 2000 2024; 94:27-78. [PMID: 37904311 DOI: 10.1111/prd.12532] [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: 05/03/2023] [Revised: 08/05/2023] [Accepted: 09/10/2023] [Indexed: 11/01/2023]
Abstract
Implant dentistry has evolved to the point that standard implant osseointegration is predictable. This is attributed in part to the advancements in material sciences that have led toward improvements in implant surface technology and characteristics. Nonetheless, there remain several cases where implant therapy fails (specifically at early time points), most commonly attributed to factors affecting bone metabolism. Among these patients, smokers are known to have impaired bone metabolism and thus be subject to higher risks of early implant failure and/or late complications related to the stability of the peri-implant bone and mucosal tissues. Notably, however, emerging data have unveiled other critical factors affecting osseointegration, namely, those related to the metabolism of bone tissues. The aim of this review is to shed light on the effects of implant-related factors, like implant surface or titanium particle release; surgical-related factors, like osseodensification or implanted biomaterials; various drugs, like selective serotonin reuptake inhibitors, proton pump inhibitors, anti-hypertensives, nonsteroidal anti-inflammatory medication, and statins, and host-related factors, like smoking, diet, and metabolic syndrome on bone metabolism, and aseptic peri-implant bone loss. Despite the infectious nature of peri-implant biological complications, these factors must be surveyed for the effective prevention and management of peri-implantitis.
Collapse
Affiliation(s)
- Angel Insua
- Department of Periodontology and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Pablo Galindo-Moreno
- Department of Periodontology and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Oral Surgery and Implant Dentistry, University of Granada, Granada, Spain
| | - Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Hom-Lay Wang
- Department of Periodontology and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alberto Monje
- Department of Periodontology and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Periodontology, University of Bern, Bern, Switzerland
- Department of Periodontology, Universitat Internacional de Catalunya, Barcelona, Spain
| |
Collapse
|
27
|
Lima Teixeira JF, Henning P, Cintra Magalhães FA, Coletto-Nunes G, Floriano-Marcelino T, Westerlund A, Movérare-Skrtic S, Oliveira GJPL, Lerner UH, Souza PPC. Osteoprotective effect by interleukin-4 (IL-4) on lipoprotein-induced periodontitis. Cytokine 2023; 172:156399. [PMID: 37898012 DOI: 10.1016/j.cyto.2023.156399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 09/15/2023] [Accepted: 10/05/2023] [Indexed: 10/30/2023]
Abstract
Lipoproteins are immunostimulatory bacterial components suggested to participate in inflammation-induced bone loss in periodontal disease through stimulation of osteoclast differentiation. Toll-like receptor 2 activation by Pam2CSK4 (PAM2), known to mimic bacterial lipoproteins, was previously shown to enhance periodontal bone resorption in mice. The anti-inflammatory cytokine interleukin-4 (IL-4) is a known inhibitor of RANKL-induced bone resorption in vitro. Here, we have investigated whether IL-4 could decrease PAM2-induced periodontal bone loss and osteoclastogenesis in vivo. In a model of periodontitis induced by gingival injections of PAM2 in mice, concomitant injections of IL-4 reduced bone loss. Histologically, IL-4 reduced the recruitment of inflammatory cells and the formation of TRAP+ osteoclasts stimulated by PAM2. Mouse bone marrow macrophages (BMMs) and neonatal calvarial osteoblasts were used to assess the effect of IL-4 on PAM2-induced osteoclastogenesis in vitro. In RANKL-primed BMMs stimulated by PAM2 Nfatc1, Ctsk, and Acp5 gene expression was up-regulated and resulted in robust formation of TRAP+ multinucleated osteoclasts, effects which were impaired by IL-4. These effects were mediated by impairment in PAM2-induced c-fos expression. In primary calvarial osteoblast cultures, IL-4 decreased PAM2-induced Tnfsf11 (encoding RANKL) mRNA and enhanced Tnfrsf11b (encoding OPG) expression. Our data demonstrate that the osteoprotective effect by IL-4 on lipoprotein-induced periodontal disease occurs through the inhibition of osteoclastogenesis by three mechanisms, one by acting directly on osteoclast progenitors, another by acting indirectly through decreasing the expression of osteoclast-regulating cytokines in osteoblasts and a third by decreasing inflammation.
Collapse
Affiliation(s)
- Jorge F Lima Teixeira
- Department of Pathology and Physiology, School of Dentistry at Araraquara, Univ. Est. Paulista - UNESP, Araraquara, Brazil
| | - Petra Henning
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | | | - Glaucia Coletto-Nunes
- Department of Pathology and Physiology, School of Dentistry at Araraquara, Univ. Est. Paulista - UNESP, Araraquara, Brazil
| | - Thais Floriano-Marcelino
- Department of Pathology and Physiology, School of Dentistry at Araraquara, Univ. Est. Paulista - UNESP, Araraquara, Brazil
| | - Anna Westerlund
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Sofia Movérare-Skrtic
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Guilherme J P L Oliveira
- Department of Periodontology and Implantodontology, Dental School, Federal University of Uberlândia - UFU, Uberlândia, Brazil
| | - Ulf H Lerner
- Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Pedro Paulo C Souza
- Innovation in Biomaterials Laboratory (iBioM), Faculty of Dentistry, Federal University of Goiás - UFG, Goiânia, Brazil.
| |
Collapse
|
28
|
Gonzalez OA, Kirakodu S, Nguyen L, Ebersole JL. Macrophage-related gingival transcriptomic patterns and microbiome alterations in experimental periodontitis in nonhuman primates. J Periodontal Res 2023; 58:1148-1170. [PMID: 37610132 DOI: 10.1111/jre.13156] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 04/05/2023] [Accepted: 06/08/2023] [Indexed: 08/24/2023]
Abstract
OBJECTIVE This study examined the microbiome features specifically related to host macrophage polarization in health, initiation and progression of periodontitis, and in resolution samples using a nonhuman primate model of ligature-induced periodontitis. BACKGROUND The oral microbiome is a complex of bacterial phyla, genera, and species acquired early in life into the individual autochthonous oral ecology. The microbiome changes overtime in response to both intrinsic and extrinsic stressors, and transitions to a dysbiotic ecology at sites of periodontal lesions. METHODS Comparisons were made between the microbial and host features in young (≤7 years) and adult (≥12 years) cohorts of animals. Footprints of macrophage-related genes in the gingival tissues were evaluated using expression profiles including M0, M1, and M2 related genes. RESULTS Within the gingival tissues, similar macrophage-related gene patterns were observed with significant increases with disease initiation and continued elevation throughout disease in both age groups. Approximately, 70% of the taxa were similar in relative abundance between the two groups; however, the adults showed a large number of OTUs that were significantly altered compared with the younger animals. Developing a correlation map identified three major node levels of interactions that comprised approximately ⅓ of the Operational Taxonomic Units (OTUs) that dominated the microbiomes across the samples. Also noted was a much greater frequency of significant correlations of individual OTUs with the macrophage phenotype markers, compared with disease and resolution samples in both age groups, with a greater frequency in the younger group. Moreover, these correlations were assigned to differentially expressed genes representing M0, M1, and M2-related phenotypes. A cluster analyses across the macrophage-related transcriptome and the OTUs demonstrated multiple somewhat distinct bacterial consortia, incorporating both commensal and putative pathogens, linked to the gene responses that differed in health, disease, and resolution samples. Finally, there were minimal alterations in the OTUs in individual clusters with specific macrophage-related responses in the younger group, while in the adult samples substantial variations were noted with genes from all macrophage phenotypes. CONCLUSIONS The results confirmed important features that could reflect macrophage polarization in periodontal lesions, and provided some initial data supporting specific members of the oral microbiome feature prominently related to specific gene response patterns consistent with macrophages in the gingival tissues.
Collapse
Affiliation(s)
- O A Gonzalez
- Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
- Division of Periodontology, College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
| | - S Kirakodu
- Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
| | - L Nguyen
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada Las Vegas, Las Vegas, Nevada, USA
| | - J L Ebersole
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada Las Vegas, Las Vegas, Nevada, USA
| |
Collapse
|
29
|
Teterina A, Niratisairak S, Morseth B, Bolstad N. General and local predictors of mandibular cortical bone morphology in adult females and males: the seventh survey of the Tromsø Study. Clin Oral Investig 2023; 27:6577-6587. [PMID: 37735212 PMCID: PMC10630240 DOI: 10.1007/s00784-023-05263-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/11/2023] [Indexed: 09/23/2023]
Abstract
OBJECTIVES To analyze factors predicting mandibular cortical width (MCW) and mandibular cortical index (MCI) in adult females and males. MATERIAL AND METHODS Data on 427 females and 335 males aged 40-84 from The Tromsø study: Tromsø7 were used. T-score, age, menopausal status (for females), remaining teeth, and periodontal status were analyzed in linear and logistic regression analyses as predictors of MCW and MCI, respectively. RESULTS T-score, age, and the number of remaining teeth significantly predicted MCW in females but not males. Standardized β coefficients were 0.286, -0.231, and 0.131, respectively. The linear regression model explained 24% of MCW variation in females. MCI in females was significantly predicted by T-score, age, and remaining teeth with the Wald values of 9.65, 6.17, and 5.83, respectively. The logistic regression model explained 16.3-23% of the variation in MCI in females. In males, T-score was the only significant predictor of the eroded cortex, and the logistic model explained only 4.3-5.8% of the variation in MCI. CONCLUSIONS The T-score demonstrated a stronger relationship with MCW and MCI than other factors in females, which supports the usefulness of those indices for osteoporosis screening. Conversely, the T-score exhibited no association with MCW and remained the only significant predictor of MCI in males, yet to a lesser extent than in females. CLINICAL RELEVANCE Understanding factors affecting mandibular cortical morphology is essential for further investigations of MCW and MCI usefulness for osteoporosis screening in females and males.
Collapse
Affiliation(s)
- Anna Teterina
- Department of Clinical Dentistry, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.
| | - Sanyalak Niratisairak
- Department of Orthopaedics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Biomechanics Laboratory, Rikshospitalet, Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway
| | - Bente Morseth
- School of Sport Sciences, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| | - Napat Bolstad
- Department of Clinical Dentistry, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| |
Collapse
|
30
|
Fu E, Kuo CY, Hsia YJ, Huang YM, Tseng HH, Fu MW, Shih KC. Role of ferroptosis in periodontitis: An animal study in rats. J Periodontal Res 2023; 58:1031-1040. [PMID: 37477155 DOI: 10.1111/jre.13165] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 06/13/2023] [Accepted: 07/08/2023] [Indexed: 07/22/2023]
Abstract
OBJECTIVE This study aimed to investigate (1) the temporal pattern of ferroptosis, an iron-dependent cell death, in ligation-induced rat periodontitis and (2) the effect of ferrostatin-1, a ferroptosis inhibitor, on the model. BACKGROUND Ferroptosis may contribute to various diseases. However, the role of ferroptosis in periodontitis is still fully understood. METHODS In the first experiment, 25 rats with ligation-induced periodontitis were sacrificed on days 0, 1, 2, 7, and 10. Gingivae were obtained to determine tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and ferroptotic biomarkers, including solute carrier family 3 member 2 (SLC3A2) and solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (Gpx4), via immunoblotting. Using microcomputed tomography (μCT) and histology, the periodontal soft and hard tissue lesions, including dental alveolar bone crest level, bony characteristics of the surrounding alveolus, periodontal tissue inflammation, and periodontal tissue losses, were evaluated. In study two, 16 rats with induced periodontitis were grouped according to ferrostatin-1 treatment. The rats were intraperitoneally injected with solvent or ferrostatin-1 (1.5 mg/kg/day) 1 day before ligation and sacrificed on days 7 and 10. Gingival protein changes and periodontal tissue damage were also examined. RESULTS In study one, SLC3A2/SLC7A11 and Gpx4 decreased since day 1; however, TNF-α/IL-1β increased on days 7 and 10. Moreover, the μCT/histology revealed resorptive bony characteristics, inflamed gingival tissue, and periodontal attachment loss. In study two, ferrostatin-1-injected rats exhibited significantly increased SLC3A2/SLC7A11 and Gpx4 but decreased TNF-α/IL-1β than vehicle rats. They also revealed lessened bone resorption, tissue inflammation, and attachment loss. CONCLUSION This study highlights the role of ferroptosis, via the system Xc/Gpx4 pathway, in experimental periodontitis and may serve as a regulatory strategy.
Collapse
Affiliation(s)
- Earl Fu
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Yi-Jan Hsia
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Yiao-Mien Huang
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Hui-Hwa Tseng
- Department of Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Min-Wen Fu
- Department of Endodontics, College of Dentistry, New York University, New York City, New York, USA
| | - Kuang-Chung Shih
- School of Medicine, National Defense Medical Center, Taipei, Taiwan
- Division of Endocrinology & Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Division of Endocrinology & Metabolism, Cheng Hsin General Hospital, Taipei, Taiwan
| |
Collapse
|
31
|
Kwon Y, Yang J, Park OJ, Park C, Kim J, Lee D, Yun CH, Han SH. Lipoteichoic acid inhibits osteoclast differentiation and bone resorption via interruption of gelsolin-actin dissociation. J Cell Physiol 2023; 238:2425-2439. [PMID: 37642258 DOI: 10.1002/jcp.31099] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 06/30/2023] [Accepted: 07/25/2023] [Indexed: 08/31/2023]
Abstract
Bone resorption can be caused by excessive differentiation and/or activation of bone-resorbing osteoclasts. While microbe-associated molecular patterns can influence the differentiation and activation of bone cells, little is known about the role of lipoteichoic acid (LTA), a major cell wall component of Gram-positive bacteria, in the regulation of bone metabolism. In this study, we investigated the effect of LTA on bone metabolism using wild-type Staphylococcus aureus and the LTA-deficient mutant strain. LTA-deficient S. aureus induced higher bone loss and osteoclast differentiation than wild-type S. aureus. LTA isolated from S. aureus (SaLTA) inhibited osteoclast differentiation from committed osteoclast precursors in the presence of various osteoclastogenic factors by downregulating the expression of NFATc1. Remarkably, SaLTA attenuated the osteoclast differentiation from committed osteoclast precursors of TLR2-/- or MyD88-/- mice and from the committed osteoclast precursors transfected with paired immunoglobulin-like receptor B-targeting siRNA. SaLTA directly interacted with gelsolin, interrupting the gelsolin-actin dissociation which is a critical process for osteoclastogenesis. Moreover, SaLTA suppressed the mRNA expression of dendritic cell-specific transmembrane protein, ATPase H+ transporting V0 subunit D2, and Integrin, which encode proteins involved in cell-cell fusion of osteoclasts. Notably, LTAs purified from probiotics, including Bacillus subtilis, Enterococcus faecalis, and Lactobacillus species, also suppressed Pam2CSK4- or RANKL-induced osteoclast differentiation. Taken together, these results suggest that LTAs have anti-resorptive activity through the inhibition of osteoclastogenesis by interfering with the gelsolin-actin dissociation and may be used as effective therapeutic agents for the prevention or treatment of inflammatory bone diseases.
Collapse
Affiliation(s)
- Yeongkag Kwon
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
- Radiation Fusion Technology Research Division, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea
| | - Jihyun Yang
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
- Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Ok-Jin Park
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Chaeyeon Park
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Jiseon Kim
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Dongwook Lee
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Cheol-Heui Yun
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea
| | - Seung Hyun Han
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| |
Collapse
|
32
|
Ebersole JL, Kirakodu SS, Nguyen LM, Gonzalez OA. Sex effects on gingival transcriptomic patterns during initiation, progression, and resolution of periodontitis. J Periodontol 2023; 94:1018-1031. [PMID: 36853808 DOI: 10.1002/jper.23-0042] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 01/12/2023] [Accepted: 02/22/2023] [Indexed: 03/01/2023]
Abstract
BACKGROUND The prevalence and severity of periodontitis demonstrates altered population distribution with age, sex, and race and ethnicity. While males exhibit greater frequency of disease, particularly with aging, the underlying basis for this observation remains obscure. OBJECTIVE This study used a nonhuman primate (Macaca mulatta) model of experimental ligature-induced periodontitis in adult animals to evaluate gingival transcriptomic differences stratified based upon sex of the animal. METHODS The 18 animals represented humans ages 40-80 years, with gingival tissue samples obtained at baseline, 0.5 months (initiation), 1 and 3 months (progression), and at 5 months that were 60 days after ligature removal for clinical disease resolution. Microarray analysis was used to quantify gene expression profiles in the gingival tissues. RESULTS The results demonstrated clear gene expression differences in healthy (baseline) tissues between the sexes, with elevations in females associated with immune responses and elevation in males related to tissue structural genes. With disease initiation, fewer genes differed between the sexes, while these differences were significantly increased in progressing disease and resolution, particularly in male animals. Overexpressed biological processes showed tissue structural/functional genes at initiation, with host response pathways altered during disease progression. Resolution samples generally demonstrated biological processes of cellular metabolism that differed from baseline healthy samples. CONCLUSION The transcriptomic findings support sex as a biological variable in periodontitis using a nonhuman primate model of experimental periodontitis.
Collapse
Affiliation(s)
- Jeffrey L Ebersole
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada Las Vegas, Las Vegas, Nevada, USA
| | - Sreenatha S Kirakodu
- Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
| | - Linh M Nguyen
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada Las Vegas, Las Vegas, Nevada, USA
| | - Octavio A Gonzalez
- Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
- Division of Periodontology, College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
| |
Collapse
|
33
|
Liu R, Gao L, Guo L, Xu W, Wu S, Tian D. The impact of fasting plasma glucose variability on osteoporotic fractures. Front Endocrinol (Lausanne) 2023; 14:1187682. [PMID: 37455924 PMCID: PMC10348823 DOI: 10.3389/fendo.2023.1187682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023] Open
Abstract
Purpose To investigate the impact of FPG variability on osteoporotic fractures in the entire community population. Methods All participants were from the Kailuan Study. Participants completed three consecutive surveys from 2006-2007, 2008-2009, and 2010-2011. We excluded individuals with an osteoporotic fracture in or prior to the index year and those without complete FPG records at the first 3 examinations. All participants were followed from the date of the 3rd examination to the first occurrence of an endpoint event or December 31, 2021. According to the SD of FPG levels, the included subjects were divided into three groups. A Cox proportional hazards model was performed to further analyze the effect of different FPG-SD groups on the risk of osteoporotic fractures. Results Ultimately, the study population included 57295 participants. During a median follow-up time of 11.00 years, we documented 772 new osteoporotic fracture cases. When evaluating the FPG-SD level as a categorical variable, the HRs for osteoporotic fractures were 1.07 (95% CI: 0.89-1.29) for T2 and 1.32 (95% CI: 1.10-1.60) for T3 when compared with T1. We found that increased FPG variability was associated with a greater risk of osteoporotic fractures in people with diabetes than in those without diabetes (47% vs. 32%). Conclusion Increased FPG variability was an independent predictor of incident osteoporotic fracture, especially in individuals older than 50 years old, nonobese individuals, diabetes patients, and individuals with positive FPG-SD variability.
Collapse
Affiliation(s)
- Ri Liu
- Department of Hand Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Joint Surgery, Second Hospital of Tangshan, Tangshan, Hebei, China
| | - Lishu Gao
- Department of Endocrinology, Tangshan People’s Hospital, Tangshan, Hebei, China
| | - Lu Guo
- Graduate School, North China University of Science and Technology, Tangshan, Hebei, China
| | - Wenqi Xu
- Graduate School, North China University of Science and Technology, Tangshan, Hebei, China
| | - Shouling Wu
- Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei, China
| | - Dehu Tian
- Department of Hand Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| |
Collapse
|
34
|
Seebach E, Kraus FV, Elschner T, Kubatzky KF. Staphylococci planktonic and biofilm environments differentially affect osteoclast formation. Inflamm Res 2023:10.1007/s00011-023-01745-9. [PMID: 37329360 DOI: 10.1007/s00011-023-01745-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/21/2023] [Accepted: 05/15/2023] [Indexed: 06/19/2023] Open
Abstract
INTRODUCTION The pathophysiology of chronic implant-related bone infections is characterized by an increase in osteoclast numbers and enhanced bone resorption. Biofilms are a major reason for chronicity of such infections as the biofilm matrix protects bacteria against antibiotics and impairs the function of immune cells. Macrophages are osteoclast precursor cells and therefore linked to inflammation and bone destruction. OBJECTIVE AND METHOD Investigations on the impact of biofilms on the ability of macrophages to form osteoclasts are yet missing and we, therefore, analyzed the effect of Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE) planktonic and biofilm environments on osteoclastogenesis using RAW 264.7 cells and conditioned media (CM). RESULTS Priming with the osteoclastogenic cytokine RANKL before CM addition enabled the cells to differentiate into osteoclasts. This effect was highest in SE planktonic or SA biofilm CM. Simultaneous stimulation with CM and RANKL, however, suppressed osteoclast formation and resulted in formation of inflammation-associated multinucleated giant cells (MGCs) which was most pronounced in SE planktonic CM. CONCLUSION Our data indicate that the biofilm environment and its high lactate levels are not actively promoting osteoclastogenesis. Hence, the inflammatory immune response against planktonic bacterial factors through Toll-like receptors seems to be the central cause for the pathological osteoclast formation. Therefore, immune stimulation or approaches that aim at biofilm disruption need to consider that this might result in enhanced inflammation-mediated bone destruction.
Collapse
Affiliation(s)
- Elisabeth Seebach
- Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.
| | - Franziska V Kraus
- Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany
- Department of Internal Medicine 5 - Hematology Oncology Rheumatology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Tabea Elschner
- Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany
- Institute for Cardiovascular Sciences and Institute of Neurovascular Cell Biology (INVZ), University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Katharina F Kubatzky
- Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.
| |
Collapse
|
35
|
Chen S, Tao L, Zhu F, Wang Z, Zhuang Q, Li Y, Yang Y, Feng C, Shi H, Shi J, Zhu L, Xiao L, Geng D, Wang Z. BushenHuoxue decoction suppresses M1 macrophage polarization and prevents LPS induced inflammatory bone loss by activating AMPK pathway. Heliyon 2023; 9:e15583. [PMID: 37153438 PMCID: PMC10160506 DOI: 10.1016/j.heliyon.2023.e15583] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 04/10/2023] [Accepted: 04/14/2023] [Indexed: 05/09/2023] Open
Abstract
Abnormal bone metabolism and subsequence osteoporotic fractures are common complications of chronic inflammatory diseases. No effective treatment for these bone-related complications is available at present. The chronic inflammatory state in these diseases has been considered as a key factor of bone loss. Therefore, the combination of inflammation inhibition and bone loss suppression may be an important strategy for reducing bone damage associated with inflammatory diseases. Bushen Huoxue Decoction (BSHXD) is a traditional Chinese herbal compound that has demonstrated the ability to improve bone quality and increase bone density. However, the efficacy of BSHXD on inflammatory bone loss and its underlying mechanisms remain unclear. This study aimed to investigate whether BSHXD inhibits inflammatory bone loss in mice and its potential molecular mechanisms. In the present study, the effect of BSHXD on lipopolysaccharide (LPS)-induced M1 polarization of RAW264.7 macrophage and on local inflammatory bone loss model of mouse skull was determined. The results showed that after treating RAW264.7 cells with LPS for 24 h, the expression levels of IL-1β (39.42 ± 3.076 ng/L, p < 0.05), IL-6 (49.24 ± 1.766 mg/L, p < 0.05) and TNF-α (286.3 ± 27.12 ng/L, p < 0.05) were significantly increased. The addition of BSHXD decreased the expression levels of IL-1β, IL-6, and TNF-α to 31.55 ± 1.296 ng/L, 37.94 ± 0.8869 mg/L, and 196.4 ± 25.25 ng/L, respectively (p < 0.05). The results of immunofluorescence staining, Western blotting (WB) and flow cytometry indicated that the proportion of M1 macrophages in RAW264.7 cells treated with BSHXD for 24 h was significantly lower than that in the LPS group (13.36% ± 0.9829% VS 24.80% ± 4.619%, p < 0.05). The evidence from in-vitro experiments showed that the immunomodulatory ability of BSHXD may be associated with the activation of AMP-dependent protein kinase (AMPK) pathway in LPS-treated macrophages. In addition, the results of micro-CT, H&E staining, immunohistochemical staining and immunofluorescence staining of mouse skull further demonstrated that BSHXD treatment significantly alleviated LPS-induced local bone loss and inflammatory damage in mouse skull model. All results indicated that BSHXD significantly inhibited inflammatory factors release and M1 polarization of macrophage through AMPK signaling pathway. Therefore, BSHXD may be a promising drug for the treatment of inflammatory bone loss.
Collapse
Affiliation(s)
- Shuangshuang Chen
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
- Department of Rheumatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Lihong Tao
- Department of Rheumatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Feng Zhu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Zhifang Wang
- Department of Orthopedics, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Qi Zhuang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Yajun Li
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
- Department of Orthopedics, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Yunshang Yang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
- Department of Orthopedics, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Chengcheng Feng
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Haiwei Shi
- Department of Orthopedics, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Jiandong Shi
- Department of Orthopedics, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Like Zhu
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
| | - Long Xiao
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Department of Orthopedics, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
- Corresponding author. Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China.
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Corresponding author. Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
| | - Zhirong Wang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
- Department of Orthopedics, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China
- Corresponding author. Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, 215600, China.
| |
Collapse
|
36
|
Cong Y, Wang Y, Yuan T, Zhang Z, Ge J, Meng Q, Li Z, Sun S. Macrophages in aseptic loosening: Characteristics, functions, and mechanisms. Front Immunol 2023; 14:1122057. [PMID: 36969165 PMCID: PMC10030580 DOI: 10.3389/fimmu.2023.1122057] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/13/2023] [Indexed: 03/10/2023] Open
Abstract
Aseptic loosening (AL) is the most common complication of total joint arthroplasty (TJA). Both local inflammatory response and subsequent osteolysis around the prosthesis are the fundamental causes of disease pathology. As the earliest change of cell behavior, polarizations of macrophages play an essential role in the pathogenesis of AL, including regulating inflammatory responses and related pathological bone remodeling. The direction of macrophage polarization is closely dependent on the microenvironment of the periprosthetic tissue. When the classically activated macrophages (M1) are characterized by the augmented ability to produce proinflammatory cytokines, the primary functions of alternatively activated macrophages (M2) are related to inflammatory relief and tissue repair. Yet, both M1 macrophages and M2 macrophages are involved in the occurrence and development of AL, and a comprehensive understanding of polarized behaviors and inducing factors would help in identifying specific therapies. In recent years, studies have witnessed novel discoveries regarding the role of macrophages in AL pathology, the shifts between polarized phenotype during disease progression, as well as local mediators and signaling pathways responsible for regulations in macrophages and subsequent osteoclasts (OCs). In this review, we summarize recent progress on macrophage polarization and related mechanisms during the development of AL and discuss new findings and concepts in the context of existing work.
Collapse
Affiliation(s)
- Yehao Cong
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yi Wang
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Tao Yuan
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Zheng Zhang
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Jianxun Ge
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Qi Meng
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Ziqing Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- *Correspondence: Ziqing Li, ; Shui Sun,
| | - Shui Sun
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- *Correspondence: Ziqing Li, ; Shui Sun,
| |
Collapse
|
37
|
Martiniakova M, Kovacova V, Mondockova V, Zemanova N, Babikova M, Biro R, Ciernikova S, Omelka R. Honey: A Promising Therapeutic Supplement for the Prevention and Management of Osteoporosis and Breast Cancer. Antioxidants (Basel) 2023; 12:567. [PMID: 36978815 PMCID: PMC10045300 DOI: 10.3390/antiox12030567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
Osteoporosis and breast cancer are serious diseases that have become a significant socioeconomic burden. There are biochemical associations between the two disorders in terms of the amended function of estrogen, receptor activator of nuclear factor kappa beta ligand, oxidative stress, inflammation, and lipid accumulation. Honey as a functional food with high antioxidant and anti-inflammatory properties can contribute to the prevention of various diseases. Its health benefits are mainly related to the content of polyphenols. This review aims to summarize the current knowledge from in vitro, animal, and human studies on the use of honey as a potential therapeutic agent for osteoporosis and breast cancer. Preclinical studies have revealed a beneficial impact of honey on both bone health (microstructure, strength, oxidative stress) and breast tissue health (breast cancer cell proliferation and apoptosis, tumor growth rate, and volume). The limited number of clinical trials, especially in osteoporosis, indicates the need for further research to evaluate the potential benefits of honey in the treatment. Clinical studies related to breast cancer have revealed that honey is effective in increasing blood cell counts, interleukin-3 levels, and quality of life. In summary, honey may serve as a prospective therapeutic supplement for bone and breast tissue health.
Collapse
Affiliation(s)
- Monika Martiniakova
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
| | - Veronika Kovacova
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
| | - Vladimira Mondockova
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
| | - Nina Zemanova
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
| | - Martina Babikova
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
| | - Roman Biro
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
| | - Sona Ciernikova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | - Radoslav Omelka
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
| |
Collapse
|
38
|
Heat-Killed Staphylococcus aureus Induces Bone Mass Loss through Telomere Erosion. Int J Mol Sci 2023; 24:ijms24043179. [PMID: 36834587 PMCID: PMC9960843 DOI: 10.3390/ijms24043179] [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: 11/21/2022] [Revised: 01/30/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
The mechanism of systemic osteoporosis caused by chronic infection is not completely clear, and there is a lack of reasonable interventions for this disease. In this study, heat-killed S. aureus (HKSA) was applied to simulate the inflammation caused by the typical clinical pathogen and to explore the mechanism of systemic bone loss caused by it. In this study, we found that the systemic application of HKSA caused bone loss in mice. Further exploration found that HKSA caused cellular senescence, telomere length shortening, and telomere dysfunction-induced foci (TIF) in limb bones. As a well-known telomerase activator, cycloastragenol (CAG) significantly alleviated HKSA-induced telomere erosion and bone loss. These results suggested that telomere erosion in bone marrow cells is a possible mechanism of HKSA-induced bone loss. CAG may protect against HKSA-induced bone loss by alleviating telomere erosion in bone marrow cells.
Collapse
|
39
|
Wang Q, Xu F, Chen J, Xie YQ, Xu SL, He WM. Serum Leukocyte Cell-Derived Chemotaxin 2 (LECT2) Level Is Associated with Osteoporosis. Lab Med 2023; 54:106-111. [PMID: 35976970 DOI: 10.1093/labmed/lmac080] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE The aim of this study was to examine serum leukocyte cell-derived chemotaxin 2 (LECT2) levels in osteoporosis subjects to confirm its association with osteoporosis. METHODS A total of 204 adult subjects were recruited. Bone mineral densities (BMD) were assessed and blood samples were collected for measurements of biomedical parameters and the bone turnover markers. Serum LECT2 levels were measured by enzyme-linked immunosorbent assay. The relationships between serum LECT2 levels and other parameters were analyzed using the Spearman correlation coefficient. RESULTS Serum LECT2 levels were significantly increased in osteoporosis subjects over controls. We found a significantly negative correlation of serum LECT2 with BMD, 25-hydroxy-vitamin D, and creatinine and a significantly positive correlation with C-terminal telopeptide of type 1 collagen and total cholesterol. CONCLUSION Serum LECT2 levels were significantly upregulated in osteoporosis subjects and correlated with the severity of bone loss. Serum LECT2 could be a potential biomarker to assess the risk of bone loss.
Collapse
Affiliation(s)
- Qiang Wang
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Feng Xu
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang, China.,State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
| | - Yan-Qing Xie
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Su-Ling Xu
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Wen-Ming He
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| |
Collapse
|
40
|
Sidiropoulos K, Christofilos SI, Tsikopoulos K, Kitridis D, Drago L, Meroni G, Romanò CL, Kavarthapu V. Viral infections in orthopedics: A systematic review and classification proposal. World J Orthop 2022; 13:1015-1028. [PMID: 36439372 PMCID: PMC9685635 DOI: 10.5312/wjo.v13.i11.1015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/01/2021] [Accepted: 10/27/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Although the impact of microbial infections on orthopedic clinical outcomes is well recognized, the influence of viral infections on the musculoskeletal system might have been underestimated. AIM To systematically review the available evidence on risk factors and musculoskeletal manifestations following viral infections and to propose a pertinent classification scheme. METHODS We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), the Reference Citation Analysis (RCA), and Scopus for completed studies published before January 30, 2021, to evaluate risk factors and bone and joint manifestations of viral infection in animal models and patient registries. Quality assessment was performed using SYRCLE's risk of bias tool for animal studies, Moga score for case series, Wylde score for registry studies, and Newcastle-Ottawa Scale for case-control studies. RESULTS Six human and four animal studies were eligible for inclusion in the qualitative synthesis. Hepatitis C virus was implicated in several peri- and post-operative complications in patients without cirrhosis after major orthopedic surgery. Herpes virus may affect the integrity of lumbar discs, whereas Ross River and Chikungunya viruses provoke viral arthritis and bone loss. CONCLUSION Evidence of moderate strength suggested that viruses can cause moderate to severe arthritis and osteitis. Risk factors such as pre-existing rheumatologic disease contributed to higher disease severity and duration of symptoms. Therefore, based on our literature search, the proposed clinical and pathogenetic classification scheme is as follows: (1) Viral infections of bone or joint; (2) Active bone and joint inflammatory diseases secondary to viral infections in other organs or tissues; and (3) Viral infection as a risk factor for post-surgical bacterial infection.
Collapse
Affiliation(s)
| | - Savvas Ilias Christofilos
- Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom
| | | | - Dimitrios Kitridis
- the First Department of Orthopaedics, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Lorenzo Drago
- Department of Biomedical Sciences for Health and Microbiome, University of Milan, Milan 20133, Italy
| | - Gabriele Meroni
- Department of Biomedical, Surgical, and Dental Sciences, One Health Unit, University of Milan, Milan 20133, Italy
| | - Carlo Luca Romanò
- Gruppo di Studio SIOT Infezioni-Clinica San Gaudenzio-Novara-Gruppo Policlinico di Monza, University of Milan, Milan 20100, Italy
| | - Venu Kavarthapu
- Trauma, and Orthopaedics, Kings College Hospital London, Denmark Hill, London SE59RS, United Kingdom
| |
Collapse
|
41
|
Tisano B, Anigian K, Kantorek N, Kenfack YJ, Johnson M, Brooks JT. The Insidious Effects of Childhood Obesity on Orthopedic Injuries and Deformities. Orthop Clin North Am 2022; 53:461-472. [PMID: 36208888 DOI: 10.1016/j.ocl.2022.06.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The current childhood obesity epidemic, affecting approximately 20% of American children and adolescents, is accompanied by unique orthopedic manifestations. The growing musculoskeletal system is susceptible to the endocrine effects of obesity, resulting in decreased bone mass and quality. As a result, obese children are at increased risk of musculoskeletal injury, fracture, and lower extremity deformities. The efficacy of nonoperative treatment such as casting or bracing may be limited by body habitus and surgical treatment is accompanied by increased risk of perioperative complications.
Collapse
Affiliation(s)
- Breann Tisano
- Department of Orthopaedic Surgery, UT-Southwestern, 1801 Inwood Road, Dallas, TX 75390, USA
| | - Kendall Anigian
- Department of Orthopaedic Surgery, UT-Southwestern, 1801 Inwood Road, Dallas, TX 75390, USA
| | - Nyssa Kantorek
- UT-Southwestern School of Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390, USA
| | - Yves J Kenfack
- UT-Southwestern School of Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390, USA
| | - Megan Johnson
- Department of Orthopaedic Surgery, Scottish Rite for Children/UT-Southwestern, 2222 Welborn Street, Dallas, TX 75219, USA
| | - Jaysson T Brooks
- Department of Orthopaedic Surgery, Scottish Rite for Children/UT-Southwestern, 2222 Welborn Street, Dallas, TX 75219, USA.
| |
Collapse
|
42
|
Wuersching SN, Hickel R, Edelhoff D, Kollmuss M. Initial biocompatibility of novel resins for 3D printed fixed dental prostheses. Dent Mater 2022; 38:1587-1597. [PMID: 36008188 DOI: 10.1016/j.dental.2022.08.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 07/27/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022]
Abstract
OBJECTIVES Several materials for 3D printing of fixed dental prostheses (FDP) have been recently introduced. This study aims to evaluate the initial biocompatibility of novel printable resins for manufacturing temporary and permanent FDP. METHODS Specimens of five printable resins (VarseoSmile Crown plus, NextDent C&B MFH, VarseoSmile Temp, Temp PRINT, P Pro Crown & Bridge), two types of resins for subtractive manufacturing (Tetric CAD, Telio CAD) and two types of resins with conventional curing processes (Tetric EvoCeram, Protemp 4) were produced and finished. Post-processing was strictly performed according to the manufacturer's protocol. Biocompatibility was evaluated by eluting specimens with cell culture medium and treating human gingival fibroblast cells with the eluates. A 72-hour continuous read cell viability assay measuring the reducing potential of the cells was performed. The cellular inflammatory response in terms of IL-6 and PGE2 levels was determined with specific ELISAs. Oxidative stress was determined by measuring oxidized glutathione concentrations after exposure to the resin eluates. A luminescence-based apoptosis assay was used to detect apoptosis. RESULTS Tetric CAD and Telio CAD were slightly toxic. All other resins were moderately to severely cytotoxic. VarseoSmile Crown plus and P Pro Crown & Bridge significantly enhanced PGE2 levels. Higher concentrations of oxidized gluthatione were determined in the presence of Telio CAD, VarseoSmile Temp and P Pro Crown & Bridge. Tetric EvoCeram and Protemp 4 reduced intracellular gluthatione levels. All printable resins slightly induced apoptosis. SIGNIFICANCE Further post-processing steps such as additional curing and washing may improve the biocompatibility of printable materials.
Collapse
Affiliation(s)
- Sabina Noreen Wuersching
- Department of Conservative Dentistry and Periodontology, University Hospital, LMU Munich, Goethestrasse 70, 80336 Munich, Germany.
| | - Reinhard Hickel
- Department of Conservative Dentistry and Periodontology, University Hospital, LMU Munich, Goethestrasse 70, 80336 Munich, Germany
| | - Daniel Edelhoff
- Department of Prosthetic Dentistry, University Hospital, LMU Munich, Goethestrasse 70, 80336 Munich, Germany
| | - Maximilian Kollmuss
- Department of Conservative Dentistry and Periodontology, University Hospital, LMU Munich, Goethestrasse 70, 80336 Munich, Germany
| |
Collapse
|
43
|
Teresa Selvin S, Thomas S, Bikeyeva V, Abdullah A, Radivojevic A, Abu Jad AA, Ravanavena A, Ravindra C, Igweonu-Nwakile EO, Ali S, Paul S, Yakkali S, Balani P. Establishing the Association Between Osteoporosis and Peptic Ulcer Disease: A Systematic Review. Cureus 2022; 14:e27188. [PMID: 36039217 PMCID: PMC9395758 DOI: 10.7759/cureus.27188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/23/2022] [Indexed: 11/05/2022] Open
Abstract
Osteoporosis is one of the most common metabolic bone diseases. Many studies were conducted to find the association between peptic ulcer disease (PUD), Helicobacter pylori infection, proton-pump inhibitor (PPI) use, and increased risk for fracture, but results remain ambiguous. We performed this systematic review to understand the association between PUD and osteoporosis. We comprehensively searched relevant articles on April 19, 2022, by exploring different databases including PubMed, PubMed Central (PMC), and Medline using relevant keywords. After applying inclusion and exclusion criteria and undergoing quality assessment, we retained 25 studies published in and after 2015. For our systematic review, we included a total of 5,600,636 participants. The studies included in our review demonstrated a significant association between PUD, H. pylori infection, and the risk of osteoporosis. Long-term PPI use was also found to be a risk factor for osteoporosis. Malabsorption of nutrients, increase in inflammatory cytokines, and alterations in hormone status were found to be the notable factors behind the association. Early management of H. pylori infection and cautious use of long-term PPIs may protect against osteoporosis. Further randomized controlled trials (RCTs) are necessary to establish a causal relationship.
Collapse
|
44
|
Wang W, Liu H, Liu T, Yang H, He F. Insights into the Role of Macrophage Polarization in the Pathogenesis of Osteoporosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2485959. [PMID: 35707276 PMCID: PMC9192196 DOI: 10.1155/2022/2485959] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/01/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022]
Abstract
Millions of people worldwide suffer from osteoporosis, which causes bone fragility and increases the risk of fractures. Osteoporosis is closely related to the inhibition of osteogenesis and the enhancement of osteoclastogenesis. In addition, chronic inflammation and macrophage polarization may contribute to osteoporosis as well. Macrophages, crucial to inflammatory responses, display different phenotypes under the control of microenvironment. There are two major phenotypes, classically activated macrophages (M1) and alternatively activated macrophages (M2). Generally, M1 macrophages mainly lead to bone resorption, while M2 macrophages result in osteogenesis. M1/M2 ratio reflects the "fluid" state of macrophage polarization, and the imbalance of M1/M2 ratio may cause disease such as osteoporosis. Additionally, antioxidant drugs, such as melatonin, are applied to change the state of macrophage polarization and to treat osteoporosis. In this review, we introduce the mechanisms of macrophage polarization-mediated bone resorption and bone formation and the contribution to the clinical strategies of osteoporosis treatment.
Collapse
Affiliation(s)
- Wenhao Wang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
| | - Hao Liu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
| | - Tao Liu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Huilin Yang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
| | - Fan He
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
| |
Collapse
|
45
|
Massaccesi L, Galliera E, Pellegrini A, Banfi G, Corsi Romanelli MM. Osteomyelitis, Oxidative Stress and Related Biomarkers. Antioxidants (Basel) 2022; 11:antiox11061061. [PMID: 35739958 PMCID: PMC9220672 DOI: 10.3390/antiox11061061] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/30/2022] Open
Abstract
Bone is a very dynamic tissue, subject to continuous renewal to maintain homeostasis through bone remodeling, a process promoted by two cell types: osteoblasts, of mesenchymal derivation, are responsible for the deposition of new material, and osteoclasts, which are hematopoietic cells, responsible for bone resorption. Osteomyelitis (OM) is an invasive infectious process, with several etiological agents, the most common being Staphylococcus aureus, affecting bone or bone marrow, and severely impairing bone homeostasis, resulting in osteolysis. One of the characteristic features of OM is a strong state of oxidative stress (OS) with severe consequences on the delicate balance between osteoblastogenesis and osteoclastogenesis. Here we describe this, analyzing the effects of OS in bone remodeling and discussing the need for new, easy-to-measure and widely available OS biomarkers that will provide valid support in the management of the disease.
Collapse
Affiliation(s)
- Luca Massaccesi
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.G.); (M.M.C.R.)
- Correspondence: ; Tel.: +39-0250316027
| | - Emanuela Galliera
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.G.); (M.M.C.R.)
- IRCCS Galeazzi Orthopaedic Institute, 20161 Milan, Italy;
| | - Antonio Pellegrini
- Centre for Reconstructive Surgery and Osteoarticular Infections, IRCCS Galeazzi Orthopaedic Institute, 20161 Milan, Italy;
| | - Giuseppe Banfi
- IRCCS Galeazzi Orthopaedic Institute, 20161 Milan, Italy;
| | - Massimiliano Marco Corsi Romanelli
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy; (E.G.); (M.M.C.R.)
- Service of Laboratory Medicine1-Clinical Pathology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy
| |
Collapse
|
46
|
Effects of Artemisia annua L. Essential Oil on Osteoclast Differentiation and Function Induced by RANKL. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1322957. [PMID: 35432559 PMCID: PMC9010179 DOI: 10.1155/2022/1322957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/17/2022] [Accepted: 02/19/2022] [Indexed: 11/18/2022]
Abstract
Objective This study aimed to assess the main components of Artemisia annua L. essential oil (AEO) and determine their effect on the proliferation and differentiation of RAW264.7 cells induced by receptor activator for nuclear factor-ligand (RANKL) in vitro. Then, we tried to explain part of the function of its possible mechanisms. Materials and Methods Essential oil was extracted from Artemisia annua L. Osteoclasts were induced in vitro by RANKL in mouse RAW264.7 cells. The experimental group was treated with different concentrations of AEO, while the control group was not treated with AEO. CCK8 was used to detect osteoclast proliferation. The osteoclasts were stained with TRAP. Western blot was used to detect protein in the MAPK pathway and the NF-κB pathway after treatment with different concentrations of AEO. RT-PCR was used to determine the expression of osteoclast-related mRNA in cells. Results The GC-MS analysis was used to obtain the main components of AEO, including camphor, borneol, camphor, borneol, terpinen-4-ol, p-cymene, eucalyptol, deoxyartemisinin, and artemisia ketone. The CCK8 results showed that the AEO volume ratio of 1 : 4000, 1 : 5000, and 1 : 6000 did not affect the proliferation of RAW264.7 cells. However, TRAP staining showed that AEO decreased osteoclast formation. Western blot results showed that the expression of protein TRAF6, p-p38, p-ERK, p-p65, and NFATc1 decreased in the MAPK pathway and the NF-κB pathway affected by AEO. Furthermore, RT-PCR results showed that the expression of osteoclast resorption-related mRNAs (MMP-9, DC-STAMP, TRAP, and CTSK) and osteoclast differentiation-related mRNAs (OSCAR, NFATc1, c-Src, and c-Fos) also decreased in the experimental group. Conclusions AEO inhibits osteoclast differentiation in vitro, probably by reducing TRAF6 activation, acting on the MAPK pathway and NF-κB pathway, and inhibiting the expression of osteoclast-related genes.
Collapse
|
47
|
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.
Collapse
|
48
|
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.
Collapse
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;
| |
Collapse
|
49
|
Roh J, Subramanian S, Weinreb NJ, Kartha RV. Gaucher disease – more than just a rare lipid storage disease. J Mol Med (Berl) 2022; 100:499-518. [DOI: 10.1007/s00109-021-02174-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/29/2021] [Accepted: 12/06/2021] [Indexed: 01/18/2023]
|
50
|
Shi W, Deng Y, Zhao C, Xiao W, Wang Z, Xiong Z, Zhao L. Integrative serum metabolomic analysis for preventive effects of Yaobitong capsule in adjuvant-induced rheumatoid arthritis rat based on RP/HILIC-UHPLC-Q-TOF MS. Anal Biochem 2022; 637:114474. [PMID: 34801482 DOI: 10.1016/j.ab.2021.114474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/04/2021] [Accepted: 11/12/2021] [Indexed: 12/16/2022]
Abstract
Yaobitong capsule (YBTC) has been used for the prevention and treatment of inflammation-related lumbago and leg pain. However, its intervention mechanism still remains unclear. This study was aimed to evaluate the control efficiency of YBTC on adjuvant-induced rheumatoid arthritis (RA) rats by metabonomic method and to explore its possible anti-arthritis mechanism. Taking into account the complexity of endogenous metabolites in serum samples, an integrated metabolomics method based on RP/HILIC-UHPLC-Q-TOF MS was developed, to overcome the limitations of a single chromatographic in this study. The results showed that 32 potential biomarkers of arthritis were identified, primarily related to amino acid metabolism, glucose metabolism, lipid metabolism and nucleotide metabolism. Further receiver operating characteristic analysis revealed that the area under the curve of two down-regulated metabolites (3-Hydroxy-hexadecanoic acid, 2-Oxoarginine) and one up-regulated metabolite (l-Glutamic acid) among 32 biomarkers were 0.906, 0.969 and 1.000, respectively, indicating that high predictive ability of this method for RA. In this study, an integrated serum metabolomics method based on high-resolution mass spectrometry was successfully established for the first time to study the intervention mechanism of YBTC in RA, providing evidence regarding the clinical application of YBTC and a new insight for the prevention of RA in the future.
Collapse
Affiliation(s)
- Wei Shi
- Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, 110016, Shenyang, Liaoning Province, China
| | - Yajie Deng
- Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, 110016, Shenyang, Liaoning Province, China
| | - Chenyang Zhao
- Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, 110016, Shenyang, Liaoning Province, China
| | - Wei Xiao
- State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang, Jiangsu, 222001, China
| | - Zhenzhong Wang
- Jiangsu Kanion Parmaceutical CO. LTD, Lianyungang, Jiangsu, 222001, China
| | - Zhili Xiong
- Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, 110016, Shenyang, Liaoning Province, China.
| | - Longshan Zhao
- Shenyang Pharmaceutical University, 103 Wenhua Road Shenhe District, 110016, Shenyang, Liaoning Province, China.
| |
Collapse
|