|
1
|
Biewer B, Rompen E, Mittelbronn M, Hammer GP, Quatresooz P, Borgmann FK. Effects of Minocycline Hydrochloride as an Adjuvant Therapy for a Guided Bone Augmentation Procedure in The Rat Calvarium. Dent J (Basel) 2023; 11:dj11040092. [PMID: 37185470 PMCID: PMC10136768 DOI: 10.3390/dj11040092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/08/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023] Open
Abstract
This in vivo study reports the influence of minocycline-HCl administration on extra-skeletal bone generation in a Guided Bone Augmentation model, utilizing titanium caps placed on the intact as well as perforated calvaria of rats. The test group was administered 0.5 mg/mL minocycline-HCl with the drinking water, and the amount of bone tissue in the caps was quantified at three time points (4, 8 and 16 weeks). A continuously increased tissue fill was observed in all groups over time. The administration of minocycline-HCl as well as perforation of the calvaria increased this effect, especially with regard to mineralization. The strongest tissue augmentation, with 1.8 times that of the untreated control group, and, at the same time, the most mineralized tissue (2.3× over untreated control), was produced in the combination of both treatments, indicating that systemic administration of minocycline-HCl has an accelerating and enhancing effect on vertical bone augmentation.
Collapse
|
|
2
|
Advances in the occurrence and biotherapy of osteoporosis. Biochem Soc Trans 2021; 48:1623-1636. [PMID: 32627832 DOI: 10.1042/bst20200005] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 12/17/2022]
Abstract
Osteoporosis (OP) is a bone metabolic disease, is characterized by degeneration of bone structure and decreased bone mass. It happens in more than 1/3 women and 1/5 men of over than 50 years old, which affects the health and lives of people. The main mechanism of OP is mainly that the dynamic balance between the bone formation and resorption is broken, so that bone resorption is more than bone formation. It is prone to result in bone metabolism disorder. There are many precipitating factor such as elder age, low hormone level, genetic factors and bad hobbies. At the same time, the occurrence of the OP and its complications has different degrees of impact on people's quality of life. Based on the current understanding of the OP, we summarized the etiology, current clinical drugs and potential targeting therapy for OP. Although the research have made many progress in explore what is the novel mechanism and how to improve the effect, there are still many problems in the treatment method that limit its application prospects and need to be solved. In this review, we mainly focus on the mechanism of OP and related research on the targeted treatment of OP. Hopefully, our summary will provide a reference to develop some novel strategies for the target therapy of OP.
Collapse
|
|
3
|
Dalhoff A. Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks? Infection 2021; 49:29-56. [PMID: 33367978 PMCID: PMC7851017 DOI: 10.1007/s15010-020-01536-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. METHODS AND OBJECTIVE This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. RESULTS Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. CONCLUSION The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.
Collapse
Affiliation(s)
- Axel Dalhoff
- Christian-Albrechts-University of Kiel, Institue for Infection Medicine, Brunswiker Str. 4, D-24105, Kiel, Germany.
| |
Collapse
|
|
4
|
Golub LM, Räisänen IT, Sorsa T, Preshaw PM. An Unexplored Pharmacologic/Diagnostic Strategy for Peri-Implantitis: A Protocol Proposal. Diagnostics (Basel) 2020; 10:diagnostics10121050. [PMID: 33291429 PMCID: PMC7762163 DOI: 10.3390/diagnostics10121050] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/28/2020] [Accepted: 12/03/2020] [Indexed: 12/18/2022] Open
Abstract
Dental implants are widely utilized for the replacement of missing teeth and are increasingly being placed in patients with systemic diseases, as well as in those who are medically healthy. Furthermore, it is recognized that peri-implant mucositis and peri-implantitis are highly prevalent, affecting large numbers of patients with implants, and it is pertinent to consider whether there may be any systemic impact of these conditions, given that there are known links between periodontitis and a number of chronic inflammatory diseases. In this article, we propose that the potential systemic complications of peri-implant diseases should be investigated in future clinical research, together with studies to identify whether systemically-administered host modulation therapies (HMTs) may be of benefit in the treatment of peri-implant diseases. These “HMTs” may prove a useful adjunct to routinely employed debridement and disinfection protocols, as well as potentially being of benefit in reducing risks of systemic complications. We also consider the use of chair-side diagnostic tests for active matrix metalloproteinase-8 (aMMP-8) in the detection of peri-implant disease given the ability of such tests to detect active tissue breakdown associated with peri-implantitis and periodontitis before conventional clinical and radiographic measurements indicate pathologic changes. These novel diagnostic and therapeutic strategies are relevant to consider as they may improve the management of peri-implant disease (beyond local debridement procedures), especially in those patients in whom systemic inflammation might be of concern.
Collapse
Affiliation(s)
- Lorne M. Golub
- Department of Oral Biology and Pathology, School of Dental Medicine, Health Sciences Center, Stony Brook University, Stony Brook, NY 11794, USA;
| | - Ismo T. Räisänen
- Department of Oral and Maxillofacial Diseases, Head and Neck Center, University of Helsinki and Helsinki University Hospital, PO Box 63 (Haartmaninkatu 8), FI-00014 Helsinki, Finland;
- Correspondence:
| | - Timo Sorsa
- Department of Oral and Maxillofacial Diseases, Head and Neck Center, University of Helsinki and Helsinki University Hospital, PO Box 63 (Haartmaninkatu 8), FI-00014 Helsinki, Finland;
- Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Philip M. Preshaw
- National University Centre for Oral Health, Faculty of Dentistry, National University of Singapore, Singapore 119077, Singapore;
- School of Dental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| |
Collapse
|
|
5
|
Gomes PS, Resende M, Fernandes MH. Doxycycline restores the impaired osteogenic commitment of diabetic-derived bone marrow mesenchymal stromal cells by increasing the canonical WNT signaling. Mol Cell Endocrinol 2020; 518:110975. [PMID: 32758627 DOI: 10.1016/j.mce.2020.110975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/21/2020] [Accepted: 07/31/2020] [Indexed: 01/09/2023]
Abstract
Diabetes mellitus comprehends a group of chronic metabolic disorders, associated with damage and dysfunction of distinct tissues, including bone. At the cellular level, an impaired osteoblastogenesis has been reported, affecting the viability, proliferation and functionality of osteoblasts and precursor populations, hampering the bone metabolic activity, remodeling and healing. Tetracyclines embrace a group of broad-spectrum antibacterial compounds with potential anabolic effects on the bone tissue, through antibacterial-independent mechanisms. Accordingly, this study aims to address the modulatory capability and associated molecular signaling of a low dosage doxycycline - a semi-synthetic tetracycline, in the functional activity of osteoblastic progenitor cells (bone marrow-derived mesenchymal stromal cells), established from a translational diabetic experimental model. Bone marrow-derived mesenchymal stromal cells were isolated from streptozotocin-induced diabetic Wistar rat with proven osteopenia. Cultures were characterized, in the presence of doxycycline (1 μg ml-1) for proliferation, metabolic activity, apoptosis, collagen synthesis and relevant gene expression with the osteogenic and adipogenic program. The activation of the Wnt/β-catenin pathway was further detailed. Doxycycline normalized the viability, proliferation and metabolic activity of the established cultures, further decreasing cell apoptosis, to levels similar to control. The addition of this drug to the culture environment further increased the osteogenic activation, upregulating the expression of osteogenic markers and collagen synthesis, at the same time that a decreased adipogenic priming was attained. These processes were found to me mediated, at least in part, by the restoration of the signaling through the Wnt/β-catenin pathway.
Collapse
Affiliation(s)
- Pedro Sousa Gomes
- BoneLab - Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, U. Porto, R. Dr. Manuel Pereira da Silva, 4200-393, Porto, Portugal; LAQV/REQUIMTE, U. Porto, Porto, 4160-007, Portugal.
| | - Marta Resende
- Faculty of Dental Medicine, U. Porto, R. Dr. Manuel Pereira da Silva, 4200-393, Porto, Portugal
| | - Maria Helena Fernandes
- BoneLab - Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, U. Porto, R. Dr. Manuel Pereira da Silva, 4200-393, Porto, Portugal; LAQV/REQUIMTE, U. Porto, Porto, 4160-007, Portugal
| |
Collapse
|
|
6
|
Huang H, Chen D, Lippuner K, Hunziker EB. Induced Experimental Periimplantitis and Periodontitis: What are the Differences in the Inflammatory Response ? J ORAL IMPLANTOL 2020; 47:359-369. [PMID: 33259586 DOI: 10.1563/aaid-joi-d-19-00362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This preliminary study investigates the differences between experimental periodontitis and periimplantitis in a dog model, with a focus on the histopathology, the inflammatory responses and specific immunoregulatory activities, driven by Th1/Th2 positive cells. Twelve dental implants were inserted into the edentulated posterior mandibles of six Beagle dogs and were given twelve weeks time for osseointegration. Experimental periimplantitis and periodontitis (first mandible molar) was then induced using cotton-floss ligatures. Twelve weeks later, alveolar bones were quantitated by cone beam-computer tomography. Histopathological analysis of the inflamed gingiva and of the periodontal tissues was performed by light microscopy, and the Th1/ Th2 cell populations were investigated by flow cytometry. Periimplantitis as well as periodontitis were both found to be associated with pronounced bone resorption effects, both to a similar degree vertically, but with a differential bone resorption pattern mesio-distally, and with a significantly higher and consistent bone resorption result in periimplantitis; however, with a higher variance of bone resorption in periodontitis. The histological appearances of the inflammatory tissues were identical. The percentages of Th1/ Th2 cells in the inflamed gingival tissues of both experimental periimplantitis and periodontitis were also found to be similar. Experimental periodontitis and periimplantitis in the dog model show essentially the same cellular pathology of inflammation. However, bone resorption was found to be significantly higher in periimplantitis; the histopathological changes in the periodontal tissues were similar in both groups, but showed a higher inter-individual variation in periodontitis, and appeared more uniform in periimplantitis. This preliminary study indicates that more focused experimental in-vivo inflammation models need to be developed to better simulate the human pathology in the two different diseases, and in order to have a valuable tool to investigate more specifically how novel treatments/prevention approaches may heal the differential adverse effects on bone tissue and on periodontium in periodontitis and in periimplantitis.
Collapse
Affiliation(s)
- Hairong Huang
- Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije University Amsterdam, Gustav Mahlerlaan 3004, 1081LA Amsterdam, Nord-Holland, the Netherlands
| | - Dong Chen
- State Key Laboratory of Basic Science of Stomatology, Laboratory of Oral Biomedicine, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Kurt Lippuner
- Department of Osteoporosis, Inselspital Bern University Hospital, Freiburgstrasse 3, CH-3010 Bern, Switzerland
| | - Ernst Bruno Hunziker
- Inselspital Universitatsspital Bern Research Head Osteoporosis and Othopaedic Research Freiburgstrasse 3 SWITZERLAND Bern Bern 3010 +41860794446551 +41794446551 Departments of Osteoporosis and Orthopaedic Surgery, Inselspital Bern University Hospital, Freiburgstrasse 3, CH-3010 Bern, Switzerland
| |
Collapse
|
|
7
|
Farhad SZ, Siadat A, Sadeghian N, Abrishamkar S, Khosraviani F, Khazaei P, Saberi-Demneh A. The effect of low-level laser radiation and doxycycline on the levels of osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Lasers Med Sci 2020; 35:1975-1979. [PMID: 32221769 DOI: 10.1007/s10103-020-02993-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 03/01/2020] [Indexed: 11/25/2022]
Abstract
The present in vitro study was conducted to investigate the effect of low-level laser (LLL) radiation and doxycycline on the levels of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) derived from MG-63 osteosarcoma cell line. MG-63 cells were divided into four groups. In the first group, 2 mg/mL of doxycycline was injected into the cell culture medium. Diode laser (810 nm, 100 mw, 75 s) was radiated to the culture medium of the second group. The third group received both doxycycline and laser radiation. In the fourth group (control), the culture medium was replaced daily, similar to the above three groups. Mentioned interventions were performed once a day for 4 consecutive days. Then, on the sixth day, the levels of OPG and RANKL mediators were measured using real-time polymerase chain reaction by isolating the cells from the samples. OPG expression had the highest to lowest levels in the laser + doxycycline, doxycycline, laser, and control groups, respectively. The level of OPG was significantly different between all the study groups (p < 0.05) except in the doxycycline + laser and doxycycline groups (p = 0.061). The highest to lowest levels of RANKL was observed in the doxycycline, laser + doxycycline, control, and laser groups, respectively. The RANKL expression was not significantly different between all the study groups (p > 0.05). The results of this study revealed that LLL and doxycycline reduced the RANKL/OPG ratio derived from the MG-63 osteosarcoma cell line, which may result in the diminished activity of osteoclasts and osteoclastogenesis.
Collapse
Affiliation(s)
- Shirin Zahra Farhad
- School of Dentistry, Islamic Azad University, Khorasgan Branch, Isfahan, Iran
| | - Amir Siadat
- School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Neda Sadeghian
- School of Dentistry, Islamic Azad University, Khorasgan Branch, Isfahan, Iran
| | - Sourena Abrishamkar
- School of Dentistry, Islamic Azad University, Khorasgan Branch, Isfahan, Iran.
| | | | - Pegah Khazaei
- School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
8
|
Medina-Cruz D, Mostafavi E, Vernet-Crua A, Cheng J, Shah V, Cholula-Diaz JL, Guisbiers G, Tao J, García-Martín JM, Webster TJ. Green nanotechnology-based drug delivery systems for osteogenic disorders. Expert Opin Drug Deliv 2020; 17:341-356. [PMID: 32064959 DOI: 10.1080/17425247.2020.1727441] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Current treatments for osteogenic disorders are often successful, however they are not free of drawbacks, such as toxicity or side effects. Nanotechnology offers a platform for drug delivery in the treatment of bone disorders, which can overcome such limitations. Nevertheless, traditional synthesis of nanomaterials presents environmental and health concerns due to its production of toxic by-products, the need for extreme and harsh raw materials, and their lack of biocompatibility over time.Areas covered: This review article contains an overview of the current status of treating osteogenic disorders employing green nanotechnological approaches, showing some of the latest advances in the application of green nanomaterials, as drug delivery carriers, for the effective treatment of osteogenic disorders.Expert opinion: Green nanotechnology, as a potential solution, is understood as the use of living organisms, biomolecules and environmentally friendly processes for the production of nanomaterials. Nanomaterials derived from bacterial cultures or biomolecules isolated from living organisms, such as carbohydrates, proteins, and nucleic acids, have been proven to be effective composites. These nanomaterials introduce enhancements in the treatment and prevention of osteogenic disorders, compared to physiochemically-synthesized nanostructures, specifically in terms of their improved cell attachment and proliferation, as well as their ability to prevent bacterial adhesion.
Collapse
Affiliation(s)
- David Medina-Cruz
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Ebrahim Mostafavi
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Ada Vernet-Crua
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Junjiang Cheng
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Veer Shah
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| | | | - Gregory Guisbiers
- Department of Physics and Astronomy, University of Arkansas at Little Rock, Little Rock, AR, USA
| | - Juan Tao
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| | | | - Thomas J Webster
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA
| |
Collapse
|
|
9
|
Inducible expression of Wnt7b promotes bone formation in aged mice and enhances fracture healing. Bone Res 2020; 8:4. [PMID: 32047703 PMCID: PMC6997361 DOI: 10.1038/s41413-019-0081-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 10/14/2019] [Accepted: 11/28/2019] [Indexed: 02/07/2023] Open
Abstract
There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested, Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.
Collapse
|
|
10
|
Abstract
With the recognition in the 1960s and 1970s of the periodontopathic importance of the microbial biofilm and its specific anaerobic microorganisms, periodontitis was treated as an infectious disease (more recently, as a dysbiosis). Subsequently, in the 1980s, host-response mechanisms were identified as the mediators of the destruction of the collagen-rich periodontal tissues (gingiva, periodontal ligament, alveolar bone), and the periodontopathogens were now regarded as the "trigger" of the inflammatory/collagenolytic response that characterizes actively destructive periodontitis. Also at this time a new pharmacologic strategy emerged, entitled "host-modulation therapy", based on 2 major findings: (1) that the ability of tetracycline antibiotics to inhibit periodontal breakdown was due (in large part) to their previously unrecognized ability to inhibit the host-derived matrix metalloproteinases (notably, the collagenases, gelatinases, macrophage metalloelastase), and by mechanisms unrelated to the antimicrobial properties of these medications; and (2) that nonsteroidal anti-inflammatory drugs, such as flurbiprofen, again by nonantimicrobial mechanisms, could reduce the severity of periodontitis (however, the adverse effects of long-term therapy precluded their development as safe and effective host-modulatory agents). Additional mechanistic studies resulted in the development of novel nonantimicrobial formulations (Periostat® [now generic] and Oracea®) and compositions of tetracyclines (notably chemically modified tetracycline-3) as host-modulator drugs for periodontitis, arthritis, cardiovascular and pulmonary diseases, cancer, and, more recently, for local and systemic bone loss in postmenopausal women. Identification of the cation-binding active site in the tetraphenolic chemically modified tetracycline molecules drove the development of a new category of matrix metalloproteinase-inhibitor compounds, with a similar active site, the biphenolic chemically modified curcumins. A lead compound, chemically modified curcumin 2.24, has demonstrated safety and efficacy in vitro, in cell culture, and in vivo in mouse, rat, rabbit, and dog models of disease. In conclusion, novel host-modulation compounds have shown significant promise as adjuncts to traditional local therapy in the clinical management of periodontal disease; appear to reduce systemic complications of this all-too-common "inflammatory/collagenolytic" disease; and Oracea® is now commonly prescribed for inflammatory dermatologic diseases.
Collapse
Affiliation(s)
- Lorne M. Golub
- Department of Oral Biology & PathologySchool of Dental MedicineStony Brook UniversityStony BrookNew York, USA
| | - Hsi‐Ming Lee
- Department of Oral Biology & PathologySchool of Dental MedicineStony Brook UniversityStony BrookNew York, USA
| |
Collapse
|
|
11
|
Silva T, Silva JC, Colaco B, Gama A, Duarte-Araújo M, Fernandes MH, Bettencourt A, Gomes P. In vivo tissue response and antibacterial efficacy of minocycline delivery system based on polymethylmethacrylate bone cement. J Biomater Appl 2019; 33:380-391. [PMID: 30223730 DOI: 10.1177/0885328218795290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This study aims the in vivo biological characterization of an innovative minocycline delivery system, based on polymethylmethacrylate bone cement. Bone cements containing 1% or 2.5% (w/w) minocycline were formulated and evaluated through solid-state characterization. Biological evaluation was conducted in vivo, within a rat model, following the subcutaneous and bone tissue implantation, and tissue implantation associated with Staphylococcus aureus is challenging. The assessment of the tissue/biomaterial interaction was conducted by histologic, histomorphometric and microtomographic techniques. Minocycline addition to the composition of the polymethylmethacrylate bone cement did not modify significantly the cement properties. Drug release profile was marked by an initial burst release followed by a low-dosage sustained release. Following the subcutaneous tissue implantation, a reduced immune-inflammatory reaction was verified, with diminished cell recruitment and a thinner fibro-connective capsule formation. Minocycline-releasing cements were found to enhance the bone-to-implant contact and bone tissue formation, following the tibial implantation. Lastly, an effective antibacterial activity was mediated by the implanted cement following the tissue challenging with S. aureus. Kinetic minocycline release profile, attained with the developed polymethylmethacrylate system, modulated adequately the in vivo biological response, lessening the immune-inflammatory activation and enhancing bone tissue formation. Also, an effective in vivo antibacterial activity was established. These findings highlight the adequacy and putative application of the developed system for orthopedic applications.
Collapse
Affiliation(s)
- Tiago Silva
- 1 Faculty of Dental Medicine, University of Porto, Porto, Portugal
| | - Jose C Silva
- 1 Faculty of Dental Medicine, University of Porto, Porto, Portugal
| | - Bruno Colaco
- 2 University of Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - Adelina Gama
- 2 University of Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | | | - Maria H Fernandes
- 1 Faculty of Dental Medicine, University of Porto, Porto, Portugal.,4 REQUIMTE/LAQV - University of Porto, Porto, Portugal
| | - Ana Bettencourt
- 5 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Pedro Gomes
- 1 Faculty of Dental Medicine, University of Porto, Porto, Portugal.,4 REQUIMTE/LAQV - University of Porto, Porto, Portugal
| |
Collapse
|
|
12
|
Pal P, Nguyen QC, Benton AH, Marquart ME, Janorkar AV. Drug‐Loaded Elastin‐Like Polypeptide–Collagen Hydrogels with High Modulus for Bone Tissue Engineering. Macromol Biosci 2019; 19:e1900142. [DOI: 10.1002/mabi.201900142] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 06/21/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Pallabi Pal
- Biomedical Materials ScienceSchool of DentistryUniversity of Mississippi Medical Center 2500 North State Street Jackson MS 39216 USA
| | - Quynh C. Nguyen
- Biomedical Materials ScienceSchool of DentistryUniversity of Mississippi Medical Center 2500 North State Street Jackson MS 39216 USA
| | - Angela H. Benton
- Microbiology and ImmunologySchool of MedicineUniversity of Mississippi Medical Center 2500 North State Street Jackson MS 39216 USA
| | - Mary E. Marquart
- Microbiology and ImmunologySchool of MedicineUniversity of Mississippi Medical Center 2500 North State Street Jackson MS 39216 USA
| | - Amol V. Janorkar
- Biomedical Materials ScienceSchool of DentistryUniversity of Mississippi Medical Center 2500 North State Street Jackson MS 39216 USA
| |
Collapse
|
|
13
|
Lima AC, Ferreira H, Reis RL, Neves NM. Biodegradable polymers: an update on drug delivery in bone and cartilage diseases. Expert Opin Drug Deliv 2019; 16:795-813. [DOI: 10.1080/17425247.2019.1635117] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Ana Cláudia Lima
- 3B’s Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Helena Ferreira
- 3B’s Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui L. Reis
- 3B’s Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| | - Nuno M. Neves
- 3B’s Research Group, I3Bs – Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| |
Collapse
|
|
14
|
Tihan GT, Rău I, Zgârian RG, Ungureanu C, Barbaresso RC, Kaya MGA, Dinu-Pîrvu C, Ghica MV. Oxytetracycline versus Doxycycline Collagen Sponges Designed as Potential Carrier Supports in Biomedical Applications. Pharmaceutics 2019; 11:pharmaceutics11080363. [PMID: 31344927 PMCID: PMC6722625 DOI: 10.3390/pharmaceutics11080363] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/19/2019] [Accepted: 07/20/2019] [Indexed: 11/23/2022] Open
Abstract
Many research studies are directed toward developing safe and efficient collagen-based biomaterials as carriers for drug delivery systems. This article presents a comparative study of the properties of new collagen sponges prepared and characterized by different methods intended for biomedical applications. The structural integrity is one of the main properties for a biomaterial in order for it to be easily removed from the treated area. Thus, the effect of combining a natural polymer such as collagen with an antimicrobial drug such as oxytetracycline or doxycycline and glutaraldehyde as the chemical cross-linking agent influences the cross-linking degree of the material, which is in direct relation to its resistance to collagenase digestion, the drug kinetic release profile, and in vitro biocompatibility. The enzymatic degradation results identified oxytetracycline as the best inhibitor of collagenase when the collagen sponge was cross-linked with 0.5% glutaraldehyde. The drug release kinetics revealed an extended release of the antibiotic for oxytetracycline-loaded collagen sponges compared with doxycycline-loaded collagen sponges. Considering the behavior of differently prepared sponges, the collagen sponge with oxytetracycline and 0.5% glutaraldehyde could represent a viable polymeric support for the prevention/treatment of infections at the application site, favoring tissue regeneration.
Collapse
Affiliation(s)
- Graţiela Teodora Tihan
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Polizu Street No. 1, 011061 Bucharest, Romania
| | - Ileana Rău
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Polizu Street No. 1, 011061 Bucharest, Romania
| | - Roxana Gabriela Zgârian
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Polizu Street No. 1, 011061 Bucharest, Romania.
| | - Camelia Ungureanu
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Polizu Street No. 1, 011061 Bucharest, Romania.
| | - Răzvan Constantin Barbaresso
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Polizu Street No. 1, 011061 Bucharest, Romania
| | - Mădălina Georgiana Albu Kaya
- Department of Collagen, Division Leather and Footwear Research Institute, National Research and Development Institute for Textile and Leather, 031215 Bucharest, Romania
| | - Cristina Dinu-Pîrvu
- Department of Physical and Colloidal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy "Carol Davila", 20956 Bucharest, Romania
| | - Mihaela Violeta Ghica
- Department of Physical and Colloidal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy "Carol Davila", 20956 Bucharest, Romania
| |
Collapse
|
|
15
|
Madhumathi K, Rubaiya Y, Doble M, Venkateswari R, Sampath Kumar TS. Antibacterial, anti-inflammatory, and bone-regenerative dual-drug-loaded calcium phosphate nanocarriers—in vitro and in vivo studies. Drug Deliv Transl Res 2018; 8:1066-1077. [DOI: 10.1007/s13346-018-0532-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
16
|
Doxycycline treatment in dialysis related amyloidosis: discrepancy between antalgic effect and inflammation, studied with FDG-positron emission tomography: a case report. BMC Nephrol 2017; 18:285. [PMID: 28874122 PMCID: PMC5586015 DOI: 10.1186/s12882-017-0698-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 08/23/2017] [Indexed: 12/24/2022] Open
Abstract
Background No effective treatment is currently available and dialysis related amyloidosis continues to be invalidating in long-term dialysis patients. A recent case series reported reduction of osteoarticular pain on doxycycline treatment, extending the indications of this drug, used in other uncommon forms of amyloidosis, to dialysis patients. Explanations of the antalgic effect were the anti-inflammatory properties and anti-coiling effects of tetracycline. Case presentation Our report regards a 54-year-old woman, who was never transplanted and has been on hemodialysis and hemodiafiltration for overall 37 years, due to renal hypoplasia. In spite of high efficiency hemodiafiltration, she complained of increasing, invalidating osteoarticular pain; history and imaging suggested beta-2 microglobulin amyloid. Positron emission tomography (PET scan) identified metabolically active lesions in the involved settings. Low-dose doxycycline (100 mg/day) was started, leading to a considerable decrease in pain (over 6 months, from 7 to 8 to 4–5 on a 0–10 scale). At 6 months, a PET scan showed unmodified or increased uptake in the involved settings. Conclusions In summary, the previously described antalgic effect of doxycycline in dialysis related amyloidosis is confirmed in our case, the first studied using PET scan. The pattern at PET can suggests that the antalgic effect is independent from inflammation and points to other factors, such as interaction with fibril geometry or with bone structure.
Collapse
|
|
17
|
Alyousef AA, Divakar DD, Muzaheed. Chemically modified tetracyclines an emerging host modulator in chronic periodontitis patients: A randomized, double-blind, placebo-controlled, clinical trial. Microb Pathog 2017; 110:279-284. [PMID: 28687322 DOI: 10.1016/j.micpath.2017.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/29/2017] [Accepted: 07/03/2017] [Indexed: 01/28/2023]
Abstract
Although periodontal diseases are caused by some of the specific pathogens, most of the tissue damage is caused by the host reaction to disease and not actually by the infections. Therefore, host modulatory therapy (HMT) has advanced benefit for the treatment of periodontitis, which works basically by reducing tissue destruction and regeneration in periodontium by altering the critical aspects of host response regulation and up regulating defensive regenerative responses. The present study was conducted with the goal to test an innovative therapeutic option using chemically modified tetracycline in patients affected with generalized, moderate and severe chronic periodontitis. We assumed that CMT might have the potential to provoke an assessable clinical result and pharmacologically impede the level inflammatory flow. CMT (incyclinide) treated group had significantly higher CAL (clinical attachment) values than Placebo Control suggesting an improved CAL in CMT treatment. Host modulation therapy width incyclinide can be as an adjunct to conventional nonsurgical therapies without antimicrobial resistance. Progress was noticed in the clinical parameters but not the serum CRP level in our study establishing the role of CMTs in controlling chronic periodontitis. Also CMT treatment indicates its role in anti-inflammatory process as it inhibited IL-12 and TNF alpha but IL-10 level was not affected. However, more randomized placebo-controlled clinical trials with large sample size are required in order to authenticate the usage of CMTs in chronic periodontitis treatment. Based on this understanding, exploration of the novel, low-cost synthetic inhibitors that can be used as potential therapeutic agents, has been tested.
Collapse
Affiliation(s)
- Abdullah A Alyousef
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, PO Box 10219, Riyadh, 11433, Saudi Arabia
| | - Darshan Devang Divakar
- Dental Biomaterials Research Chair, Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh, 11433, Saudi Arabia.
| | - Muzaheed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, PO Box 2435, University of Dammam, Dammam, 31441, Saudi Arabia
| |
Collapse
|
|
18
|
Paiva KBS, Granjeiro JM. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 148:203-303. [PMID: 28662823 DOI: 10.1016/bs.pmbts.2017.05.001] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering.
Collapse
Affiliation(s)
- Katiucia B S Paiva
- Laboratory of Extracellular Matrix Biology and Cellular Interaction (LabMec), Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
| | - José M Granjeiro
- National Institute of Metrology, Quality and Technology (InMetro), Bioengineering Laboratory, Duque de Caxias, RJ, Brazil; Fluminense Federal University, Dental School, Niterói, RJ, Brazil
| |
Collapse
|
|
19
|
Silva T, Grenho L, Barros J, Silva JC, Pinto RV, Matos A, Colaço B, Fernandes MH, Bettencourt A, Gomes PS. A minocycline-releasing PMMA system as a space maintainer for staged bone reconstructions-in vitro antibacterial, cytocompatibility and anti-inflammatory characterization. ACTA ACUST UNITED AC 2017; 12:035009. [PMID: 28333042 DOI: 10.1088/1748-605x/aa68b8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the present work, we study the development and biological characterization of a polymethyl methacrylate (PMMA)-based minocycline delivery system, to be used as a space maintainer within craniofacial staged regenerative interventions. The developed delivery systems were characterized regarding solid state characteristics and assayed in vitro for antibacterial and anti-inflammatory activity, and cytocompatibility with human bone cells. A drug release profile allowed for an initial burst release and a more sustained and controlled release over time, with minimum inhibitory concentrations for the assayed and relevant pathogenic bacteria (i.e., Staphylococcus aureus, slime-producer Staphylococcus epidermidis and Escherichia coli) being easily attained in the early time points, and sustained up to 72 h. Furthermore, an improved osteoblastic cell response-with enhancement of cell adhesion and cell proliferation-and increased anti-inflammatory activity were verified in developed systems, compared to a control (non minocycline-loaded PMMA cement). The obtained results converge to support the possible efficacy of the developed PMMA-based minocycline delivery systems for the clinical management of complex craniofacial trauma. Here, biomaterials with space maintenance properties are necessary for the management of staged reconstructive approaches, thus minimizing the risk of peri-operative infections and enhancing the local tissue healing and early stages of regeneration.
Collapse
Affiliation(s)
- Tiago Silva
- Laboratory for Bone Metabolism and Regeneration-Faculty of Dental Medicine, U. Porto-Porto, Portugal
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Carbone EJ, Rajpura K, Allen BN, Cheng E, Ulery BD, Lo KWH. Osteotropic nanoscale drug delivery systems based on small molecule bone-targeting moieties. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 13:37-47. [PMID: 27562211 DOI: 10.1016/j.nano.2016.08.015] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 08/02/2016] [Accepted: 08/05/2016] [Indexed: 12/22/2022]
Abstract
Bone-targeted drug delivery is an active research area because successful clinical applications of this technology can significantly advance the treatment of bone injuries and disorders. Molecules with bone-targeting potential have been actively investigated as promising moieties in targeted drug delivery systems. In general, bone-targeting molecules are characterized by their high affinity for bone and their predisposition to persist in bone tissue for prolonged periods, while maintaining low systemic concentrations. Proteins, such as monoclonal antibodies, have shown promise as bone-targeting molecules; however, they suffer from several limitations including large molecular size, high production cost, and undesirable immune responses. A viable alternative associated with significantly less side effects is the use of small molecule-based targeting moieties. This review provides a summary of recent findings regarding small molecule compounds with bone-targeting capacity, as well as nanoscale targeted drug delivery approaches employing these molecules.
Collapse
Affiliation(s)
- Erica J Carbone
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; UConn Stem Cell Institute, University of Connecticut Health Center, Farmington, CT, USA
| | - Komal Rajpura
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; Connecticut Institute for Clinical and Translational Science, University of Connecticut Health Center, Farmington, CT, USA
| | - Brittany N Allen
- Department of Bioengineering, University of Missouri, Columbia, MO, USA
| | - Emily Cheng
- Department of Chemical Engineering, University of Missouri, Columbia, MO, USA
| | - Bret D Ulery
- Department of Chemical Engineering, University of Missouri, Columbia, MO, USA
| | - Kevin W-H Lo
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, School of Medicine, Farmington, CT, USA; UConn Stem Cell Institute, University of Connecticut Health Center, Farmington, CT, USA; Department of Biomedical Engineering, University of Connecticut, School of Engineering, Storrs, CT, USA; Connecticut Institute for Clinical and Translational Science, University of Connecticut Health Center, Farmington, CT, USA.
| |
Collapse
|
|
21
|
Golub LM, Elburki MS, Walker C, Ryan M, Sorsa T, Tenenbaum H, Goldberg M, Wolff M, Gu Y. Non-antibacterial tetracycline formulations: host-modulators in the treatment of periodontitis and relevant systemic diseases. Int Dent J 2016; 66:127-35. [PMID: 27009489 PMCID: PMC9376645 DOI: 10.1111/idj.12221] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Traditionally, the dental profession has primarily treated periodontitis using a mechanical/surgical, rather than a pharmaceutical, approach. However, based on experiments several decades ago which demonstrated that tetracyclines, unexpectedly, inhibit collagen- and bone-destructive mammalian-derived enzymes (e.g. the collagenases), and through non-antibiotic mechanisms, the concept of host-modulation therapy (HMT) was developed. Accordingly, two drug-development strategies evolved: (i) the development of non-antimicrobial formulations of doxycycline; and (ii) the chemical modification of tetracyclines to eliminate their antibiotic activity but retain (or even enhance) their anti-collagenase properties. Regarding the latter, these chemically modified tetracyclines (CMTs) showed efficacy in vitro, in animal models of periodontal (and relevant systemic) disease, and in preliminary clinical trials on patients with Kaposi's sarcoma (however, at the high doses used, photosensitivity was a significant side-effect). In the first strategy, subantimicrobial-dose doxycycline (SDD) demonstrated safety and efficacy in human clinical trials and was approved by the U S Food and Drug Administration (U S FDA) and in other countries for the treatment of periodontitis (20 mg, twice daily, i.e. once every 12 hours) adjunctive to scaling and root planing, and for chronic inflammatory skin diseases (40-mg sustained-release 'beads'). SDD also showed efficacy in patients with systemic diseases relevant to periodontitis, including diabetes mellitus and arthritis, and in postmenopausal women with local and systemic bone loss. Importantly, long-term administration of SDD, of up to 2 years, in clinical trials did not produce antibiotic side-effects. SDD (and in the future, new HMTs, such as low-dose CMT-3, resolvins and chemically modified curcumins) may shift the paradigm of periodontal therapy from a predominantly surgical approach to the greater use of medicinal/pharmacologic strategies, ultimately to benefit larger numbers of patients.
Collapse
Affiliation(s)
- Lorne M. Golub
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Muna S. Elburki
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
- Department of Periodontics, Faculty of Dentistry, Benghazi University, Benghazi, Libya
| | - Clay Walker
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA
| | - Maria Ryan
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Timo Sorsa
- Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Institute of Dentistry, University of Helsinki, Helsinki, Finland
- Division of Periodontology, Department of Dental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Howard Tenenbaum
- Department of Periodontics, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
- Department of Periodontology, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael Goldberg
- Department of Periodontics, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Mark Wolff
- Department of Cariology and Comprehensive Care, College of Dentistry, New York University, New York City, NY, USA
| | - Ying Gu
- Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| |
Collapse
|
|
22
|
Elburki MS, Moore DD, Terezakis NG, Zhang Y, Lee HM, Johnson F, Golub LM. A novel chemically modified curcumin reduces inflammation-mediated connective tissue breakdown in a rat model of diabetes: periodontal and systemic effects. J Periodontal Res 2016; 52:186-200. [PMID: 27038334 DOI: 10.1111/jre.12381] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2016] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND OBJECTIVE Periodontal disease is the most common chronic inflammatory disease known to mankind (and the major cause of tooth loss in the adult population) and has also been linked to various systemic diseases, particularly diabetes mellitus. Based on the literature linking periodontal disease with diabetes in a "bidirectional manner", the objectives of the current study were to determine: (i) the effect of a model of periodontitis, complicated by diabetes, on mechanisms of tissue breakdown including bone loss; and (ii) the response of the combination of this local and systemic phenotype to a novel pleiotropic matrix metalloproteinase inhibitor, chemically modified curcumin (CMC) 2.24. MATERIAL AND METHODS Diabetes was induced in adult male rats by intravenous injection of streptozotocin (nondiabetic rats served as controls), and Escherichia coli endotoxin (lipopolysaccharide) was repeatedly injected into the gingiva to induce periodontitis. CMC 2.24 was administered by oral gavage (30 mg/kg) daily; untreated diabetic rats received vehicle alone. After 3 wk of treatment, the rats were killed, and gingiva, jaws, tibia and skin were collected. The maxillary jaws and tibia were dissected and radiographed. The gingival tissues of each experimental group (n = 6 rats/group) were pooled, extracted, partially purified and, together with individual skin samples, analyzed for matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography; MMP-8 was analyzed in gingival and skin tissue extracts, and in serum, by western blotting. The levels of three bone-resorptive cytokines [interleukin (IL)-1β, IL-6 and tumor necrosis factor-α], were measured in gingival tissue extracts and serum by ELISA. RESULTS Systemic administration of CMC 2.24 to diabetic rats with endotoxin-induced periodontitis significantly inhibited alveolar bone loss and attenuated the severity of local and systemic inflammation. Moreover, this novel tri-ketonic phenylaminocarbonyl curcumin (CMC 2.24) appeared to reduce the pathologically excessive levels of inducible MMPs to near-normal levels, but appeared to have no significant effect on the constitutive MMPs required for physiologic connective tissue turnover. In addition to the beneficial effects on periodontal disease, induced both locally and systemically, CMC 2.24 also favorably affected extra-oral connective tissues, skin and skeletal bone. CONCLUSION This study supports our hypothesis that CMC 2.24 is a potential therapeutic pleiotropic MMP inhibitor, with both intracellular and extracellular effects, which reduces local and systemic inflammation and prevents hyperglycemia- and bacteria-induced connective tissue destruction.
Collapse
Affiliation(s)
- M S Elburki
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA.,Department of Periodontics, Faculty of Dentistry, Benghazi University, Benghazi, Libya
| | - D D Moore
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| | - N G Terezakis
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Y Zhang
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| | - H-M Lee
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| | - F Johnson
- Departments of Chemistry and Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA
| | - L M Golub
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
| |
Collapse
|
|
23
|
Naghsh N, Razavi SM, Minaiyan M, Shahabooei M, Birang R, Behfarnia P, Hajisadeghi S. Evaluation of the effects of two different bone resorption inhibitors on osteoclast numbers and activity: An animal study. Dent Res J (Isfahan) 2016; 13:500-507. [PMID: 28182072 PMCID: PMC5256013 DOI: 10.4103/1735-3327.197034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Background: The aim of this study was to evaluate the effects of bone resorption inhibitors, doxycycline (DOX) and erythromycin (EM), on osseous wound healing in rat alveolar socket. Materials and Methods: In this randomized controlled trial, 45 8–10-week-old male Wistar rats had their maxillary right molar extracted. They were divided into three groups of 15. In Group 1 normal saline, Group 2 DOX, and Group 3 EM were administered at the doses of 5 ml/kg/day, 5 mg/kg/day, and 2 mg/kg/day, respectively, for 7 consecutive days. The rats were sacrificed 7, 14, and 21 days after surgery. Real-time polymerase chain reaction was employed to evaluate the mRNA expression of receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) and immunohistochemical staining for tartrate-resistant acid phosphatase (TRAP) to determine osteoclasts. The data were analyzed by one-way analysis of variance followed by Tukey's post hoc test using SPSS version 20. Significant level was set at 0.05. Results: The results showed that when drug-treated groups compared to control groups, RANKL gene expression significantly decreased, TRAP+ cells decreased on day 7. The RANKL/OPG ratios in the first two weeks in the test groups were significantly lower than the control group. There was no significant difference in the studied indices between DOX and EM groups. Conclusion: Following administration of DOX and EM, the number of osteoclasts and RANKL/OPG ratio decreased suggesting their anti-osteoclastogenesis activity. These two drugs have no advantage over each other in increasing the bone formation.
Collapse
Affiliation(s)
- Narges Naghsh
- Department of Periodontology, Dental Implants Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sayed Mohammad Razavi
- Department of Oral and Maxillofacial Pathology, Dental Implants Research Center, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohsen Minaiyan
- Department of Pharmacology, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Shahabooei
- Department of Periodontology, Dental Implants Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Birang
- Department of Periodontology, Dental Research Center, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parichehr Behfarnia
- Department of Periodontology, Dental Implants Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samira Hajisadeghi
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Qom University of Medical Sciences, Qom, Iran
| |
Collapse
|
|
24
|
Abstract
Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.
Collapse
|
|
25
|
Rossi F, Bellini G, Tortora C, Bernardo ME, Luongo L, Conforti A, Starc N, Manzo I, Nobili B, Locatelli F, Maione S. CB(2) and TRPV(1) receptors oppositely modulate in vitro human osteoblast activity. Pharmacol Res 2015; 99:194-201. [PMID: 26117426 DOI: 10.1016/j.phrs.2015.06.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 06/20/2015] [Accepted: 06/20/2015] [Indexed: 01/15/2023]
Abstract
In the current study, we have investigated the effect of CB2 and TRPV1 receptor ligands on in vitro osteoblasts from bone marrow of human healthy donors. A pivotal role for the endocannabinoid/endovanilloid system in bone metabolism has been highlighted. We have demonstrated a functional cross-talk between CB2 and TRPV1 in human osteoclasts, suggesting these receptors as new pharmacological target for the treatment of bone resorption disease as osteoporosis. Moreover, we have shown the presence of these receptors on human mesenchimal stem cells, hMSCs. Osteoblasts are mononucleated cells originated from hMSCs by the essential transcription factor runt-related transcription factor 2 and involved in bone formation via the synthesis and release of macrophage colony-stimulating factor, receptor activator of nuclear factor kappa-B ligand and osteoprotegerin. For the first time, we show that CB2 and TRPV1 receptors are both expressed on human osteoblasts together with enzymes synthesizing and degrading endocannabinoids/endovanilloids, and oppositely modulate human osteoblast activity in culture in a way that the CB2 receptor stimulation improves the osteogenesis whereas TRPV1 receptor stimulation inhibits it.
Collapse
Affiliation(s)
- Francesca Rossi
- Department of Woman, Child and of General and Specialist Surgery, Second University of Naples, Naples, Italy.
| | - Giulia Bellini
- Department of Experimental Medicine, Pharmacology Division, The Second University of Naples, Italy
| | - Chiara Tortora
- Department of Experimental Medicine, Pharmacology Division, The Second University of Naples, Italy
| | - Maria Ester Bernardo
- Department of Onco-Haematology, IRCCS "Bambino Gesù" Children Hospital, Rome, Italy
| | - Livio Luongo
- Department of Experimental Medicine, Pharmacology Division, The Second University of Naples, Italy
| | - Antonella Conforti
- Department of Onco-Haematology, IRCCS "Bambino Gesù" Children Hospital, Rome, Italy
| | - Nadia Starc
- Department of Onco-Haematology, IRCCS "Bambino Gesù" Children Hospital, Rome, Italy
| | - Iolanda Manzo
- Department of Woman, Child and of General and Specialist Surgery, Second University of Naples, Naples, Italy
| | - Bruno Nobili
- Department of Woman, Child and of General and Specialist Surgery, Second University of Naples, Naples, Italy
| | - Franco Locatelli
- Department of Onco-Haematology, IRCCS "Bambino Gesù" Children Hospital, Rome, Italy
| | - Sabatino Maione
- Department of Experimental Medicine, Pharmacology Division, The Second University of Naples, Italy
| |
Collapse
|
|
26
|
Fowlkes JL, Nyman JS, Bunn RC, Cockrell GE, Wahl EC, Rettiganti MR, Lumpkin CK, Thrailkill KM. Effects of long-term doxycycline on bone quality and strength in diabetic male DBA/2J mice. Bone Rep 2015; 1:16-19. [PMID: 25685827 PMCID: PMC4324548 DOI: 10.1016/j.bonr.2014.10.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 09/15/2014] [Accepted: 10/15/2014] [Indexed: 11/30/2022] Open
Abstract
In type 1 diabetes, diabetic bone disease (DBD) is characterized by decreased bone mineral density, a state of low bone turnover and an increased risk of fracture. Animal models of DBD demonstrate that acquired alterations in trabecular and cortical bone microarchitecture contribute to decreased bone strength in diabetes. With anti-collagenolytic and anti-inflammatory properties, tetracycline derivatives may prevent diabetes-related decreases in bone strength. To determine if doxycycline, a tetracycline class antibiotic, can prevent the development of DBD in a model of long-term diabetes, male DBA/2J mice, with or without diabetes, were treated with doxycycline-containing chow for 10 weeks (dose range, 28-92 mg/kg/day). Long-term doxycycline exposure was not deleterious to the microarchitecture or biomechanical properties of healthy bone in male DBA/2J mice. Doxycycline treatment also did not prevent or alleviate the deleterious changes in trabecular microarchitecture, cortical structure, and biomechanical properties of bone induced by chronic diabetes.
Collapse
Affiliation(s)
- John L. Fowlkes
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
| | - Jeffry S. Nyman
- VA Tennessee Valley Health Care System, Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - R. Clay Bunn
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
| | - Gael E. Cockrell
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
| | - Elizabeth C. Wahl
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
| | - Mallikarjuna R. Rettiganti
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
| | - Charles K. Lumpkin
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
| | - Kathryn M. Thrailkill
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA
| |
Collapse
|
|
27
|
Bhansali RS. Non-surgical periodontal therapy: An update on current evidence. World J Stomatol 2014; 3:38-51. [DOI: 10.5321/wjs.v3.i4.38] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 11/06/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Periodontal disease is an inflammatory condition that involves a complex interaction between pathogenic bacteria, environmental and acquired factors and host related factors. Till recently periodontal treatment was directed primarily towards reduction of bacterial load by subgingival debridement of root surfaces and modification of environmental risk factors. The current paradigm of periodontal disease stresses greater role of host-mediated inflammatory response in tissue destruction characteristic of periodontal disease. Various therapeutic modalities have been developed adjuvant to mechanical periodontal therapy. The use of laser and photodynamic therapy show great promise but their effectiveness has still not been conclusively proven. Chemotherapeutic agents, either systemic and local antimicrobials or host modulating drugs, played pivotal role in better and more predictable management of periodontal disease. The present review focuses on the best available evidence, for the current management of the chronic periodontal patients, gathered from systematic reviews and meta-analysis of mechanical non surgical periodontal therapy (NSPT) (subgingival debridement, laser therapy and photodynamic therapy) and the adjunctive chemotherapeutic approaches such as systematic and local antibiotics and antiseptics, subgingival pocket irrigation and host modulation therapies. The review also attempts to briefly introduce future developments in some of these modalities. At the end, the review summarizes the analysis of the current evidence that suggests that thorough subgingival debridement remains the mainstay of NSPT and that adjunct use of chemotherapeutic agents may offer better management of clinical parameters in periodontitis patients.
Collapse
|
|
28
|
A novel chemically modified curcumin reduces severity of experimental periodontal disease in rats: initial observations. Mediators Inflamm 2014; 2014:959471. [PMID: 25104884 PMCID: PMC4101223 DOI: 10.1155/2014/959471] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 05/01/2014] [Accepted: 05/19/2014] [Indexed: 12/24/2022] Open
Abstract
Tetracycline-based matrix metalloproteinase- (MMP-) inhibitors are currently approved for two inflammatory diseases, periodontitis and rosacea. The current study addresses the therapeutic potential of a novel pleiotropic MMP-inhibitor not based on an antibiotic. To induce experimental periodontitis, endotoxin (LPS) was repeatedly injected into the gingiva of rats on one side of the maxilla; the contralateral (control) side received saline injections. Two groups of rats were treated by daily oral intubation with a chemically modified curcumin, CMC 2.24, for two weeks; the control groups received vehicle alone. After sacrifice, gingiva, blood, and maxilla were collected, the jaws were defleshed, and periodontal (alveolar) bone loss was quantified morphometrically and by μ-CT scan. The gingivae were pooled per experimental group, extracted, and analyzed for MMPs (gelatin zymography; western blot) and for cytokines (e.g., IL-1β; ELISA); serum and plasma samples were analyzed for cytokines and MMP-8. The LPS-induced pathologically excessive bone loss was reduced to normal levels based on either morphometric (P = 0.003) or μ-CT (P = 0.008) analysis. A similar response was seen for MMPs and cytokines in the gingiva and blood. This initial study, on a novel triketonic zinc-binding CMC, indicates potential efficacy on inflammatory mediators and alveolar bone loss in experimental periodontitis and warrants future therapeutic and pharmacokinetic investigations.
Collapse
|
|
29
|
Sun H, Kim JK, Mortensen R, Mutyaba LP, Hankenson KD, Krebsbach PH. Osteoblast-targeted suppression of PPARγ increases osteogenesis through activation of mTOR signaling. Stem Cells 2014; 31:2183-92. [PMID: 23766271 DOI: 10.1002/stem.1455] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 05/03/2013] [Accepted: 05/21/2013] [Indexed: 01/21/2023]
Abstract
Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is an essential transcription factor for adipocyte differentiation. In mesenchymal stem cells, PPARγ has been assumed to play a negative role in osteoblastic differentiation, by working in an adipogenesis dependent manner, due to the reciprocal relationship between osteoblast and adipocyte differentiation. However, the direct role of PPARγ in osteoblast function is not fully understood, due in part to inadequate model systems. Here, we describe an adenoviral-mediated PPARγ knockout system in which suppression of PPARγ in mesenchymal stem cells enhanced osteoblast differentiation and inhibited adipogenesis in vitro. Consistent with this in vitro observation, lipoatrophic A-ZIP/F1 mice, which do not form adipocytes, displayed a phenotype in which both cortical and trabecular bone was significantly increased compared with wild-type mice. We next developed an inducible osteoblast-targeted PPARγ knockout (Osx Cre/flox- PPARγ) mouse to determine the direct role of PPARγ in bone formation. Data from both in vitro cultures of mesenchymal stem cells and in vivo µCT analysis of bones suggest that suppression of PPARγ activity in osteoblasts significantly increased osteoblast differentiation and trabecular number. Endogenous PPARγ in mesenchymal stem cells and osteoblasts strongly inhibited Akt/mammalian target of rapamycin (mTOR)/p70S6k activity and led to decreased osteoblastic differentiation. Therefore, we conclude that PPARγ modulates osteoblast differentiation and bone formation through both direct and indirect mechanisms. The direct mode, as shown here, involves PPARγ regulation of the mTOR pathway, while the indirect pathway is dependent on the regulation of adipogenesis.
Collapse
Affiliation(s)
- Hongli Sun
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
| | | | | | | | | | | |
Collapse
|
|
30
|
Tilakaratne A, Soory M. Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities. Open Dent J 2014; 8:109-24. [PMID: 24976875 PMCID: PMC4073587 DOI: 10.2174/1874210601408010109] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 04/08/2014] [Accepted: 05/12/2014] [Indexed: 02/08/2023] Open
Abstract
The non-antimicrobial properties of tetracyclines such as anti-inflammatory, proanabolic and anti-catabolic actions make them effective pharmaceuticals for the adjunctive management of chronic inflammatory diseases. An over-exuberant inflammatory response to an antigenic trigger in periodontitis and other chronic inflammatory diseases could contribute to an autoimmune element in disease progression. Their adjunctive use in managing periodontitis could have beneficial effects in curbing excessive inflammatory loading from commonly associated comorbidities such as CHD, DM and arthritis. Actions of tetracyclines and their derivatives include interactions with MMPs, tissue inhibitors of MMPs, growth factors and cytokines. They affect the sequence of inflammation with implications on immunomodulation, cell proliferation and angiogenesis; these actions enhance their scope, in treating a range of disease entities. Non-antimicrobial chemically modified tetracyclines (CMTs) sustain their diverse actions in organ systems which include anti-inflammatory, anti-apoptotic, anti-proteolytic actions, inhibition of angiogenesis and tumor metastasis. A spectrum of biological actions in dermatitis, periodontitis, atherosclerosis, diabetes, arthritis, inflammatory bowel disease, malignancy and prevention of bone resorption is particularly relevant to minocycline. Experimental models of ischemia indicate their specific beneficial effects. Parallel molecules with similar functions, improved Zn binding and solubility have been developed for reducing excessive MMP activity. Curbing excessive MMP activity is particularly relevant to periodontitis, and comorbidities addressed here, where specificity is paramount. Unique actions of tetracyclines in a milieu of excessive inflammatory stimuli make them effective therapeutic adjuncts in the management of chronic inflammatory disorders. These beneficial actions of tetracyclines are relevant to the adjunctive management of periodontitis subjects presenting with commonly prevalent comorbidities addressed here.
Collapse
Affiliation(s)
- Aruni Tilakaratne
- Department of Oral Medicine and Periodontology, Faculty of Dental Science, University of Peradeniya, Sri-Lanka
| | - Mena Soory
- Periodontology King's College London Dental Institute, Denmark Hill, London SE5 9RW, UKB
| |
Collapse
|
|
31
|
Madhumathi K, Sampath Kumar TS. Regenerative potential and anti-bacterial activity of tetracycline loaded apatitic nanocarriers for the treatment of periodontitis. Biomed Mater 2014; 9:035002. [DOI: 10.1088/1748-6041/9/3/035002] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
|
|
32
|
Abstract
Biological functions of antibiotics are not limited to killing. The most likely function of antibiotics in natural microbial ecosystems is signaling. Does this signaling function of antibiotics also extend to the eukaryotic – in particular mammalian – cells? In this review, the host modulating properties of three classes of antibiotics (macrolides, tetracyclines, and β-lactams) will be briefly discussed. Antibiotics can be effective in treatment of a broad spectrum of diseases and pathological conditions other than those of infectious etiology and, in this capacity, may find widespread applications beyond the intended antimicrobial use. This use, however, should not compromise the primary function antibiotics are used for. The biological background for this inter-kingdom signaling is also discussed.
Collapse
Affiliation(s)
- Rustam I Aminov
- Faculty of Medical Sciences, University of the West Indies Kingston, Jamaica
| |
Collapse
|
|
33
|
Periodontal disease: linking the primary inflammation to bone loss. Clin Dev Immunol 2013; 2013:503754. [PMID: 23762091 PMCID: PMC3676984 DOI: 10.1155/2013/503754] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 05/06/2013] [Indexed: 01/22/2023]
Abstract
Periodontal disease (PD), or periodontitis, is defined as a bacterially induced disease of the tooth-supporting (periodontal) tissues. It is characterized by inflammation and bone loss; therefore understanding how they are linked would help to address the most efficacious therapeutic approach. Bacterial infection is the primary etiology but is not sufficient to induce the disease initiation or progression. Indeed, bacteria-derived factors stimulate a local inflammatory reaction and activation of the innate immune system. The innate response involves the recognition of microbial components by host cells, and this event is mediated by toll-like receptors (TLRs) expressed by resident cells and leukocytes. Activation of these cells leads to the release of proinflammatory cytokines and recruitment of phagocytes and lymphocytes. Activation of T and B cells initiates the adaptive immunity with Th1 Th2 Th17 Treg response and antibodies production respectively. In this inflammatory scenario, cytokines involved in bone regulation and maintenance have considerable relevance because tissue destruction is believed to be the consequence of host inflammatory response to the bacterial challenge. In the present review, we summarize host factors including cell populations, cytokines, and mechanisms involved in the destruction of the supporting tissues of the tooth and discuss treatment perspectives based on this knowledge.
Collapse
|
|
34
|
Moreno Villagrana AP, Gómez Clavel JF. Antimicrobial or subantimicrobial antibiotic therapy as an adjunct to the nonsurgical periodontal treatment: a meta-analysis. ISRN DENTISTRY 2012; 2012:581207. [PMID: 23150830 PMCID: PMC3485543 DOI: 10.5402/2012/581207] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 07/24/2012] [Indexed: 12/02/2022]
Abstract
The use of antibiotics in nonsurgical periodontal treatment is indicated in cases in which scaling and root planing present important limitations. However, their use is controversial due to the secondary effects associated with them and the disagreements regarding their prescription. The aim of this study is to determine the effectiveness of systemic antibiotics in the management of aggressive and chronic periodontitis. The study was based on a search of randomized, controlled clinical trials. Common data were concentrated and evaluated by means of an analysis of variance (ANOVA), and a meta-analysis of the results was performed. The meta-analysis (P < 0.05, 95% confidence interval, post hoc Bonferroni) determined that the supplementation of nonsurgical periodontal therapy with a systemic antibiotic treatment—amoxicillin with clavulanic acid and metronidazole or subantimicrobial dose doxycycline—provides statistically significant results in patients with aggressive or chronic periodontitis under periodontal treatment, whilst increasing the clinical attachment level of the gingiva and reducing periodontal probing depth.
Collapse
|
|
35
|
Gu Y, Walker C, Ryan ME, Payne JB, Golub LM. Non-antibacterial tetracycline formulations: clinical applications in dentistry and medicine. J Oral Microbiol 2012; 4:19227. [PMID: 23071896 PMCID: PMC3471324 DOI: 10.3402/jom.v4i0.19227] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2012] [Revised: 09/06/2012] [Accepted: 09/11/2012] [Indexed: 12/22/2022] Open
Abstract
In 1983, it was first reported that tetracyclines (TCs) can modulate the host response, including (but not limited to) inhibition of pathologic matrix metalloproteinase (MMP) activity, and by mechanisms unrelated to the antibacterial properties of these drugs. Soon thereafter, strategies were developed to generate non-antibacterial formulations (subantimicrobial-dose doxycycline; SDD) and compositions (chemically modified tetracyclines; CMTs) of TCs as host-modulating drugs to treat periodontal and other inflammatory diseases. This review focuses on the history and rationale for the development of: (a) SDD which led to two government-approved medications, one for periodontitis and the other for acne/rosacea and (b) CMTs, which led to the identification of the active site of the drugs responsible for MMP inhibition and to studies demonstrating evidence of efficacy of the most potent of these, CMT-3, as an anti-angiogenesis agent in patients with the cancer, Kaposi's sarcoma, and as a potential treatment for a fatal lung disease (acute respiratory distress syndrome; ARDS). In addition, this review discusses a number of clinical studies, some up to 2 years' duration, demonstrating evidence of safety and efficacy of SDD formulations in humans with oral inflammatory diseases (periodontitis, pemphigoid) as well as medical diseases, including rheumatoid arthritis, post-menopausal osteopenia, type II diabetes, cardiovascular diseases, and a rare and fatal lung disease, lymphangioleiomyomatosis.
Collapse
Affiliation(s)
- Ying Gu
- Department of General Dentistry, School of Dental Medicine, Stony Brook Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Clay Walker
- Department of Oral Biology, School of Dental Medicine, University of Florida at Gainesville, Gainesville, FL, USA
| | - Maria E. Ryan
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Jeffrey B. Payne
- Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE, USA
| | - Lorne M. Golub
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook Medicine, Stony Brook University, Stony Brook, NY, USA
| |
Collapse
|
|
36
|
Local delivery of small and large biomolecules in craniomaxillofacial bone. Adv Drug Deliv Rev 2012; 64:1152-64. [PMID: 22429663 DOI: 10.1016/j.addr.2012.03.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 02/08/2012] [Accepted: 03/05/2012] [Indexed: 12/18/2022]
Abstract
Current state of the art reconstruction of bony defects in the craniomaxillofacial (CMF) area involves transplantation of autogenous or allogenous bone grafts. However, the inherent drawbacks of this approach strongly urge clinicians and researchers to explore alternative treatment options. Currently, a wide interest exists in local delivery of biomolecules from synthetic biomaterials for CMF bone regeneration, in which small biomolecules are rapidly emerging in recent years as an interesting adjunct for upgrading the clinical treatment of CMF bone regeneration under compromised healing conditions. This review highlights recent advances in the local delivery small and large biomolecules for the clinical treatment of CMF bone defects. Further, it provides a perspective on the efficacy of biomolecule delivery in CMF bone regeneration by reviewing presently available reports of pre-clinical studies using various animal models.
Collapse
|
|
37
|
Zhao Y, Su Y, Ye L. Slit-Robo: a potential way to treat periodontitis. Med Hypotheses 2012; 79:186-8. [PMID: 22595808 DOI: 10.1016/j.mehy.2012.04.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2011] [Accepted: 04/20/2012] [Indexed: 12/28/2022]
Abstract
Slit is a secreted protein known to function through the Roundabout (Robo) receptor. Slit has recently been shown to be an endogenously available inhibitor of leukocyte chemotaxis and as a chemoattractant to recruit vascular endothelial cells to sites for angiogenesis both in vivo and in vitro. The initiation and progression of periodontal diseases, is the result of complex interactions between the colonizing bacteria in the periodontal pockets and host immune and inflammatory responses. Antibiotics such as tetracyclines are commonly used in the management of periodontal infections and yet, have shown modest success in reducing neutrophil-mediated injury. Angiogenesis is important for the maintenance of homeostatus of periodontal tissues. However, few studies have been reported about angiogenesis targeted treatment for periodontitis. Based on its angiogenesis promoting effect and leukocyte chemotaxis inhibition effect, we hypothesize that Slit can be an effective immunotherapeutic agent in the treatment of periodontitis.
Collapse
Affiliation(s)
- Yuan Zhao
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | | | | |
Collapse
|
|
38
|
Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov 2012; 11:234-50. [PMID: 22378270 DOI: 10.1038/nrd3669] [Citation(s) in RCA: 617] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss. Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis). Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk. Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone.
Collapse
Affiliation(s)
- Kurt Redlich
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
| | | |
Collapse
|
|
39
|
78495111110.1038/nrd3669" />
|
|
40
|
Payne JB, Stoner JA, Lee HM, Nummikoski PV, Reinhardt RA, Golub LM. Serum bone biomarkers and oral/systemic bone loss in humans. J Dent Res 2011; 90:747-51. [PMID: 21422479 DOI: 10.1177/0022034511402993] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
UNLABELLED We recently reported that subantimicrobial-dose doxycycline (SDD) significantly reduced serum bone-resorption biomarkers in subgroups of post-menopausal women. We hypothesize that changes in serum bone biomarkers are associated not only with systemic bone mineral density (BMD) changes, but also with alveolar bone changes over time. One hundred twenty-eight eligible post-menopausal women with periodontitis and systemic osteopenia were randomly assigned to receive SDD or placebo tablets twice daily for two years, adjunctive to periodontal maintenance. Sera were analyzed for bone biomarkers. As expected, two-year changes in a serum bone biomarker were significantly associated with systemic BMD loss at the lumbar spine (osteocalcin, bone-turnover biomarker, p = 0.0002) and femoral neck (osteocalcin p = 0.0025). Two-year changes in serum osteocalcin and serum pyridinoline-crosslink fragment of type I collagen (ICTP; bone-resorption biomarker) were also significantly associated with alveolar bone density loss (p < 0.0001) and alveolar bone height loss (p = 0.0008), respectively. Thus, we have shown that serum bone biomarkers are associated with not only systemic BMD loss, but with alveolar bone loss as well. CLINICAL TRIAL REGISTRATION INFORMATION Protocol registered at ClinicalTrials.gov, NCT00066027.
Collapse
Affiliation(s)
- J B Payne
- Department of Surgical Specialties, University of Nebraska Medical Center College of Dentistry, Lincoln, NE 68583-0740, USA.
| | | | | | | | | | | |
Collapse
|