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Development (Cambridge, England) Apr 2022The mechanisms underlying bone development, repair and regeneration are reliant on the interplay and communication between osteoclasts and other surrounding cells.... (Review)
Review
The mechanisms underlying bone development, repair and regeneration are reliant on the interplay and communication between osteoclasts and other surrounding cells. Osteoclasts are multinucleated monocyte lineage cells with resorptive abilities, forming the bone marrow cavity during development. This marrow cavity, essential to hematopoiesis and osteoclast-osteoblast interactions, provides a setting to investigate the origin of osteoclasts and their multi-faceted roles. This Review examines recent developments in the embryonic understanding of osteoclast origin, as well as interactions within the immune environment to regulate normal and pathological bone development, homeostasis and repair.
Topics: Bone Development; Bone Resorption; Cell Differentiation; Homeostasis; Humans; Osteoclasts
PubMed: 35502779
DOI: 10.1242/dev.199908 -
Head & Face Medicine Nov 2022The evaluation of bone remodelling and dental root resorption can be performed by histological techniques or micro-computed tomography (micro-CT). The present study...
BACKGROUND
The evaluation of bone remodelling and dental root resorption can be performed by histological techniques or micro-computed tomography (micro-CT). The present study aimed to evaluate the relationship between these two procedures in the context of cleft repair in a rat model.
METHODS
The reconstructed maxillae and the orthodontically-moved first molar of 12 rats were analysed for correlations between the histological and radiological findings retrospectively. The alveolar cleft repairs were performed using bone autografts or (human) xenografts. Four weeks after the operation, the intervention of the first molar protraction was initiated and lasted for eight weeks. The newly formed bone and the root resorption lacunae were determined via histology. In the micro-CT analysis, the average change of bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness and trabecular separation of the jaw, as well as the volume of the root resorptions were determined. The Pearson correlation coefficient was applied to study the associations between groups.
RESULTS
Positive correlations were found only between the newly formed bone (histology) and BMD changes (micro-CT) in the autograft group (r = 0.812, 95% CI: 0.001 to 0.979, p = 0.05). The relationship of newly formed bone and BV/TV was similar but not statistically significant (r = 0.691, 95% CI: -0.274 to 0.963, p = 0.013). Regarding root resorption, no significant correlations were found.
CONCLUSIONS
Due to the lack of correlation between histological and radiological findings of bone remodelling and the development of root resorptions, both methods should be combined in this cleft model in rats for a comprehensive analysis.
Topics: Humans; Rats; Animals; Root Resorption; X-Ray Microtomography; Rodentia; Retrospective Studies; Bone Remodeling; Bone Density
PubMed: 36357936
DOI: 10.1186/s13005-022-00338-x -
World Journal of Orthopedics Jan 2016Calcific tendinitis within the rotator cuff tendon is a common shoulder disorder that should be differentiated from dystrophic calcification as the pathogenesis and... (Review)
Review
Calcific tendinitis within the rotator cuff tendon is a common shoulder disorder that should be differentiated from dystrophic calcification as the pathogenesis and natural history of both is totally different. Calcific tendinitis usually occurs in the fifth and sixth decades of life among sedentary workers. It is classified into formative and resorptive phases. The chronic formative phase results from transient hypoxia that is commonly associated with repeated microtrauma causing calcium deposition into the matrix vesicles within the chondrocytes forming bone foci that later coalesce. This phase may extend from 1 to 6 years, and is usually asymptomatic. The resorptive phase extends from 3 wk up to 6 mo with vascularization at the periphery of the calcium deposits causing macrophage and mononuclear giant cell infiltration, together with fibroblast formation leading to an aggressive inflammatory reaction with inflammatory cell accumulation, excessive edema and rise of the intra-tendineous pressure. This results in a severely painful shoulder. Radiological investigations confirm the diagnosis and suggest the phase of the condition and are used to follow its progression. Although routine conventional X-ray allows detection of the deposits, magnetic resonance imaging studies allow better evaluation of any coexisting pathology. Various methods of treatment have been suggested. The appropriate method should be individualized for each patient. Conservative treatment includes pain killers and physiotherapy, or "minimally invasive" techniques as needling or puncture and aspiration. It is almost always successful since the natural history of the condition ends with resorption of the deposits and complete relief of pain. Due to the intolerable pain of the acute and severely painful resorptive stage, the patient often demands any sort of operative intervention. In such case arthroscopic removal is the best option as complete removal of the deposits is unnecessary.
PubMed: 26807357
DOI: 10.5312/wjo.v7.i1.55 -
Journal of Mid-life Health Jul 2013Osteoporosis is a chronic disease of the osseous system characterized by decreased bone strength and increased fracture risk. It is due to an imbalance in the dynamic... (Review)
Review
Osteoporosis is a chronic disease of the osseous system characterized by decreased bone strength and increased fracture risk. It is due to an imbalance in the dynamic ongoing processes of bone formation and bone resorption. Currently available osteoporosis therapies like bisphosphonates, selective estrogen receptor modulators (SERMs), and denosumab are anti-resorptive agents. Parathyroid hormone analogs like teriparatide are the only anabolic agents currently approved for osteoporosis treatment. The side-effects and limited efficacy of the presently available therapies has encouraged extensive research into the pathophysiology of the disease and newer drug targets for its treatment. The novel anti-resorptive agents being developed are newer SERMs, osteoprotegerin, c-src (cellular-sarcoma) kinase inhibitors, αVβ3 integrin antagonists, cathepsin K inhibitors, chloride channel inhibitors, and nitrates. Upcoming anabolic agents include calcilytics, antibodies against sclerostin and Dickkopf-1, statins, matrix extracellular phosphoglycoprotein fragments activin inhibitiors, and endo-cannabinoid agonists. Many of these new drugs are still in development. This article provides an insight into the emerging drugs for the treatment of osteoporosis.
PubMed: 24672186
DOI: 10.4103/0976-7800.118991 -
International Journal of Oral Science Jan 2022Inflammation-associated proteinase functions are key determinants of inflammatory stromal tissues deconstruction. As a specialized inflammatory pathological process,...
Inflammation-associated proteinase functions are key determinants of inflammatory stromal tissues deconstruction. As a specialized inflammatory pathological process, dental internal resorption (IR) includes both soft and hard tissues deconstruction within the dentin-pulp complex, which has been one of the main reasons for inflammatory tooth loss. Mechanisms of inflammatory matrix degradation and tissue resorption in IR are largely unclear. In this study, we used a combination of Cre-loxP reporter, flow cytometry, cell transplantation, and enzyme activities assay to mechanistically investigate the role of regenerative cells, odontoblasts (ODs), in inflammatory mineral resorption and matrices degradation. We report that inflamed ODs have strong capabilities of matrix degradation and tissue resorption. Traditionally, ODs are regarded as hard-tissue regenerative cells; however, our data unexpectedly present ODs as a crucial population that participates in IR-associated tissue deconstruction. Specifically, we uncovered that nuclear factor-kappa b (NF-κB) signaling orchestrated Tumor necrosis factor α (TNF-α)-induced matrix metalloproteinases (Mmps) and Cathepsin K (Ctsk) functions in ODs to enhance matrix degradation and tissue resorption. Furthermore, TNF-α increases Rankl/Opg ratio in ODs via NF-κB signaling by impairing Opg expression but increasing Rankl level, which utterly makes ODs cell line 17IIA11 (A11) become Trap and Ctsk multinucleated cells to perform resorptive actions. Blocking of NF-κB signaling significantly rescues matrix degradation and resorptive functions of inflamed ODs via repressing vital inflammatory proteinases Mmps and Ctsk. Utterly, via utilizing NF-κB specific small molecule inhibitors we satisfactorily attenuated inflammatory ODs-associated human dental IR in vivo. Our data reveal the underlying mechanisms of inflammatory matrix degradation and resorption via proteinase activities in IR-related pathological conditions.
Topics: Humans; Matrix Metalloproteinases; Minerals; NF-kappa B; Odontoblasts; Osteoclasts; RANK Ligand; Tumor Necrosis Factor-alpha
PubMed: 35082271
DOI: 10.1038/s41368-022-00159-3 -
International Journal of Molecular... Apr 2021Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican...
Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.
Topics: Animals; Apoptosis; Bone Resorption; Cell Differentiation; Cell Fusion; Cell Movement; Cells, Cultured; Dose-Response Relationship, Drug; Lumican; Macrophage Colony-Stimulating Factor; Macrophages; Mice; Mice, Inbred ICR; Osteoclasts; Osteogenesis; Osteoprotegerin; Proto-Oncogene Proteins c-akt; RANK Ligand; Recombinant Proteins; Signal Transduction
PubMed: 33946862
DOI: 10.3390/ijms22094717 -
Orthodontics & Craniofacial Research Nov 2023Pathological dental root resorption and alveolar bone loss are often detected only after irreversible damage. Biomarkers in the gingival crevicular fluid or saliva could...
AIMS
Pathological dental root resorption and alveolar bone loss are often detected only after irreversible damage. Biomarkers in the gingival crevicular fluid or saliva could provide a means for early detection; however, such biomarkers have proven elusive. We hypothesize that a multiomic approach might yield reliable diagnostic signatures for root resorption and alveolar bone loss. Previously, we showed that extracellular vesicles (EVs) from osteoclasts and odontoclasts differ in their protein composition. In this study, we investigated the metabolome of EVs from osteoclasts, odontoclasts and clasts (non-resorbing clastic cells).
MATERIALS AND METHODS
Mouse haematopoietic precursors were cultured on dentine, bone or plastic, in the presence of recombinant RANKL and CSF-1 to trigger differentiation along the clastic line. On Day 7, the cells were fixed and the differentiation state and resorptive status of the clastic cells were confirmed. EVs were isolated from the conditioned media on Day 7 and characterized by nanoparticle tracking and electron microscopy to ensure quality. Global metabolomic profiling was performed using a Thermo Q-Exactive Orbitrap mass spectrometer with a Dionex UHPLC and autosampler.
RESULTS
We identified 978 metabolites in clastic EVs. Of those, 79 are potential biomarkers with Variable Interdependent Parameters scores of 2 or greater. Known metabolites cytidine, isocytosine, thymine, succinate and citrulline were found at statistically higher levels in EVs from odontoclasts compared with osteoclasts.
CONCLUSION
We conclude that numerous metabolites found in odontoclast EVs differ from those in osteoclast EVs, and thus represent potential biomarkers for root resorption and periodontal tissue destruction.
Topics: Mice; Animals; Osteoclasts; Root Resorption; Alveolar Bone Loss; Extracellular Vesicles; Biomarkers
PubMed: 36997279
DOI: 10.1111/ocr.12658 -
Journal of Musculoskeletal & Neuronal... 2008The strength and integrity of the human skeleton depends on a delicate equilibrium between bone resorption by osteoclasts and bone formation by osteoblasts. This... (Review)
Review
The strength and integrity of the human skeleton depends on a delicate equilibrium between bone resorption by osteoclasts and bone formation by osteoblasts. This equilibrium is continuously compromised by a variety of genetic, humoral, and mechanical alterations. In osteoporosis, this balance shifts in favor of osteoclasts, and bone resorption exceeds bone formation. More detailed knowledge of the biology of osteoclasts and osteoclastogenesis has shown that the involved procedures can provide opportunities for developing therapeutic agents. Osteoclastogenesis is a multi-complex procedure that includes many stages, and each one of them presents as a potential target for therapeutic intervention, except for the stage of commitment of pre-osteoclasts,at least for the time being. Because the osteoclast is derived from the pluripotent hematopoietic stem cell, any intervention in this stage could result in serious adverse effects from the hematopoietic system. On the contrary, intervention in the later stages of differentiation, multi-nucleation, and activation, has proved to be very promising in the development of novel potent anti-resorptive agents. In the present review we summarized the current knowledge related to osteoclast differentiation and the new developing targets of pharmacological intervention in each stage of this extremely complicated and not completely elucidated process.
Topics: Animals; Bone Density Conservation Agents; Bone Resorption; Cell Differentiation; Cell Nucleus; Humans; Macrophage Colony-Stimulating Factor; Osteoclasts; Osteogenesis; Osteoporosis; Physiology; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Transcription Factors
PubMed: 18799853
DOI: No ID Found -
The Bone & Joint Journal Feb 2016The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in... (Review)
Review
UNLABELLED
The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in the form of osteoporotic fractures and metastatic bone disease. In recent years there has been an increasing understanding of the pathways involved in bone metabolism relevant to osteoporosis and metastases in bone. Newer therapies may aid the management of these problems. One group of drugs, the antibody mediated anti-resorptive therapies (AMARTs) use antibodies to block bone resorption pathways. This review seeks to present a synopsis of the guidelines, pharmacology and potential pathophysiology of AMARTs and other new anti-resorptive drugs. We evaluate the literature relating to AMARTs and new anti-resorptives with special attention on those approved for use in clinical practice. Denosumab, a monoclonal antibody against Receptor Activator for Nuclear Factor Kappa-B Ligand. It is the first AMART approved by the National Institute for Health and Clinical Excellence and the US Food and Drug Administration. Other novel anti-resorptives awaiting approval for clinical use include Odanacatib. Denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases. Recent evidence suggests, however, that denosumab may have an adverse event profile similar to bisphosphonates, including atypical femoral fractures. It is, therefore, essential that orthopaedic surgeons are conversant with these medications and their safe usage.
TAKE HOME MESSAGE
Denosumab has important orthopaedic indications and has been shown to significantly reduce patient morbidity in osteoporosis and metastatic bone disease.
Topics: Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal, Humanized; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone Neoplasms; Bone Resorption; Cost-Benefit Analysis; Denosumab; Diphosphonates; Drug Approval; Femoral Fractures; Genetic Markers; Humans; Hypocalcemia; Osteoporosis; Osteoporotic Fractures; Practice Guidelines as Topic; Quality-Adjusted Life Years; RANK Ligand
PubMed: 26850419
DOI: 10.1302/0301-620X.98B2.36161 -
Bone Reports Jun 2023The bone resorbing osteoclasts are a complex type of cell essential for bone remodeling. There is no consensus on medium composition and seeding density for...
The bone resorbing osteoclasts are a complex type of cell essential for bone remodeling. There is no consensus on medium composition and seeding density for osteoclastogenesis, despite the importance thereof on osteoclastic differentiation and activity. The aim of this study was to investigate the relative effect of monocyte or peripheral blood mononuclear cell (PBMC) seeding density, osteoclastic supplement concentration and priming on the generation of functional osteoclasts, and to explore and evaluate the usefulness of commonly used markers for osteoclast cultures. Morphology and osteoclast formation were analyzed with fluorescence imaging for tartrate resistant acid phosphatase (TRAP) and integrin β3 (Iβ3). TRAP release was analyzed from supernatant samples, and resorption was analyzed from culture on Corning® Osteo Assay plates. In this study, we have shown that common non-standardized culturing conditions of monocyte or PBMCs had a significant effect on the generation of functional osteoclasts. We showed how increased osteoclastic supplement concentrations supported osteoclastic differentiation and resorption but not TRAP release, while priming resulted in increased TRAP release as well. Increased monocyte seeding densities resulted in more and large TRAP positive bi-nuclear cells, but not directly in more multinucleated osteoclasts, resorption or TRAP release. Increasing PBMC seeding densities resulted in more and larger osteoclasts and more resorption, although resorption was disproportionally low compared to the monocyte seeding density experiment. Exploration of commonly used markers for osteoclast cultures demonstrated that Iβ3 staining was an excellent and specific osteoclast marker in addition to TRAP staining, while supernatant TRAP measurements could not accurately predict osteoclastic resorptive activity. With improved understanding of the effect of seeding density and osteoclastic supplement concentration on osteoclasts, experiments yielding higher numbers of functional osteoclasts can ultimately improve our knowledge of osteoclasts, osteoclastogenesis, bone remodeling and bone diseases.
PubMed: 36588781
DOI: 10.1016/j.bonr.2022.101651