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European Cells & Materials Oct 2021Osteomyelitis associated with periprosthetic joint infection (PJI) signals a chronic infection and the need for revision surgery. An osteomyelitic bone exhibits distinct...
Osteomyelitis associated with periprosthetic joint infection (PJI) signals a chronic infection and the need for revision surgery. An osteomyelitic bone exhibits distinct morphological features, including evidence for osteolysis and an accelerated bone remodelling into poorly organised, poor-quality bone. In addition to immune cells, various bone cell-types have been implicated in the pathology. The present study sought to determine the types of bone-cell activities in human PJI bones. Acetabular biopsies from peri-implant bone from patients undergoing revision total hip replacement (THR) for chronic PJI (with several identified pathogens) as well as control bone from the same patients and from patients undergoing primary THR were analysed. Histological analysis confirmed that PJI bone presented increased osteoclastic activity compared to control bone. Analysis of osteocyte parameters showed no differences in osteocyte lacunar area between the acetabular bone taken from PJI patients or primary THR controls. Analysis of bone matrix composition using Masson's trichrome staining and second-harmonic generation microscopy revealed widespread lack of mature collagen, commonly surrounding osteocytes, in PJI bone. Increased expression of known collagenases, such as matrix metallopeptidase (MMP) 13, MMP1 and cathepsin K (CTSK), was measured in infected bone compared to non-infected bone. Human bone and cultured osteocyte-like cells experimentally exposed to Staphylococcus aureus exhibited strongly upregulated expression of MMP1, MMP3 and MMP13 compared to non-exposed controls. In conclusion, the study identified previously unrecognised bone-matrix changes in PJI caused by multiple organisms deriving from osteocytes. Histological examination of bone collagen composition may provide a useful adjunct diagnostic measure of PJI.
Topics: Arthroplasty, Replacement, Hip; Bone Matrix; Humans; Osteocytes; Osteolysis; Persistent Infection; Prosthesis-Related Infections
PubMed: 34622431
DOI: 10.22203/eCM.v042a19 -
Wiener Klinische Wochenschrift Jun 2022Tuberculosis is among the leading causes of death from infectious diseases and affects many organ systems, including the skeleton. Skeletal tuberculosis is an...
Tuberculosis is among the leading causes of death from infectious diseases and affects many organ systems, including the skeleton. Skeletal tuberculosis is an extrapulmonary stage of tuberculosis, which occurs after the early and post-primary pulmonary stages of the disease. The aim of our study was to assess the microarchitecture of historic dry bone samples of subjects who have died of tuberculosis documented by post-mortem examinations. These preparations date to the pre-antibiotic era, and were provided by the Pathological-Anatomical Collection in the "Fools Tower" of the Natural History Museum Vienna (PASiN-NHM).We investigated macerated samples of 20 vertebral bodies, 19 femoral heads, and 20 tibiae of a total of 59 individuals diagnosed with tuberculosis from the nineteenth and early twentieth century. 10 femora and 10 tibiae from body donors that did not exhibit signs of infection and 10 (unaffected) vertebrae kept at the PASiN-NHM were studied as controls. The affected regions of the bone samples (and the corresponding regions of the control bones) were analyzed by microcomputed tomography using a Viscom X 8060 II system. Obtained images were analyzed semi-quantitatively. In samples with tuberculosis, independent of the investigated skeletal region, trabecular defects and decreased trabecular thickness were observed. Cortical porosity was seen in affected vertebrae and tibia; in tuberculous tibiae (but not in the femora) cortical thickness was decreased. In half of the individuals, cortical sclerosis was present; signs of ankylosis were observed mainly at the femoral heads affected with tuberculosis. We conclude that a combination of several alterations at the trabecular compartment could be suggestive of the presence of tuberculosis in historic skeletal remains.
Topics: Bone Density; Bone and Bones; Humans; Tibia; Tuberculosis; X-Ray Microtomography
PubMed: 35307770
DOI: 10.1007/s00508-022-02017-y -
The Yale Journal of Biology and Medicine 1990Sickle-cell disease is a well-recognized clinical entity. The pathophysiology of this hemoglobinopathy has been described in detail by numerous investigators since the... (Review)
Review
Sickle-cell disease is a well-recognized clinical entity. The pathophysiology of this hemoglobinopathy has been described in detail by numerous investigators since the first case report appeared in 1910. Orthopaedic manifestations of sickle-cell disease account for much of the morbidity associated with this disorder, including pain, osteonecrosis, arthritis, and sepsis. Effective management of these bone and joint sequelae reflect accurate diagnosis, understanding of this disorder's pathophysiology, and knowledge of available medical and surgical treatment alternatives. In this review, the authors summarize the major orthopaedic manifestations of sickle-cell disease with special emphasis placed upon osteonecrosis and osteomyelitis, since these conditions are the most disabling and serious complications in patients with sickle-cell disease.
Topics: Anesthesia; Arthritis, Infectious; Bone Diseases; Bone and Bones; Femur Head; Humans; Infarction; Muscular Diseases; Osteonecrosis; Pain; Postoperative Complications; Risk Factors; Sickle Cell Trait
PubMed: 2238715
DOI: No ID Found -
Bone Sep 2010It is now well established that important regulatory interactions occur between the cells in the hematopoietic, immune and skeletal systems (osteoimmunology). B... (Review)
Review
It is now well established that important regulatory interactions occur between the cells in the hematopoietic, immune and skeletal systems (osteoimmunology). B lymphocytes (B cells) are responsible for the generation and production of antibodies or immunoglobulins in the body. Together with T cells these lymphocytes comprise the adaptive immune system, which allows an individual to develop specific responses to an infection and retain memory of that infection, allowing for a faster and more robust response if that same infection occurs again. In addition to this immune function, B cells have a close and multifaceted relationship with bone cells. B cells differentiate from hematopoietic stem cells (HSCs) in supportive niches found on endosteal bone surfaces. Cells in the osteoblast lineage support HSC and B cell differentiation in these niches. B cell differentiation is regulated, at least in part, by a series of transcription factors that function in a temporal manner. While these transcription factors are required for B cell differentiation, their loss causes profound changes in the bone phenotype. This is due, in part, to the close relationship between macrophage/osteoclast and B cell differentiation. Cross talk between B cells and bone cells is reciprocal with defects in the RANKL-RANK, OPG signaling axis resulting in altered bone phenotypes. While the role of B cells during normal bone remodeling appears minimal, activated B cells play an important role in many inflammatory diseases with associated bony changes. This review examines the relationship between B cells and bone cells and how that relationship affects the skeleton and hematopoiesis during health and disease.
Topics: Animals; B-Lymphocytes; Bone Diseases, Metabolic; Bone and Bones; Cell Differentiation; Estrogens; Hematopoietic Stem Cells; Humans; Immune System; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Transcription Factors
PubMed: 20601290
DOI: 10.1016/j.bone.2010.06.011 -
Molecules (Basel, Switzerland) Mar 2021Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the...
Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the design and synthesis of a novel bone-binding antibiotic (BBA-1) and its subsequent structural and functional characterization. The synthesis of BBA-1 was the result of a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90) and the bisphosphonate alendronate (ALN) via a heterobifunctional linker. This was analytically confirmed by HPLC, FT-IR, MS and NMR spectroscopy. BBA-1 showed rapid binding and high affinity to bone mineral in an in vitro hydroxyapatite binding assay. Kirby-Baur assays confirmed that BBA-1 shows a potent antibacterial activity against and methicillin-resistant comparable to CSA-90. Differentiation of cultured osteoblasts in media supplemented with BBA-1 led to increased alkaline phosphatase expression, which is consistent with the pro-osteogenic activity of CSA-90. Bisphosphonates, such as ALN, are inhibitors of protein prenylation, however, the amine conjugation of ALN to CSA-90 disrupted this activity in an in vitro protein prenylation assay. Overall, these findings support the antimicrobial, bone-binding, and pro-osteogenic activities of BBA-1. The compound and related agents have the potential to ensure lasting activity against osteomyelitis after systemic delivery.
Topics: 3T3 Cells; Alendronate; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bone and Bones; Calcification, Physiologic; Cell Differentiation; Cells, Cultured; Diphosphonates; Methicillin-Resistant Staphylococcus aureus; Mice; Osteoblasts; Osteogenesis; Osteomyelitis; Pregnanes; Propylamines; Spectroscopy, Fourier Transform Infrared; Staphylococcal Infections; Staphylococcus aureus
PubMed: 33799713
DOI: 10.3390/molecules26061541 -
Proceedings of the National Academy of... Apr 2014Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. The ability of...
Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. The ability of alphaviruses to induce bone pathologies remains poorly defined. Here we show that primary human osteoblasts (hOBs) can be productively infected by RRV. RRV-infected hOBs produced high levels of inflammatory cytokine including IL-6. The RANKL/OPG ratio was disrupted in the synovial fluid of RRV patients, and this was accompanied by an increase in serum Tartrate-resistant acid phosphatase 5b (TRAP5b) levels. Infection of bone cells with RRV was validated using an established RRV murine model. In wild-type mice, infectious virus was detected in the femur, tibia, patella, and foot, together with reduced bone volume in the tibial epiphysis and vertebrae detected by microcomputed tomographic (µCT) analysis. The RANKL/OPG ratio was also disrupted in mice infected with RRV; both this effect and the bone loss were blocked by treatment with an IL-6 neutralizing antibody. Collectively, these findings provide previously unidentified evidence that alphavirus infection induces bone loss and that OBs are capable of producing proinflammatory mediators during alphavirus-induced arthralgia. The perturbed RANKL/OPG ratio in RRV-infected OBs may therefore contribute to bone loss in alphavirus infection.
Topics: Acid Phosphatase; Adult; Alphavirus Infections; Animals; Antibodies, Neutralizing; Arthritis; Bone Resorption; Bone and Bones; Female; Growth Plate; Humans; Inflammation Mediators; Interleukin-6; Isoenzymes; Male; Mice; Mice, Inbred C57BL; Neutralization Tests; Osteoblasts; Osteoclasts; Osteogenesis; Osteoprotegerin; Phenotype; RANK Ligand; Ross River virus; Synovial Fluid; Tartrate-Resistant Acid Phosphatase; Virus Replication; X-Ray Microtomography
PubMed: 24733914
DOI: 10.1073/pnas.1318859111 -
Journal of Orthopaedic Research :... Feb 2021A significant proportion of orthopedic devices are implanted in osteoporotic patients, but it is currently unclear how estrogen deficiency and/or exposure to...
A significant proportion of orthopedic devices are implanted in osteoporotic patients, but it is currently unclear how estrogen deficiency and/or exposure to antiresorptive bisphosphonates (BPs) influence orthopedic device-related infection (ODRI), or response to therapy. The aim of this study is to characterize the bone changes resulting from Staphylococcus epidermidis infection in a rodent ODRI model and to determine if ovariectomy (OVX) or BP treatment influences the infection or the success of antibiotic therapy. A sterile or S. epidermidis-contaminated screw was implanted into the proximal tibia of skeletally mature female Wistar rats (n = 6-9 per group). Bone changes were monitored over 28 days using in vivo micro-computed tomography scanning. OVX was performed 12 weeks before screw implantation. The BP zoledronic acid (ZOL) was administered 4 days before screw insertion. A combination antibiotic regimen (rifampin plus cefazolin) was administered from Days 7-21. In skeletally healthy animals, S. epidermidis induced marked changes in bone, with peak osteolysis occurring at Day 9 and woven bone deposition and periosteal mineralization from Day 14 onwards. Antibiotic therapy cleared the infection in the majority of animals (2/9 infected) but did not affect bone responses. OVX did not affect the pattern of infection-induced changes in bone, nor bacterial load, but reduced antibiotic efficacy (5/9 infected). ZOL treatment did not protect from osteolysis in OVX animals, or further affect antibiotic efficacy (5/9 infected) but did significantly increase the bacterial load. This study suggests that both BPs and OVX can influence host responses to bone infections involving S. epidermidis.
Topics: Animals; Anti-Bacterial Agents; Bone Density Conservation Agents; Bone and Bones; Disease Models, Animal; Estrogens; Female; Prosthesis-Related Infections; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus epidermidis; X-Ray Microtomography
PubMed: 33325074
DOI: 10.1002/jor.24951 -
The Journal of Clinical Endocrinology... Dec 2017Mineral and bone disorders (MBDs) might be relevant in the etiology of infection.
CONTEXT
Mineral and bone disorders (MBDs) might be relevant in the etiology of infection.
OBJECTIVE
To determine whether MBD biomarkers were associated with the incidence of hospitalization with infection. We also assessed the cross-sectional association between MBD biomarker levels and kidney function.
DESIGN, SETTING, PARTICIPANTS
Community-based cohort study of 11,218 participants with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 in the Atherosclerosis Risk in Communities study. We assessed the cross-sectional associations of five MBD markers-fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), calcium corrected for hypoalbuminemia, and phosphorus-with eGFR from 1990 to 1992 and their longitudinal associations with incident hospitalization with infection in 1990 to 2013.
MAIN OUTCOME
Incident hospitalization with infection.
RESULTS
In age-, sex-, and race-adjusted models, lower eGFRs were significantly associated with greater levels of FGF23, PTH, and corrected calcium but not 25(OH)D or phosphorus. During follow-up, 5078 hospitalizations with infection occurred. In fully adjusted Cox models, with the second quartile as the reference, the hazard ratio (HR) was significantly greater in the highest quartile of FGF23 [HR, 1.12; 95% confidence interval (CI), 1.03 to 1.21], PTH (HR, 1.09; 95% CI, 1.01 to 1.18), and corrected calcium (HR, 1.11; 95% CI, 1.03 to 1.20), and lowest quartile for 25(OH)D (HR, 1.11; 95% CI, 1.03 to 1.21). The association with phosphorus was significant only when the outcome was restricted to primary diagnosis of infection. These findings were consistent across subgroups of age, sex, race, and eGFR (<60 vs ≥60 mL/min/1.73 m2).
CONCLUSIONS
MBD biomarkers were associated with eGFR and the subsequent risk of infection, supporting MBD involvement in the etiology of infection.
Topics: Atherosclerosis; Biomarkers; Bone and Bones; Cohort Studies; Cross-Sectional Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Hospitalization; Humans; Incidence; Infections; Longitudinal Studies; Male; Middle Aged; Minerals; Parathyroid Hormone; Prospective Studies; Risk Assessment; Vitamin D
PubMed: 29029099
DOI: 10.1210/jc.2017-01868 -
Journal of Acquired Immune Deficiency... May 2020Reduced bone mineral mass by dual x-ray absorptiometry is reported in children living with HIV (CLWH), but few studies of bone microarchitecture, particularly in...
BACKGROUND
Reduced bone mineral mass by dual x-ray absorptiometry is reported in children living with HIV (CLWH), but few studies of bone microarchitecture, particularly in sub-Saharan Africa, have been conducted. Here, we compare bone architecture and strength in black South African CLWH and uninfected control children by peripheral quantitative computed tomography (pQCT).
SETTING AND METHODS
One hundred seventy-two CLWH on antiretroviral therapy (ART) and 98 controls in the CHANGES Bone Study in Johannesburg, South Africa received pQCT scans of the radius and tibia. Measurements included trabecular and cortical volumetric bone mineral density (vBMD) and bone strength, estimated by the polar strength strain index (SSI), a validated measure of fracture risk.
RESULTS
CLWH (51% boys) and controls (63% boys) were an average of age 10.4 years. Mean ART duration for CLWH was 9.5 years, with 70.9% on an efavirenz-based, 28.5% on a lopinavir/ritonavir-based, and 1 child on an atazanavir/ritonavir-based regimen. Male CLWH had lower trabecular vBMD at the radius than controls after adjustment for age, radial length, and Tanner stage (β = -17.3, standard error = 7.2, P = 0.018). Bone strength by polar SSI was lower in CLWH than controls (778 vs. 972 mm, P < 0.01). CLWH on an LPV/r-based regimen had lower trabecular vBMD (199 vs. 222 mg/cm, P < 0.001) and cortical vBMD (1074 vs. 1093 mg/cm, P = 0.004) than those on an efavirenz-based regimen. No difference in bone strength by polar SSI was observed between treatment groups.
CONCLUSION
CLWH initiated on ART early in life with well-controlled HIV have deficits in bone architecture and reductions in bone strength as detected by pQCT.
Topics: Anti-HIV Agents; Bone Density; Bone and Bones; Case-Control Studies; Child; Female; HIV Infections; Humans; Male; Tomography, X-Ray Computed
PubMed: 32141960
DOI: 10.1097/QAI.0000000000002309 -
Journal of Immunology Research 2018Following severe tissue injury, patients are exposed to various danger- and microbe-associated molecular patterns, which provoke a strong activation of the neutrophil... (Review)
Review
Following severe tissue injury, patients are exposed to various danger- and microbe-associated molecular patterns, which provoke a strong activation of the neutrophil defense system. Neutrophils trigger and modulate the initial posttraumatic inflammatory response and contribute critically to subsequent repair processes. However, severe trauma can affect central neutrophil functions, including circulation half-life, chemokinesis, phagocytosis, cytokine release, and respiratory burst. Alterations in neutrophil biology may contribute to trauma-associated complications, including immune suppression, sepsis, multiorgan dysfunction, and disturbed tissue regeneration. Furthermore, there is evidence that neutrophil actions depend on the quality of the initial stimulus, including trauma localization and severity, the micromilieu in the affected tissue, and the patient's overall inflammatory status. In the present review, we describe the effects of severe trauma on the neutrophil phenotype and dysfunction and the consequences for tissue repair. We particularly concentrate on the role of neutrophils in wound healing, lung injury, and bone fractures, because these are the most frequently affected tissues in severely injured patients.
Topics: Animals; Bone and Bones; Cytokines; Fractures, Bone; Humans; Lung; Neutrophil Activation; Neutrophils; Oxidative Stress; Phagocytosis; Sepsis; Skin; Wound Healing; Wounds and Injuries
PubMed: 29850639
DOI: 10.1155/2018/8173983