Aims. Osteoporosis is characterized by decreased trabecular bone volume, and microarchitectural deterioration in the medullary cavity. Interleukin-19 (IL-19), a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. The aim of our study was to investigate the effect of IL-19 on osteoporosis. Methods. Blood and femoral bone marrow suspension IL-19 levels were first measured in the lipopolysaccharide (LPS)-induced bone loss model. Small interfering RNA (siRNA) was applied to knock down IL-19 for further validation. Thereafter, osteoclast production was stimulated with IL-19 in combination with mouse macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The effect of IL-19 was subsequently evaluated using tartrate-resistant acid phosphatase (TRAP) staining and quantitative real-time polymerase chain reaction (RT-qPCR). The effect of IL-19 on osteoprotegerin (OPG) was then assessed using in vitro recombinant IL-19 treatment of primary osteoblasts and MLO-Y4 osteoblast cell line. Finally, transient transfection experiments and chromatin immunoprecipitation (ChIP) experiments were used to examine the exact mechanism of action. Results. In the LPS-induced bone loss mouse model, the levels of IL-19 in peripheral blood serum and femoral bone marrow suspension were significantly increased. The in vivo results indicated that global IL-19 deletion had no significant effect on RANKL content in the serum and bone marrow, but could increase the content of OPG in serum and femoral bone marrow, suggesting that IL-19 inhibits OPG expression in bone marrow mesenchymal stem cells (BMSCs) and thus increases
Aims. Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice. Methods. We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR). Results. Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE.
Recently, concerns arose over the medial tibial bone resorption of a novel cobalt-chromium (CoCr) implant. This study aimed to investigate the effects of tibial component material, design, and patient factors on periprosthetic
Bone remodeling effects is a significant issue in predicting long term stability of hip arthroplasty. It has been frequently observed around the femoral components especially with the implantation of prosthesis stem. Presence of the stiffer materials into the femur has altering the stress distribution and induces changes in the architecture of the bone. Phenomenon of
Aseptic loosening is currently the leading cause of failure of total hip arthroplasty. The aetiology of periprosthetic
Osteoclastic
A heavy infiltrate of foreign-body macrophages is commonly seen in the fibrous membrane which surrounds an aseptically loose cemented implant. This is in response to particles of polymethylmethacrylate (PMMA) bone cement and other biomaterials. We have previously shown that monocytes and macrophages responding to particles of bone cement are capable of differentiating into osteoclastic cells which resorb bone. To determine whether the radio-opaque additives barium sulphate (BaSO. 4. ) and zirconium dioxide (ZrO. 2. ) influence this process, particles of PMMA with and without these agents were added to mouse monocytes and cocultured with osteoblast-like cells on bone slices. Osteoclast differentiation, as shown by the presence of the osteoclast-associated enzyme tartrate-resistant acid phosphatase (TRAP) and lacunar
Introduction. Revision total knee arthroplasy (TKA) has been often used with a metal block augmentation for patients with poor bone quality. However,
Summary Statement. In this study it has been considered an alternative therapeutic approach to
We investigated the possibility that the macrophages which are seen around implants may stimulate
We investigated in vitro a mechanism by which particulate debris may induce
Summary Statement. Obovatol inhibits receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and prevents inflammatory bone loss in mice. Introduction. Adult skeletal mass and integrity are maintained by balancing osteoclast-mediated
Mast cells (MC), the tissue-based effector cells in allergic diseases, have many functions. Within bone tissue, they have been linked with new blood vessel formation and marrow fibrosis and it has been proposed that they are capable of promoting osteoclastic
Introduction: Tumor necrosis factor-alpha (TNF-a) has been shown to be a potent stimulator of
Calvaria from six-day-old infant mice were grown on a grid culture in a chemically defined medium under varying oxygen tensions. Quantitative isotope studies demonstrated a linear association between
Using a rat model, we created a bone-to-titanium interface and applied phagocytosable high-density polyethylene pArticles between the bone and implant, either initially or when the interface had matured. No fibrous membrane developed and no
Introduction: A collar can be defined as any projection from the surface of the proximal third of the femoral stem that interferes with the capacity of the stem to move distally within the cement mantle and provide optimal load distribution along the calcar area. Contraversy exists concerning the usage of a collared or collarless prosthesis and the ability of the collar to perform its effect on the medial femoral neck. The purpose of this study is to compare the proximal femoral
Introduction. Stress shielding is one of the major concerns of load bearing implants (e.g. hip prostheses). Stiff implants cause stress shielding, which is thought to contribute to bone resorption1. On the contrary, low-stiffness implants generate high interfacial stresses that have been related to pain and interfacial micro-movements². Different attempts have been made to reduce these problems by optimizing either the stem design3 or using functionally graded implants (FGI) where the stem's mechanical properties are optimized4. In this way, new additive manufacturing technologies allow fabricating porous materials with well-controlled mesostructure, which allows tailoring their mechanical properties. In this work, Finite Element (FE) simulations are used to develop an optimization methodology for the shape and material properties of a FGI hip stem. The resorbed bone mass fraction and the stem head displacement are used as objective functions. Methodology. The 2D-geometry of a femur model (Sawbones®) with an implanted Profemur-TL stem (Wright Medical Technology Inc.) was used for FE simulations. The stem geometry was parameterized using a set of 8 variables (Figure 1-a). To optimize the stem's material properties, a grid was generated with equally spaced points for a total of 96 points (Figure 1-b). Purely elastic materials were used for the stem and the bone. Two bone qualities were considered: good (Ecortical=20 GPa, Etrabecular=1.5 GPa) and medium (Ecortical=15 GPa, Etrabecular=1 GPa). Poisson ratio was fixed to v=0.3. Loading corresponded to stair climbing. Hip contact force along with abductors, vastus lateralis and vastus medialis muscles were considered5 for a bodyweight of 847 N. The resorbed bone mass fraction was evaluated from the differences in strain energy densities between the intact bone and the implanted bone2. The displacement of the load point on the femoral head was computed. The optimization problem was formulated as the minimization of the resorbed bone mass fraction and the head displacement. It was solved using a genetic algorithm. Results. For the Profemur-TL design,
We reviewed at a minimum elapsed time of five years a consecutive series of 143 primary Exeter hip replacements in which matt-surfaced femoral stems had been used. Twenty-five patients had died and six stems and two sockets had been revised before follow-up. The remaining 110 hips were all examined clinically and radiographically. In 15 hips there were radiographic signs of definite loosening of the stem and in eight suspected loosening. The acetabulum was loose in four hips. In another eight hips localised
Introduction: Many claim that an inflammatory reaction to wear debris particles is the main cause for prosthetic loosening. We have rat model in which
The association of auraptene (AUR), a 7-geranyloxycoumarin, on osteoporosis and its potential pathway was predicted by network pharmacology and confirmed in experimental osteoporotic mice. The network of AUR was constructed and a potential pathway predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms enrichment. Female ovariectomized (OVX) Institute of Cancer Research mice were intraperitoneally injected with 0.01, 0.1, and 1 mM AUR for four weeks. The bone mineral density (BMD) level was measured by dual-energy X-ray absorptiometry. The bone microstructure was determined by histomorphological changes in the femora. In addition, biochemical analysis of the serum and assessment of the messenger RNA (mRNA) levels of osteoclastic markers were performed.Aims
Methods
INTRODUCTION.
Higher than expected rates of tibial loosening with the ATTUNE® total knee arthroplasty (TKA) implant has been reported. Component loosening can be associated with the development of radiolucency lines (RLL) and our study aim was to systematically assess the reported rates of these. A systematic search was undertaken using the Cochrane methodology in four online databases. Identified studies were assessed and screened against predetermined inclusion criteria. Meta-analysis was conducted using a random-effects model.Abstract
Introduction
Methodology
Aims: To examine the relationship between the Interleukin 6 (IL-6) −174 G>
C promoter polymorphism and exercise-induced femoral cortical
Wear particles commonly used for experiments may carry adherent endotoxin on their surfaces, which may be responsible for the observed effects. In this study, we attached titanium plates to the tibiae of 20 rats. After osseointegration, endotoxin-contaminated or uncontaminated high-density-polyethylene (HDPE) particles were applied. Contaminated specimens showed a dramatic resorption of bone after seven days but new bone filled the site again at 21 days. Uncontaminated specimens showed no resorption. In 18 rats we implanted intramuscularly discs of ultra-high-molecular-weight polyethylene (UHMWPE) with baseline or excess contamination of endotoxin. Excess endotoxin disappeared within 24 hours and the amount of endotoxin remained at baseline level (contamination from production). Uncontaminated titanium discs did not adsorb endotoxin in vivo. The endotoxin was measured by analytical chemistry. Locally-applied endotoxin stimulated
Inadequate bone stock is often found in revision surgery of femoral components of total knee replacements. Our aim was to test the hypothesis that these remodelling patterns can be explained by stress shielding, and that prosthetic bonding characteristics affect maintenance of bone mass. We made a three-dimensional finite-element model of an average male femur with a cemented femoral knee component. This model was integrated with iterative remodelling procedures. Two extreme prosthetic bonding conditions were analysed and gradual changes in bone density were calculated. The long-term bone loss under the femoral knee component resembled clinical findings which confirms the hypothesis that stress shielding can cause distal femoral bone loss. Our study predicts, contrary to clinical findings, that an equilibrium situation is not reached after two years, but that
Matrix metalloproteinases (MMPs) may have a role in the process of aseptic loosening. Doxycycline has been shown to inhibit MMPs. Our aim was to investigate the potential pharmacological effect of doxycycline on aseptic loosening. We used radiolabelled mouse calvariae cultured with human interface membrane cells from aseptically loosened hips.
Introduction: In a rat model, fluid pressure causes more
A common location for radius fracture is the proximal radial head. With the arm in neutral position, the fracture usually happens in the anterolateral quadrant (Lacheta et al., 2019). If traditional surgeries are not enough to induce bone stabilization and vascularization, or the fracture can be defined grade III or grade IV (Mason classification), a radial head prosthesis can be the optimal compromise between bone saving and recovering the “terrible triad”. A commercially available design of radial head prosthesis such as Antea (Adler Ortho, Milan, Italy) is characterized by flexibility in selecting the best matching size for patients and induced osteointegration thanks to the Ti-Por® radial stem realized by 3D printing with laser technique (Figure 1). As demonstrated, Ti-Por® push-out resistance increased 45% between 8 −12 weeks after implantation, hence confirming the ideal bone-osteointegration. Additional features of Antea are: bipolarity, modularity, TiN coating, radiolucency, hypoallergenic, 10° self-aligning. The osteointegration is of paramount importance for radius, in fact the literature is unfortunately reporting several clinical cases for which the fracture of the prosthesis happened after bone-resorption. Even if related to an uncommon activity, the combination of mechanical resistance provided by the prosthesis and the stabilization due to the osteointegration should cover also accidental movements. Based upon Lacheta et al. (2019), after axial compression-load until radii failure, all native specimens survived a compression-load of 500N, while the failure happened for a mean compression force of 2560N. The aim of this research study was to test the mechanical resistance of a radial head prosthesis obtained by 3D printing. In detail, a finite element analysis (FEA) was used to understand the mechanical resistance of the core of the prosthesis and the potential bone fracture induced in the radius with simulated bone- resorption (Figure 2a). The critical level was estimated at the height for which the thickness of the core is the minimum (Figure 2b). Considered boundary conditions:
- Full-length prosthesis plus radius out of the cement block equal to 60mm (Figure 2a); - Bone inside the cement equal to 60mm (Figure 2b); - Load inclined 10° epiphysiary component (Figure 2c); - Radius with physiological or osteoporotic bone conditions; - Load (concentrated in the sphere simulating full transmission from the articulation) of 500N or 1300N or 2560N. Figure 3 shows the results in terms of maximum stress on the core of the prosthesis and the risk of fracture (Schileo et al., 2008). According to the obtained results, the radial head prosthesis shows promising mechanical resistance despite of the simulated bone-resorption for all applied loads except for 2560N. The estimated mechanical limit for the material in use is 200MPa. The risk of fracture is in agreement with the experimental findings (Lacheta et al. (2019)), in fact bone starts to fail for the minimum reported failure load, but only for osteoporotic conditions. The presented FEA aimed at investigating the behavior of a femoral head prostheses made by 3D printing with simulated bone-resorption. The prosthesis shows to be a skilled solution even during accidental loads. For any figures or tables, please contact the authors directly.
It has been hypothesized that proximal radial neck resorption (PRNR) following press-fit radial head arthroplasty (RHA) is due to stress-shielding. We compared two different press-fit stems by means of radiographs to investigate whether the shape and size of the stems are correlated with the degree of PRNR. The radiographs of 52 RHAs were analyzed both at 14 days postoperatively and after two years. A cylindrical stem and a conical stem were implanted in 22 patients (group 1) and 30 patients (group 2), respectively. The PRNR was measured in the four quadrants of the radial neck and the degree of stem filling was calculated by analyzing the ratio between the prosthetic stem diameter (PSD) and the medullary canal diameter (MCD) at the proximal portion of the stem (level A), halfway along the stem length (level B), and distally at the stem tip (level C).Aims
Methods
Similar to the radiological findings in rapidly destructive arthrosis of the hip joint (RDA), subchondral insufficiency fracture of the femoral head (SIF) can result in progressive femoral head collapse of unknown etiology. We thus examined the osteoclast activity in hip joint fluid in SIF with progressive collapse in comparison to that in RDA. Twenty-nine hip joint fluid samples were obtained intraoperatively with whole femoral heads from 12 SIF patients and 17 RDA patients. SIF cases were classified into subgroups based on the presence of ≥2mm collapse on preoperative radiographs: SIF with progressive collapse (n=5) and SIF without progressive collapse (n=7). The levels of tartrate-resistant acid phosphatase (TRACP)-5b, interleukin-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP)-9 were measured. Numbers of multinuclear giant cells at the subchondral region were assessed histopathologically using mid-coronal slices of each femoral head specimen. Median levels of all markers and median numbers of multinuclear giant cells in SIF with progressive collapse were significantly higher than those in SIF without progressive collapse, while there were no significant differences in SIF with progressive collapse versus RDA. Regression analysis showed that the number of multinuclear giant cells correlated positively with the level of TRACP-5b in joint fluid. This study suggests an association of increased osteoclast activity with the existing condition of progressive collapse in SIF, which was quite similar to the findings in RDA. Therefore, high activation of osteoclast cell may reflect the condition of progressive collapse in SIF as well as RDA.
Surgeons and most engineers believe that bone compaction improves implant primary stability without causing undue damage to the bone itself. In this study, we developed a murine distal femoral implant model and tested this dogma. Each mouse received two femoral implants, one placed into a site prepared by drilling and the other into the contralateral site prepared by drilling followed by stepwise condensation.Aims
Methods
The radiographs of sixty-four patients with seventy humeral head replacements were reviewed for signs of stress shielding. Forty-nine were implanted for rheumatoid arthritis, twenty-one for osteoarthritis. The radiographic follow-up averaged 5. 3 years. Measurements of cortex thickness were performed in four regions along the stem of the implant and the differences between the post-operative radiograph and radiograph at follow-up were calculated. The size of the stem in relation to the diameter of the humerus was calculated using validated measures, resulting in the relative stem size. A reduction of 1.6 millimeters or more was considered to be a significant reduction, because this lay outside of the calculated 95% normal range for the group as a whole. In six patients (9%) a significant reduction, in cortical thickness was observed in the proximal lateral region of the humeral stem. Five of these had rheumatoid arthritis and one osteoarthritis. In the stress shielding group the relative stem size was found to be significantly higher (p=0. 013) than in the non-stress shielding group (0. 58 versus 0. 48). Osteoporosis, especially present in rheumatoid arthritis, could well be a risk factor. It was concluded that stress shielding is a long-term complication of shoulder arthroplasty and that the relative stem size is an important factor in its genesis. These resorptive processes may lead to a higher risk of failure of the implant and gives an increased risk for mid-stem fractures, due to cantilever loading. It is also desirable to preserve the proximal bone stock, considering the difficulties that arise when, for whatever reason, revision of the implant is necessary.
Osteoclast Associated Receptor (OSCAR) is a novel member of leucocyte receptor complex (LCR)-encoded family expressed by pre-osteoclasts and mature osteoclasts (OC). Blocking of OSCAR binding to its putative ligand has been shown to inhibit osteoclast formation. To date there is no data available regarding the expression of OSCAR in tissues associated with osteolysis and the objective of this study is to determine if OSCAR is expressed adjacent to focal bone osteolysis near failed implants. A total of 22 samples (10 Peri-implant tissue and 12 OA) were studied. OSCAR antibodies were a gift from R&
D Systems Inc. (Minneapolis, MN, USA). The tissues were analysed semi-qualitatively using semi-quantitative scoring (SQA) independently by two observers. Non-parametric Mann Whitney-U test was used to test statistical significance. Dual labelling for OSCAR and CD68 expression was also carried out. Strong expression of OSCAR was seen in the majority of multinucleated cells in peri-implant tissues while OA tissues showed very low levels of OSCAR expression. Dual labelling studies revealed that the cells expressing OSCAR also expressed CD68. There was a significant difference in the expression of OSCAR between peri-implant tissue and OA synovial tissue (p<
0.003). This study shows that OSCAR is expressed at high levels by the numerous CD68 multinucleated cells present is these tissues in peri-implant tissues. These findings and recent reports on the role OSCAR may play in OC formation indicate that OSCAR could be an important mediator of peri-implant osteolysis
Peri-prosthetic osteolysis and subsequent aseptic
loosening is the most common reason for revising total hip replacements.
Wear particles originating from the prosthetic components interact
with multiple cell types in the peri-prosthetic region resulting
in an inflammatory process that ultimately leads to peri-prosthetic
bone loss. These cells include macrophages, osteoclasts, osteoblasts
and fibroblasts. The majority of research in peri-prosthetic osteolysis
has concentrated on the role played by osteoclasts and macrophages.
The purpose of this review is to assess the role of the osteoblast
in peri-prosthetic osteolysis. In peri-prosthetic osteolysis, wear particles may affect osteoblasts
and contribute to the osteolytic process by two mechanisms. First,
particles and metallic ions have been shown to inhibit the osteoblast
in terms of its ability to secrete mineralised bone matrix, by reducing
calcium deposition, alkaline phosphatase activity and its ability
to proliferate. Secondly, particles and metallic ions have been
shown to stimulate osteoblasts to produce pro inflammatory mediators Cite this article:
Aims
Patients and Methods
The aim of this study was to evaluate the clinical and radiological
outcome of using an anatomical short-stem shoulder prosthesis to
treat primary osteoarthritis of the glenohumeral joint. A total of 66 patients (67 shoulders) with a mean age of 76 years
(63 to 92) were available for clinical and radiological follow-up
at two different timepoints (T1, mean 2.6 years, Aims
Patients and Methods
Aims. The management of periprosthetic joint infection (PJI) remains a major challenge in orthopaedic surgery. In this study, we aimed to characterize the local bone microstructure and metabolism in a clinical cohort of patients with chronic PJI. Methods. Periprosthetic femoral trabecular bone specimens were obtained from patients suffering from chronic PJI of the hip and knee (n = 20). Microbiological analysis was performed on preoperative joint aspirates and tissue specimens obtained during revision surgery. Microstructural and cellular bone parameters were analyzed in bone specimens by histomorphometry on undecalcified sections complemented by tartrate-resistant acid phosphatase immunohistochemistry. Data were compared with control specimens obtained during primary arthroplasty (n = 20) and aseptic revision (n = 20). Results. PJI specimens exhibited a higher bone volume, thickened trabeculae, and increased osteoid parameters compared to both control groups, suggesting an accelerated bone turnover with sclerotic microstructure. On the cellular level, osteoblast and osteoclast parameters were markedly increased in the PJI cohort. Furthermore, a positive association between serum (CRP) but not synovial (white blood cell (WBC) count) inflammatory markers and osteoclast indices could be detected. Comparison between different pathogens revealed increased osteoclastic
Aims. The aim of this study was to analyze how proximal radial neck resorption (PRNR) starts and progresses radiologically in two types of press-fit radial head arthroplasties (RHAs), and to investigate its clinical relevance. Methods. A total of 97 patients with RHA were analyzed: 56 received a bipolar RHA (Group 1) while 41 received an anatomical implant (Group 2). Radiographs were performed postoperatively and after three, six, nine, and 12 weeks, six, nine, 12, 18, and 24 months, and annually thereafter. PRNR was measured in all radiographs in the four radial neck quadrants. The Mayo Elbow Performance Score (MEPS), the abbreviated version of the Disabilities of the Arm, Shoulder, and Hand questionnaire (QuickDASH), and the patient-assessed American Shoulder and Elbow Surgeons score - Elbow (pASES-E) were used for the clinical assessment. Radiological signs of implant loosening were investigated. Results. The mean follow-up was six years (2 to 14). PRNR started after a mean of 7.5 weeks (SD 2.1) and progressed significantly during the first two years, by the end of which the
Abstract. OBJECTIVE. Knee varus malalignment increases medial knee compartment loading and is associated with knee osteoarthritis (OA) progression and severity. 1. Altered biomechanical loading and dysregulation of joint tissue biology drive OA progression, but mechanistic links between these factors are lacking. Subchondral bone structural changes are biomechanically driven, involve
Aims. Bone turnover markers (BTMs) follow distinct trends after fractures and limited evidence suggests differential levels in BTMs in patients with delayed healing. The effect of vitamin D, and other factors that influence BTMs and fracture healing, is important to elucidate the use of BTMs as surrogates of fracture healing. We sought to determine whether BTMs can be used as early markers of delayed fracture healing, and the effect of vitamin D on BTM response after fracture. Methods. A total of 102 participants aged 18 to 50 years (median 28 years (interquartile range 23 to 35)), receiving an intramedullary nail for a tibial or femoral shaft fracture, were enrolled in a randomized controlled trial comparing vitamin D. 3. supplementation to placebo. Serum C-terminal telopeptide of type I collagen (CTX;
Introduction and Objective. In recent years, along with the extending longevity of patients and the increase in their functional demands, the number of annually performed RSA and the incidence of complications are also increasing. When a complication occurs, the patient often needs multiple surgeries to restore the function of the upper limb. Revision implants are directly responsible for the critical reduction of the bone stock, especially in the shoulder. The purpose of this paper is to report the use of allograft bone to restore the bone stock of the glenoid in the treatment of an aseptic glenoid component loosening after a reverse shoulder arthroplasty (RSA). Materials and Methods. An 86-years-old man came to our attention for aseptic glenoid component loosening after RSA. Plain radiographs showed a complete dislocation of the glenoid component with 2 broken screws in the neck of glenoid. CT scans confirmed the severe reduction of the glenoid bone stock and critical
During the last decades, several research groups have used bisphosphonates for local application to counteract secondary
Aims. LY3023414 is a novel oral phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor designed for advanced cancers, for which a phase II clinical study was completed in March 2020; however, little is known about its effect on bone modelling/remodelling. In this study, we aimed to explore the function of LY3023414 in bone modelling/remodelling. Methods. The function of LY3023414 was explored in the context of osteogenesis (bone formation by osteoblasts) and osteoclastogenesis (osteoclast formation and bone resorption). Murine preosteoblast MC3T3-E1 cell line and murine bone marrow-derived macrophage cells (BMMs) were subjected to different treatments. An MTS cell proliferation assay was used to examine the cytotoxicity. Thereafter, different induction conditions were applied, such as MCSF and RANKL for osteoclastogenesis and osteogenic media for osteogenesis. Specific staining, a
Hip and knee arthroplasty (HKA) are two of the most successful orthopaedic procedures. However, one major complication necessitating revision surgery is osteolysis causing aseptic loosening of the prosthesis. JAK-STAT has been demonstrated to influence bone metabolism and can be regulated by microRNA (miRNA). Adult patients with osteolysis or aseptic loosening undergoing revision HKA were recruited. Age and gender matched patients undergoing primary hip or knee arthroplasty were our controls. Samples of bone, tissue and blood were collected and RNA isolation was performed. The best quality samples were used for RNA-sequencing. Data analysis was performed using RStudio and Galaxy to identify differentially expressed genes. Western blotting of IL6 was used to confirm protein expression. Five circulating miRNA were identified which had 10 differentially expressed genes in bone and 11 differentially expressed genes in tissue related to the JAK-STAT pathway. IL6 in bone and EpoR in bone were highly significant and IL6 in tissue, MPL in bone, SOCS3 in tissue, JAK3 in bone and SPRED1 in bone were borderline significant. Western blot results demonstrated up-expression of IL6 in bone tissue of revision patients. Periprosthetic osteolysis and aseptic loosening can be attributed to miRNA regulation of the JAK-STAT pathway in osteoblasts and osteoclasts, leading to increased
Paget's disease of bone (PDB) is characterised by increased
Bone regeneration is pivotal for the healing of fractures. In case this process is disturbed a non-union can occur. This can be induced by environmental factors such as smoking, overloading etc. Co-morbidities such as diabetes, osteoporosis etc. may be more intrinsic factors besides other disturbances in the process. Those pathways negatively influence the bone regeneration process. Several intrinsic signal transduction pathways (WNT, BMP etc.) can be affected. Furthermore, on the transcriptional level, important mRNA expression can be obstructed by deregulated miRNA levels. For instance, several miRNAs have been shown to be upregulated during osteoporotic fractures. They are detrimental for osteogenesis as they block bone formation and accelerate
Osteoporosis is a progressive, chronic disease of bone metabolism, characterized by decreased bone mass and mineral density, predisposing individuals to an increased risk of fractures. The use of animal models, which is the gold standard for the screening of anti-osteoporosis drugs, raises numerous ethical concerns and is highly debated because the composition and structure of animal bones is very different from human bones. In addition, there is currently a poor translation of pre-clinical efficacy in animal models to human trials, meaning that there is a need for an alternative method of screening and evaluating new therapeutics for metabolic bone disorders, in vitro. The aim of this project is to develop a 3D Bone-On-A-Chip that summarizes the spatial orientation and mutual influences of the key cellular components of bone tissue, in a citrate and hydroxyapatite-enriched 3D matrix, acting as a 3D model of osteoporosis. To this purpose, a polydimethylsiloxane microfluidic device was developed by CAD modelling, stereolithography and replica molding. The device is composed by two layers: (i) a bottom layer for a 3D culture of osteocytes embedded in an osteomimetic collagen-enriched matrigel matrix with citrate-doped hydroxyapatite nanocrystals, and (ii) a upper layer for a 2D perfused co-culture of osteoblasts and osteoclasts seeded on a microporous PET membrane. Cell vitality was evaluated via live/dead assay. Bone deposition and
Anatomically, bone consists of building blocks called osteons, which in turn comprise a central canal that contains nerves and blood vessels. This indicates that bone is a highly innervated and vascularized tissue. The function of vascularization in bone (development) is well-established: providing oxygen and nutrients that are necessary for the formation, maintenance, and healing. As a result, in the field of bone tissue engineering many research efforts take vascularization into account, focusing on engineering vascularized bone. In contrast, while bone anatomy indicates that the role of innervation in bone is equally important, the role of innervation in bone tissue engineering has often been disregarded. For many years, the role of innervation in bone was mostly clear in physiology, where innervation of a skeleton is responsible for sensing pain and other sensory stimuli. Unraveling its role on a cellular level is far more complex, yet more recent research efforts have unveiled that innervation has an influence on osteoblast and osteoclast activity. Such innervation activities have an important role in the regulation of bone homeostasis, stimulating bone formation and inhibiting resorption. Furthermore, due to their anatomical proximity, skeletal nerves and blood vessels interact and influence each other, which is also demonstrated by pathways cross-over and joint responses to stimuli. Besides those closely connected sytems, the immune system plays also a pivotal role in bone regeneration. Certain cytokines are important to attract osteogenic cells and (partially) inhibit
Metabolic bone diseases, such as osteoporosis and osteopetrosis, result from an imbalanced bone remodeling process. In vitro bone models are often used to investigate either bone formation or resorption independently, while in vivo, these processes are coupled. Combining these processes in a co-culture is challenging as it requires finding the right medium components to stimulate each cell type involved without interfering with the other cell type's differentiation. Furthermore, differentiation stimulating factors often comprise growth factors in supraphysiological concentrations, which can overshadow the cell-mediated crosstalk and coupling. To address these challenges, we aimed to recreate the physiological bone remodeling process, which follows a specific sequence of events starting with cell activation and