Meniscal degeneration in human knee osteoarthritis: in situ hybridization and immunohistochemistry study.

OBJECTIVE: Meniscus injury is one of the causes of secondary osteoarthritis (OA). However, the role of meniscus is still unclear. Human meniscal distribution of cells and cartilage oligomeric matrix protein (COMP) and their changes in advanced OA were analyzed. PATIENTS AND METHODS: Thirty-one medial menisci from patients with knee OA that underwent a total knee arthroplasty were studied. Normal meniscal tissue was obtained from partial arthroscopic meniscectomy. Meniscal samples were processed for histology, immunohistochemistry and in situ hybridization, for cell assessment including density, active divisions, apoptosis, COMP distribution and proteoglycan content. RESULTS: Osteoarthritic menisci demonstrated areas of cell depletion and significant decrease in COMP immunostaining. Actively dividing cells were only found in the meniscectomy group, but not in the osteoarthritic group. Proteoglycan staining was less prominent in menisci from the osteoarthritis group. CONCLUSIONS: Our results show a decreased cell population, with low COMP and altered matrix organization in osteoarthritis menisci that suggest an altered meniscal scaffold and potential impairment of meniscal function. These meniscal changes may be associated with the development of knee osteoarthritis.

New materials and complications of prostheses in humans: situation in Spain.

Prostheses or implantable medical devices (IMDs) are parts made of natural or artificial materials intended to replace a body structure and therefore must be well tolerated by living tissues. The types of IMDs currently available and usable are very varied and capable of replacing almost any human organ. A high but imprecise percentage of Spaniards are carriers of one or more IMDs to which they often owe their quality of life or survival. IMDs are constructed with different types of materials that are often combined in the same prosthesis. These materials must combine harmlessness to human tissues with high wear resistance. Their durability depends on many factors both on the host and the type of prosthesis, but the vast majority last for more than 10-15 years or remain in function for the lifetime of the patient. The most frequently implanted IMDs are placed in the heart or great vessels, joints, dental arches or breast and their most frequent complications are classified as non-infectious, particularly loosening or intolerance, and infectious. Complications, when they occur, lead to a significant increase in morbidity, their repair or replacement multiplies the health care cost and, on occasions, can cause the death of the patient. The fight against IMD complications is currently focused on the design of new materials that are more resistant to wear and infection and the use of antimicrobial substances that are released from these materials. Their production requires multidisciplinary technical teams, but also a willingness on the part of industry and health authorities that is not often found in Spain or in most European nations. Scientific production on prostheses and IMD in Spain is estimated to be less than 2% of the world total, and probably below what corresponds to our level of socio-economic development. The future of IMDs involves, among other factors, examining the potential role of Artificial Intelligence in their design, knowledge of tissue regeneration, greater efficiency in preventing infections and taking alternative treatments beyond antimicrobials, such as phage therapy. For these and other reasons, the Ramón Areces Foundation convened a series of experts in different fields related to prostheses and IMDs who answered and discussed a series of questions previously formulated by the Scientific Council. The following lines are the written testimony of these questions and the answers to them.

Gait parameters in a reference sample of healthy Spanish schoolchildren: multivariate descriptive statistics and asymmetries observed in left and right cycles.

INTRODUCTION: Instrumental gait analysis is an emerging technology used increasingly to evaluate motor disorders in children. Normal reference data is necessary in order to evaluate patients, but there are few reference resources for the Spanish paediatric population. OBJECTIVE: We aim to describe the values of 16 clinically relevant gait variables in healthy Spanish schoolchildren, and identify any linear associations or left-right asymmetries. SUBJECTS AND METHODS: The values of 16 gait variables were determined in schoolchildren (n=27, aged 5-13 years) using instrumental gait analysis. We analysed asymmetries for each variable (Student's t-test for dependent samples) and calculated their confidence intervals (95% of the standardised difference in right and left means [SMD]). Values and associations between variables were represented using a heat map. RESULTS: Our project presents normal values tables for 16 variables in the gait cycle. Significant asymmetries were detected in the mean values for minimum hip flexion (SMD: 0.25 95% CI, 0.11-0.39) and peak hip abduction in swing (SMD: -1.05 95% CI: -1.71--0.27). Functional associations among gait variables are present. CONCLUSIONS: We present a reference dataset for Spanish school-aged children in which left-right asymmetries and functional associations may be observed for different variables.

Mullins effect behaviour under compression in micelle-templated silica and micelle-templated silica/agarose systems.

The mechanical properties of bioceramic conformed pieces based on micelle-templated silica (MTS) such as SBA15, MCM41 and MCM48 as well as MTS/agarose systems have been evaluated under static and cyclic compressive tests. The MTS pieces exhibited a brittle behaviour. Agarose, a biocompatible and biodegradable hydrogel, has been used to shape ceramic-agarose pieces following a low temperature shaping method. Agarose conferred toughness, ductility and a rubbery consistency up to a 60% strain in ceramic MTS/agarose systems leading to a maximum strength of 10-50 MPa, without losing their initial cylindrical structure. This combination of ceramic and organic matrix contributes to avoiding the inherent brittleness of the bioceramic and enhances the compression resistance of hydrogel. The presence of mechanical hysteresis, permanent deformation after the first cycle and recovery of the master monotonous curve of MTS/agarose systems indicate a Mullins-like effect similar to that found in carbon-filled rubber systems. We report this type of mechanical behaviour, the Mullins effect, for the first time in MTS bioceramics and MTS bioceramic/agarose systems.

Explant analysis and implant registries are both needed to further improve patient safety.

In the early days of total joint replacement, implant fracture, material problems and wear presented major problems for the long-term success of the operation. Today, failures directly related to the implant comprise only 2-3% of the reasons for revision surgeries, which is a result of the material and design improvements in combination with the standardization of pre-clinical testing methods and the post-market surveillance required by the legal regulation. Arthroplasty registers are very effective tools to document the long-term clinical performance of implants and implantation techniques such as fixation methods in combination with patient characteristics. Revisions due to implant failure are initially not reflected by the registries due to their small number. Explant analysis including patient, clinical and imaging documentation is crucial to identify failure mechanisms early enough to prevent massive failures detectable in the registries. In the past, early reaction was not always successful, since explant analysis studies have either been performed late or the results did not trigger preventive measures until clinical failures affected a substantial number of patients. The identification of implant-related problems is only possible if all failures are reported and related to the number of implantations. A system that analyses all explants from revisions attributed to implant failure is mandatory to reduce failures, allowing improvement of risk assessment in the regulatory process.

Bone regeneration and stem cells.

This invited review covers research areas of central importance for orthopaedic and maxillofacial bone tissue repair, including normal fracture healing and healing problems, biomaterial scaffolds for tissue engineering, mesenchymal and foetal stem cells, effects of sex steroids on mesenchymal stem cells, use of platelet-rich plasma for tissue repair, osteogenesis and its molecular markers. A variety of cells in addition to stem cells, as well as advances in materials science to meet specific requirements for bone and soft tissue regeneration by addition of bioactive molecules, are discussed.

Bacterial adherence on UHMWPE with vitamin E: an in vitro study.

Orthopaedic materials may improve its capacity to resist bacterial adherence, and subsequent infection. Our aim was to test the bacterial adherence to alpha-tocopherol (frequently named vitamin E, VE) doped or blended UHMWPE with S. aureus and S. epidermidis, compared to virgin material. Collection strains and clinical strains isolated from patients with orthopaedic infections were used, with the biofilm-developing ability as a covariable. While collection strains showed significantly less adherence to VE-UHMWPE, some clinical strains failed to confirm this effect, leading to the conclusion that VE doped or blended UHMWPE affects the adherence of some S. epidermidis and S. aureus strains, independently of the concentration in use, but the results showed important intraspecies differences and cannot be generalized.

An experimental study of COMP (cartilage oligomeric matrix protein) in the rabbit menisci.

INTRODUCTION: Secondary knee osteoarthritis (OA) is currently associated with meniscal injuries, but the pathogenesis is unclear. We analyzed the distribution of cells and cartilage oligomeric matrix protein (COMP) and its changes in the early stages of degeneration in meniscus. METHOD: Ten New Zealand rabbits underwent anterior cruciate ligament (ACL)-transection of the right knee-joint. Left knee-joints were used as controls. The animals were killed at 4 and 12 weeks. Gross injuries in meniscus and articular cartilage were scored. Meniscal tissues were immunostained with a specific antibody against COMP, with Ki-67, using TUNEL-assay and alcian blue stain. The number of cells was counted. RESULTS: At 4 weeks post-ACL-transection, 2/5 of the operated knees showed articular damages and medial menisci tears. Menisci showed a weak increase of cells, higher in cells under division and an increase of apoptosis, COMP and proteoglycans. At 12 weeks, 5/5 of the medial menisci and 2/5 of lateral menisci presented tears, and osteoarthritic changes were seen in the cartilage of all the operated knees. Meniscal cells reverted to normal number, while active cell division decreased below normal, apoptotic events were still high, COMP remained elevated, and glycosaminoglycans were even more elevated. CONCLUSION: Extracellular matrix changes and altered cell distribution occur early in the degenerative meniscus. There is a close relationship between changes in the articular cartilage and the menisci at the onset of secondary OA.

Special modes of corrosion under physiological and simulated physiological conditions.

The aim of this article is to review those aspects of corrosion behaviour that are most relevant to the clinical application of implant alloys. The special modes of corrosion encountered by implant alloys are presented. The resistance of the different materials against the most typical corrosion modes (pitting corrosion, crevice corrosion and fretting corrosion) is compared, together with observations of metal ion release from different biomaterials. A short section is dedicated to possible galvanic effects in cases when different types of materials are combined in a biomedical device. The different topics covered are introduced from the viewpoint of materials science, and then placed into the context of medicine and clinical experience.

Comparative fatigue behavior and toughness of remelted and annealed highly crosslinked polyethylenes.

Highly cross-linked polyethylenes (HXLPEs) have been incorporated into the hip replacement armamentarium based on their improved wear resistance. However, two different methods of thermal treatment separate the orthopedic community as strategies to control potential long-term oxidation, and controversy remains with problems in the long-term use of acetabular liners (long-term oxidation, rim fracture after impingement, etc.). Meanwhile, the mechanical properties of HXLPEs that may alleviate these problems are still unclear. On the other hand, HXLPEs are scarcely used in knee replacements, as there exists concern about the probably reduced fatigue and fracture performances of these materials. Thus, our aim was to compare the effects of both thermal treatment regimes on mechanical properties and to associate these findings with the material microstructure. The fatigue behavior of annealed and remelted HXLPEs was characterized using short-term cyclic stress-strain, long-term fatigue, and fatigue crack propagation tests. On the other hand, impact tests, tensile experiments, and the J-integral multispecimen method allowed us to assess toughness. Microstructure features such as crosslink density, crystallinity percentage, and lamellar thickness were investigated by swelling measurements, differential scanning calorimetry, and transmission electron microscopy, respectively. This study confirms that annealing preserves mechanical properties better than remelting from both fatigue and fracture resistance points of view, and it remarks that a suitable selection of irradiation and stabilization conditions is needed to achieve optimal mechanical performances of ultra high molecular weight polyethylenes for each specific total joint replacement.

Reliability of a simple fluoroscopic method to study sagittal plane femorotibial contact changes in total knee arthroplasties during flexion.

Clinical interest in sagittal plane kinematic analysis of the knee undergoing total knee replacement fosters the development of simple, reliable methods to estimate femorotibial contact in a regular clinical setting. In this study, the sagittal femorotibial contact was analysed in lateral X-rays and lateral fluoroscopic views, from extension to knee flexion. Quantitative and categorical data were obtained from these views by two different observers, and compared with data from direct views of the components. Interobserver and intermethod errors for quantitative and categorical data were evaluated based on correlation, kappa coefficient, and Bland-Altman graphs. Interobserver reproducibility of quantitative measurement from fluoroscopic views was r=0.96 while categorical assignment exhibited a kappa coefficient of 0.95. Reproducibility from plain radiographs was not so high, with a kappa coefficient of 0.64. High concordance was also obtained when the method was compared with the direct view of the implant, supporting these measurement techniques. Bland-Altman graphs confirmed the absence of bias in the intermethod comparison. Therefore, with the obvious limitation of rotational assessment, lateral fluoroscopic evaluation enhanced by a simple fitting technique can be used as a valuable tool for clinical evaluation of knee kinematics in the sagittal plane.

Proprioception in the ACL-ruptured knee: the contribution of the medial collateral ligament and patellar ligament. An in vivo experimental study in the cat.

In the absence of anterior cruciate ligament (ACL), secondary restraints such as menisci, ligaments, and tendons restrict anterior knee laxity. Strain detection at these sites could define the contribution of this alternative signalling system to knee proprioception after ACL injury. The hypothesis in this study questions if measurements of anterior tibial translation (ATT) from surface strain gauges on the insertions of the medial collateral ligament (MCL) and the patellar tendon (PT) are sufficiently sensitive and specific to differentiate normal, stable knees from acutely unstable knees due to ACL section. Twelve cats received miniaturized strain gauges on the surface of MCL and PT distal insertions. A purpose-made receiver transformed into measurements any voltage variation obtained during passive knee flexion-extension and anterior tibial translation manoeuvres. Variables under evaluation included first peak latency, normalized amplitude, and slope of voltage along time. Femorotibial displacements were video recorded, digitized, and used as the ATT reference. The proposed system detected significant changes in the slope of the voltage/time signal, with higher specificity and sensitivity during ATT after experimental ACL section. Changes were not significant during flexion or extension. It was found that a pattern of earlier and more intense strain in MCL and PT distal insertions was found during ATT in the ACL deficient knee. Enhanced pattern recognition learning from these structures could be a future target for proprioceptive training after ACL injury.

Evaluation of bacterial adherence of clinical isolates of Staphylococcus sp. using a competitive model: An in vitro approach to the "race for the surface" theory.

OBJECTIVES: Implant-related infection is one of the most devastating complications in orthopaedic surgery. Many surface and/or material modifications have been developed in order to minimise this problem; however, most of the in vitro studies did not evaluate bacterial adhesion in the presence of eukaryotic cells, as stated by the 'race for the surface' theory. Moreover, the adherence of numerous clinical strains with different initial concentrations has not been studied. METHODS: We describe a method for the study of bacterial adherence in the presence of preosteoblastic cells. For this purpose we mixed different concentrations of bacterial cells from collection and clinical strains of staphylococci isolated from implant-related infections with preosteoblastic cells, and analysed the minimal concentration of bacteria able to colonise the surface of the material with image analysis. RESULTS: Our results show that clinical strains adhere to the material surface at lower concentrations than collection strains. A destructive effect of bacteria on preosteoblastic cells was also detected, especially with higher concentrations of bacteria. CONCLUSIONS: The method described herein can be used to evaluate the effect of surface modifications on bacterial adherence more accurately than conventional monoculture studies. Clinical strains behave differently than collection strains with respect to bacterial adherence.Cite this article: M. Martinez-Perez, C. Perez-Jorge, D. Lozano, S. Portal-Nuñez, R. Perez-Tanoira, A. Conde, M. A. Arenas, J. M. Hernandez-Lopez, J. J. de Damborenea, E. Gomez-Barrena, P. Esbrit, J. Esteban. Evaluation of bacterial adherence of clinical isolates of Staphylococcus sp. using a competitive model: An in vitro approach to the "race for the surface" theory. Bone Joint Res 2017;6:315-322. DOI: 10.1302/2046-3758.65.BJR-2016-0226.R2.

Cartilage oligomeric matrix protein (COMP) is modified by intra-articular liposomal clodronate in an experimental model of arthritis.

OBJECTIVE: High-dose liposomal bisphosphonates exert apoptotic effects. This work studies the chondroprotective and anti-inflammatory properties of intra-articularly administered low-dose, non-cytotoxic liposomal clodronate. METHODS: Antigen induced arthritis in rabbits was treated with intra-articular injections of liposomal clodronate. Drug effects on cartilage oligomeric matrix protein COMP was assessed using immunohistochemistry and morphometry of synovial membrane and hyaline articular cartilage. RESULTS: COMP remained close to normal in liposomal clodronate treated superficial articular cartilage compared to a significant loss of COMP in arthritis controls treated with empty liposomes. The middle and deep layers of the hyaline articular cartilage were characterized by highly increased COMP expression in liposomal clodronate treated AIA joints compared to controls. In contrast to cartilage, synovial COMP expression was slightly decreased as a result of liposomal clodronate treatment. CONCLUSION: Low-dose, non-cytotoxic liposomal clodronate exerts a dichotomous effect on synovial membrane and articular cartilage COMP in the AIA model. COMP is a useful inflammation marker in the synovial tissue, but it also contributes to the structural integrity of the hyaline articular cartilage forming bridges between type II and IX collagens. Enhancement of COMP in clodronate treated AIA cartilage suggests a chondroprotective and anti-inflammatory effect in the inflammatorily damaged and mechanically strained cartilage.

Influence of the remelting process on the fatigue behavior of electron beam irradiated UHMWPE.

Electron beam irradiation at doses below 150 kGy is a widely used technique to obtain highly crosslinked ultra-high-molecular-weight polyethylene (UHMWPE). Its current use in total joint replacement components may improve wear resistance and decrease UHMWPE particle debris. However, currently used post-irradiation thermal treatments, which aim to decrease the free radicals within the material, introduce microstructural changes that affect UHMWPE mechanical properties, particularly the fatigue strength. This influence may be crucial in total knee replacements, where fatigue-related damage limits the lifespan of the prosthesis. Therefore, more studies are required to understand UHMWPE fatigue after current crosslinking protocols. This study was planned to evaluate the influence of UHMWPE remelting after irradiation on the material fatigue resistance. The remelting was achieved at 150 degrees C for 2 h on UHMWPE previously irradiated at 50, 100, and 150 kGy. Fatigue evaluation included short-term tests under cyclic tensile stress with zero load ratio, R = 0, and 1 Hz. In addition, stress-life testing was performed using 12% yield as the criterion for failure. Near-threshold fatigue crack propagation experiments were also performed at a frequency of 5 Hz, and crack length was measured in nonthermally treated and remelted irradiated UHMWPE. Crystallinity percentage was calculated from DSC measurements. The results pointed out that irradiation positively contributed to total life analysis, but the further remelting process decreased the flaw initiation resistance. On the other hand, both processes negatively affected the fatigue resistance of notched components. From a clinical point of view, the results suggest that the material fatigue behavior should be carefully studied in new UHMWPE to avoid changes related to material processing.

Fracture behavior of UHMWPE in non-implanted, shelf-aged knee prostheses after gamma irradiation in air.

We studied non-implanted ultra-high molecular weight polyethylene (UHMWPE) knee components, that were gamma-sterilized in air and shelf-aged during 6 and 7 years, to explore fracture mechanisms in the degraded material. Prior to the fractography study, we assessed degradation through FTIR and optical density measurements in microtome sections. Then, we morphologically compared the surface fractography of degraded, oxidized UHMWPE with that of non-degraded material in specimens from the same implants, fractured after uniaxial tensile tests in standardized samples. Fractography surface analysis clearly differentiated the behavior of non-degraded and degraded UHMWPE. Failure in non-degraded samples occurred through craze formation, followed by fast crack propagation. Quantitative fracture analysis suggested a ductile behavior. This was supported by the identified local plasticity in the region close to the initial flaw. In the fractography surface analysis of degraded material, a fibrillar behavior was observed. A heterogeneous domain structure appeared, showing different coarseness with multiple void sizes. Our results, based on mechanical measurements and fracture morphology in the subsurface region, confirmed the embrittlement of oxidized UHMWPE.

Fractography evolution in accelerated aging of UHMWPE after gamma irradiation in air.

We studied the fracture surface evolution of ultra high molecular weight polyethylene (UHMWPE) specimens, manufactured from GUR 1050 compression moulded sheets, after gamma sterilisation in air followed by different aging times after thermal treatment at 120 degrees C. Degradation profiles were obtained by FTIR and DSC measurements after 0, 7, 14, 24 and 36h aging. We observed by SEM the morphology patterns at these aging times, in surface fractographies after uniaxial tensile test of standardised samples. The results pointed out clear differences between short and long aging times. At shorter times, 7h, the behaviour was similar to non-degraded UHMWPE, exhibiting ductile behaviour. At longer times, 24-36h, this thermal protocol provided a highly degraded zone in the subsurface, similar to the white band found after gamma irradiation in air followed by natural aging, although closer to the surface, at 150-200mum. The microstructure of this oxidation zone, similarly found in gamma irradiated samples shelf-aged for 6-7 years, although with different distribution of microvoids, was formed by fibrils, associated with embrittlement of the oxidised UHMWPE. In addition, the evolution of the oxidation index, the enthalpy content, the mechanical parameters, and the depth of the oxidation front deduced from the fractographies versus aging time showed that a changing behaviour in the degradation rate appeared at intermediate aging times.

Intrinsic innervation in the intestine of the lizard Podarcis hispanica.

The aim of this study was the description of the morphology and distribution of nerve structure elements in the intestine of the lizard Podarcis hispanica using different histochemical methods; namely acetylcholinesterase (AChE), formol-induced fluorescence for catecholamines (FIF), nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), and immunohistochemistry for vasoactive intestinal peptide (VIP), as well as substance P (SP) and electron microscopy. The AChE method showed fibres in the myenteric and submucosal plexus, with a higher fibre density in the large intestine. The highest number of related neurons was located in the myenteric plexus ganglia. Noradrenergic innervation was distributed through the myenteric and submucosal plexus, and also around blood vessels, with the highest fibre density in the large intestine. VIP immunohistochemistry showed a wide distribution of positive fibres throughout the intestine, although the highest density was again detected in the large intestine. Small positive cells for VIP were located at internodal segments in the plexus. SP labeling, although subtle, was present all along the intestine. It showed delicate varicose nets and few fibres innervating blood vessels. Small positive cells for SP were located in the large intestine. The indirect method to detect nitric oxide (NO)-producing system showed neural cells in the myenteric plexus ganglia of the large intestine. Electron microscopy showed ganglion neurons with scattered chromatin condensations, glial cells with higher electron density, and axons with varicosities occupied by different vesicles. We also identified certain cells as interstitial cells of Cajal due to their ultrastructural features. They were mostly located in the region of the myenteric plexus.

Gold chloride technique to study articular innervation. A protocol validated through computer-assisted colorimetry.

We studied variations in gold chloride techniques to elicit neural elements within articular samples, after "in toto" staining. These techniques attempt the differentiation of neural and vascular structures. Major changes in differential staining were observed when the gold chloride concentration was empirically modified. After the rest of the technique was standardized, we selected three gold chloride solutions to perform quantitative color experiments: 1%, 0.75%, and 0.5%. Significant sections of the same thickness were acquired with a digital camera to perform computer-assisted colorimetry. Color was measured through RGB (red-green-blue) channels in vessels, nerves, and background connective tissue as an internal control. By means of multivariate regression analysis, we compared differences in color measurements after 1%, 0.75% and 0.5% gold chloride preparation. Statistically significant coefficients confirmed that red color signals in vessels after the 0.75% and the 0.5% solution were both less intense than after the 1% preparation. Green and blue signals in vessels were also significantly less intense after the 0.5% protocol than after using the 1% solution. Red color signals in nerves between the 1% and the 0.75% preparation protocols were more intense and not significantly different, while the 0.5% preparation produced significantly less intense red signals in nerves. Non-significant differences were observed in green or blue signals from nerves after any protocol. We concluded that the 0.75% gold chloride solution protocol produced more intense red signals in nerves and less intense red signals in vessels. This was the most discriminant protocol in our series, based on color signals.

Interleukin-6 in aseptic loosening of total hip replacement prostheses.

OBJECTIVE: To investigate the level of interleukin-6 (IL-6) expression in the synovial-like interface membrane (SLIM) and in the pseudosynovial tissue surrounding the artificial hip joints, as well as in the pseudosynovial fluid from aseptically loosened total hip replacement (THR) prostheses. METHODS: A series of methods were used in this study including immunohistochemical staining, double immunofluorescence labeling, enzyme-linked immunosorbent assay (ELISA), and reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: IL-6 was found in all SLIM and the pseudosynovial tissue samples from aseptic loosening of THR. Semi-quantitative morphometry showed that IL-6 containing cells were more numerous in the SLIM (911 +/- 197; p < 0.01) and the pseudosynovial tissue samples (883 +/- 310; p < 0.01) than in the control synovial tissue (291 +/- 184). Double labeling confirmed that macrophages and fibroblasts were the predominant cell types expressing IL-6. These findings were confirmed by RT-PCR. ELISA revealed no difference in the IL-6 concentration between the pseudosynovial fluid and the control synovial fluid obtained from the patients undergoing hip arthroscopy. CONCLUSIONS: IL-6 locally produced in SLIM may in a paracrine manner contribute to periprosthetic osteolysis of the nearby bone. In contrast, fluid phase IL-6 does not seem to contribute to this end.