High circulating concentrations of estradiol are anabolic for bone mass and strength in an adult male to female transgender mouse model.

The effects of gender affirming hormone therapy (GAHT) on bone microarchitecture and fracture risk in adult transgender women is unclear. To investigate the concept that skeletal integrity and strength in trans women may be improved by treatment with a higher dose of GAHT than commonly prescribed, we treated adult male mice with a sustained, high dose of estradiol. Adult male mice at 16 weeks of age were administered ~1.3 mg estradiol by silastic implant, implanted intraperitoneally, for 12 weeks. Controls included vehicle treated intact females and males. High-dose estradiol treatment in males stimulated the endocortical deposition of bone at the femoral mid-diaphysis, increasing cortical thickness and bone area. This led to higher stiffness, maximum force, and the work required to fracture the bone compared to male controls, while post-yield displacement was unaffected. Assessment of the material properties of the bone showed an increase in both elastic modulus and ultimate stress in the estradiol treated males. Treatment of male mice with high dose estradiol was also anabolic for trabecular bone, markedly increasing trabecular bone volume, number and thickness in the distal metaphysis which was accompanied by an increase in the histomorphometric markers of bone remodelling, mineralizing surface/bone surface, bone formation rate and osteoclast number. In conclusion, a high dose of estradiol is anabolic for cortical and trabecular bone in a male to female transgender mouse model, increasing both stiffness and strength. These findings suggest that increasing the current dose of GAHT administered to trans women, while considering other potential adverse effects, may be beneficial to preserving their bone microstructure and strength.

Glycosaminoglycan-Mediated Interactions in Articular, Auricular, Meniscal, and Nasal Cartilage.

Glycosaminoglycans (GAGs) are ubiquitous components in the cartilage extracellular matrix (ECM). Ultrastructural arrangement of ECM and GAG-mediated interactions with collagen are known to govern the mechanics in articular cartilage, but these interactions are less clear in other cartilage types. Therefore, this article reviews the current literature on ultrastructure of articular, auricular, meniscal, and nasal septal cartilage, seeking insight into GAG-mediated interactions influencing mechanics. Ultrastructural features of these cartilages are discussed to highlight differences between them. GAG-mediated interactions are reviewed under two categories: interactions with chondrocytes and interactions with other fibrillar macromolecules of the ECM. Moreover, efforts to replicate GAG-mediated interactions to improve mechanical integrity of tissue-engineered cartilage constructs are discussed. In conclusion, studies exploring cartilage specific GAGs are poorly represented in the literature, and the ultrastructure of nasal septal and auricular cartilage is less studied compared with articular and meniscal cartilages. Understanding the contribution of GAGs in cartilage mechanics at the ultrastructural level and translating that knowledge to engineered cartilage will facilitate improvement of cartilage tissue engineering approaches.

Navigating the path of progress: The OMERACT 2023 emerging leaders program.

OBJECTIVES: The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Emerging Leaders Program (ELP) aims to cultivate a cohort of skilled leaders within the OMERACT community empowering them with expertise and knowledge to help shape and steer the organization into the future. This publication highlights the significance of the ELP in driving leadership excellence, its impact on OMERACT's evolution, and the outcomes and learnings from the OMERACT 2023 ELP. METHODS: Insights from the 2018 ELP report informed 2023 program improvements. Engagement was measured by attendance and WhatsApp interactions. Positive program aspects, areas for improvement and ideas for enhancing future ELPs were captured via anonymous survey and participant focus groups. RESULTS: Engagement with the ELP was high with 9 participants, 96 % attendance at all workshops, 154 WhatsApp interactions. All program components were highly rated, with the highest being the 'Psychological Safety' and 'Methodology/Process/Politics' workshops. Future enhancements included creating further networking, connection and support activities, practical leadership and methodological skill development opportunities, and a new stream focussing on organisational advancement. CONCLUSIONS: The 2023 OMERACT ELP was well received and successfully addressed areas previously identified as requiring improvement. New educational enhancements were valued, and the importance of fostering psychological safety at all levels was highlighted. The ELP fortifies OMERACT by nurturing a diverse array of skilled leaders who embody OMERACTs core values. Continuing to refine and evolve the ELP over time will help OMERACT sustain its global influence in patient-centered outcome research.

Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy.

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown. To address this knowledge gap, we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment. Puberty was suppressed by orchidectomy in male mice at 5 weeks of age. At 3 weeks post-surgery, male-to-female mice were treated with a high dose of estradiol (~0.85 mg) by intraperitoneal silastic implantation for 12 weeks. Controls included intact and orchidectomized males at 3 weeks post-surgery, vehicle-treated intact males, intact females and orchidectomized males at 12 weeks post-treatment. Compared to male controls, orchidectomized males exhibited decreased peak bone mass accrual and a decreased maximal force the bone could withstand prior to fracture. Estradiol treatment in orchidectomized male-to-female mice compared to mice in all control groups was associated with an increased cortical thickness in the mid-diaphysis, while the periosteal circumference increased to a level that was intermediate between intact male and female controls, resulting in increased maximal force and stiffness. In trabecular bone, estradiol treatment increased newly formed trabeculae arising from the growth plate as well as mineralizing surface/bone surface and bone formation rate, consistent with the anabolic action of estradiol on osteoblast proliferation. These data support the concept that skeletal integrity can be preserved and that long-term fractures may be prevented in trans girls treated with GnRHa and a sufficiently high dose of GAHT. Further study is needed to identify an optimal dose of estradiol that protects the bone without adverse side effects.

Erosion Identification in Metacarpophalangeal Joints in Rheumatoid Arthritis using High-Resolution Peripheral Quantitative Computed Tomography.

Bone erosions are a pathological feature of several forms of inflammatory arthritis including rheumatoid arthritis (RA). The increased presence and size of erosions are associated with poor outcomes, joint function, and disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unparalleled in vivo visualization of bone erosions. However, at this resolution, discontinuities in the cortical shell (cortical breaks) that are associated with normal physiological processes and pathology are also visible. The Study grouP for xtrEme Computed Tomography in Rheumatoid Arthritis previously used a consensus process to develop a definition of pathological erosion in HR-pQCT: a cortical break detected in at least two consecutive slices, in at least two perpendicular planes, non-linear in shape, with underlying trabecular bone loss. However, despite the availability of a consensus definition, erosion identification is a demanding task with challenges in inter-rater variability. The purpose of this work is to introduce a training tool to provide users with guidance on identifying pathological cortical breaks on HR-pQCT images for erosion analysis. The protocol presented here uses a custom-built module (Bone Analysis Module (BAM) - Training), implemented as an extension to an open-source image processing software (3D Slicer). Using this module, users can practice identifying erosions and compare their results to erosions annotated by expert rheumatologists.

Image Registration in Longitudinal Bone Assessment Using Computed Tomography.

PURPOSE OF REVIEW: Rigid image registration is an important image processing tool for the assessment of musculoskeletal chronic disease. In this paper, we critically review applications of rigid image registration in terms of similarity measurement methods over the past three years (2019-2022) in the context of monitoring longitudinal changes to bone microstructure and mechanical properties using computed tomography. This review identifies critical assumptions and trade-offs underlying different similarity measurement methods used in image registration and demonstrates the effect of using different similarity measures on registration outcomes. RECENT FINDINGS: Image registration has been used in recent studies for: correcting positional shifts between longitudinal scans to quantify changes to bone microstructural and mechanical properties over time, developing registration-based workflows for longitudinal assessment of bone properties in pre-clinical and clinical studies, and developing and validating registration techniques for longitudinal studies. In evaluating the recent literature, it was found that the assumptions at the root of different similarity measures used in rigid image registration are not always confirmed and reported. Each similarity measurement has its advantages and disadvantages, as well as underlying assumptions. Breaking these assumptions can lead to poor and inaccurate registration results. Thus, care must be taken with regards to the choice of similarity measurement and interpretation of results. We propose that understanding and verifying the assumptions of similarity measurements will enable more accurate and efficient quantitative assessments of structural changes over time.

Modeling human skeletal development using human pluripotent stem cells.

Chondrocytes and osteoblasts differentiated from induced pluripotent stem cells (iPSCs) will provide insights into skeletal development and genetic skeletal disorders and will generate cells for regenerative medicine applications. Here, we describe a method that directs iPSC-derived sclerotome to chondroprogenitors in 3D pellet culture then to articular chondrocytes or, alternatively, along the growth plate cartilage pathway to become hypertrophic chondrocytes that can transition to osteoblasts. Osteogenic organoids deposit and mineralize a collagen I extracellular matrix (ECM), mirroring in vivo endochondral bone formation. We have identified gene expression signatures at key developmental stages including chondrocyte maturation, hypertrophy, and transition to osteoblasts and show that this system can be used to model genetic cartilage and bone disorders.

Near-infrared spectroscopy for structural bone assessment.

Disorders of bone integrity carry a high global disease burden, frequently requiring intervention, but there is a paucity of methods capable of noninvasive real-time assessment. Here we show that miniaturized handheld near-infrared spectroscopy (NIRS) scans, operated via a smartphone, can assess structural human bone properties in under three seconds. A hand-held NIR spectrometer was used to scan bone samples from 20 patients and predict: bone volume fraction (BV/TV); and trabecular (Tb) and cortical (Ct) thickness (Th), porosity (Po), and spacing (Sp). NIRS scans on both the inner (trabecular) surface or outer (cortical) surface accurately identified variations in bone collagen, water, mineral, and fat content, which then accurately predicted bone volume fraction (BV/TV, inner R2 = 0.91, outer R2 = 0.83), thickness (Tb.Th, inner R2 = 0.9, outer R2 = 0.79), and cortical thickness (Ct.Th, inner and outer both R2 = 0.90). NIRS scans also had 100% classification accuracy in grading the quartile of bone thickness and quality. We believe this is a fundamental step forward in creating an instrument capable of intraoperative real-time use.

A novel device for investigating structure-function relationships and mechanoadaptation of biological tissues.

Exploring the structure-function relationships of cartilage on a microstructural level is crucial for tissue engineering approaches aiming to restore function. Therefore, a combination of mechanical testing with cell and tissue-level imaging would allow for longitudinal studying loading mechanisms, biological responses and mechanoadaptation of tissues at a microstructural level. This paper describes the design and validation of FELIX, a custom-built device for non-destructive image-guided micromechanical evaluation of biological tissues and tissue-engineered constructs. It combines multiphoton microscopy with non-destructive mechanical testing of native soft tissues. Ten silicone samples of the same size were mechanically tested with FELIX by different users to assess the repeatability and reproducibility. The results indicate that FELIX can successfully substitute mechanical testing protocols with a commercial device without compromising precision. Furthermore, FELIX demonstrated consistent results across repeated measurements, with very small deviations. Therefore, FELIX can be used to accurately measure biomechanical properties by different users for separate studies. Additionally, cell nuclei and collagen of porcine articular cartilage were successfully imaged under compression. Cell viability remained high in chondrocytes cultured in agarose over 21 days. Furthermore, there were no signs of contamination indicating a cell friendly, sterile environment for longitudinal studies. In conclusion, this work demonstrates that FELIX can consistently quantify mechanical measures without compromising precision. Furthermore, it is biocompatible allowing for longitudinal measurements.

Analysis of Hand Joint Space Morphology in Women and Men with Hereditary Hemochromatosis.

Hereditary hemochromatosis (HH) causes unbalanced iron deposition in many organs including the joints leading to severe cartilage loss and bone damage in the metacarpophalangeal joints (MCPJ). High-resolution peripheral quantitative computed tomography (HR-pQCT) and its joint space width (JSW) quantification algorithm quantifies in vivo 3D joint morphology. We therefore aimed to (i) determine feasibility and performance of the JSW algorithm in HH, (ii) quantify joint space morphology, and (iii) investigate the relationship between morphological and clinical parameters in HH. Here, we performed an exploratory study on 24 HH patients and sex- and age-matched controls using HR-pQCT imaging of MCPJ. Mineralized bone structure was automatically segmented from the grayscale image data and periosteal surface bone masks and joint space masks were generated. Mean, minimal, and maximal joint space width (JSW; JSW.MIN; JSW.MAX), JSW heterogeneity (JSW.SD), JSW asymmetry (JSW.AS), and joint space volume (JSV) were computed. Demographics and, for HH patients, disease-specific parameters were recorded. Segmentation of JS was very good with 79.7% of MCPJs successfully segmented at first attempt and 20.3% requiring semi-manual correction. HH men showed larger JSV at all MCPs (+ 25.4% < JSV < + 41.8%, p < 0.05), larger JSW.MAX at MCP 3-4 (+ 14%, 0.006 < p < 0.062), and wider JSW (+ 13%, p = 0.043) at MCP 4 relative to HH women. Compared to controls, both HH men and HH women showed larger JSW.AS and smaller JSW.MIN at all MCP levels, reaching significance for HH men at MCP 2 and 3 (JSW.AS: + 323% < JSW.AS < + 359%, 0.020 < p < 0.043; JSW.MIN: - 216% < JSW.MIN < - 225%, p < 0.043), and for women at MCP 3 (JSW.AS: + 180%, p = 0.025; JSW.MIN: - 41.8%, p = 0.022). Time since HH diagnosis was correlated positively with MCP 4 JSW.AS and JSW.SD (0.463 < ρ < 0.499, p < 0.040), and the number of phlebotomies since diagnosis was correlated with JSW.SD at all MCPs (0.432 < ρ < 0.535, p < 0.050). HR-pQCT-based JSW quantification in MCPJ of HH patients is feasible, performs well even in narrow JS, and allows to define the microstructural joint burden of HH.

Evaluation of a lanthanide nanoparticle-based contrast agent for microcomputed tomography of porous channels in subchondral bone.

Osteoarthritis (OA) is a chronic joint disease that causes disability and pain. The osteochondral interface is a gradient tissue region that plays a significant role in maintaining joint health. It has been shown that during OA, increased neoangiogenesis creates porous channels at the osteochondral interface allowing the transport of molecules related to OA. Importantly, the connection between these porous channels and the early stages of OA development is still not fully understood. Microcomputed tomography (microCT) offers the ability to image the porous channels at the osteochondral interface, however, a contrast agent is necessary to delineate the different X-ray attenuations of the tissues. In this study BaYbF5 -SiO2 nanoparticles are synthesized and optimized as a microCT contrast agent to obtain an appropriate contrast attenuation for subsequent segmentation of structures of interest, that is, porous channels, and mouse subchondral bone. For this purpose, BaYbF5 nanoparticles were synthesized and coated with a biocompatible silica shell (SiO2 ). The optimized BaYbF5 -SiO2 27 nm nanoparticles exhibited the highest average microCT attenuation among the biocompatible nanoparticles tested. The BaYbF5 -SiO2 27 nm nanoparticles increased the mean X-ray attenuation of structures of interest, for example, porous channel models and mouse subchondral bone. The BaYbF5 -SiO2 contrast attenuation was steady after diffusion into mouse subchondral bone. In this study, we obtained for the first time, the average microCT attenuation of the BaYbF5 -SiO2 nanoparticles into porous channel models and mouse subchondral bone. In conclusion, BaYbF5 -SiO2 nanoparticles are a potential contrast agent for imaging porous channels at the osteochondral interface using microCT.

A microCT imaging protocol for reproducible and efficient quantitative morphometric analysis (QMA) of joint structures of the in situ mouse tibio-femoral joint.

Micro-computed tomography (microCT) offers a three-dimensional (3D), high-resolution technique for the visualisation and analysis of bone microstructure. Using contrast-enhanced microCT, this capability has been expanded in recent studies to include cartilage morphometry and whole joint measures, known together as quantitative morphometric analysis (QMA). However, one of the main challenges in quantitative analysis of joint images is sensitivity to joint pose and alignment, which may influence measures related to both joint space and joint biomechanics. Thus, this study proposes a novel microCT imaging protocol for reproducible and efficient QMA of in situ mouse tibio-femoral joint. This work consists of two parts: an in situ diffusion kinetics study for a known cationic iodinated contrast agent (CA4+) for QMA of the cartilage, and a joint positioning and image processing workflow for whole joint QMA. In the diffusion kinetics study, 8 mice were injected at both of their tibio-femoral joints with distinct CA4+ concentrations and diffusion times. The mice were scanned at different time points after injection, and evaluated using attenuation and cartilage QMA measures. Results show that cartilage segmentation and QMA could be performed for CA4+ solution at a concentration of 48 mg/ml, and that reliable measurement and quantification of cartilage were achieved after 5 min of diffusion following contrast agent injection. We established the joint positioning and image processing workflow by developing a novel positioning device to control joint pose during scanning, and a spherical harmonics-based image processing workflow to ensure consistent alignment during image processing. Both legs of seven mice were scanned 10 times, 5 prior to receiving CA4+ and 5 after, and evaluated using whole joint QMA parameters. Joint QMA evaluation of the workflow showed excellent reproducibility; intraclass correlation coefficients ranged from 0.794 to 0.930, confirming that the imaging protocol enables reproducible and efficient QMA of joint structures in preclinical models, and that contrast agent injection did not cause significant alteration to the measured parameters.

Open-source image analysis tool for the identification and quantification of cortical interruptions and bone erosions in high-resolution peripheral quantitative computed tomography images of patients with rheumatoid arthritis.

Identification of bone erosions and quantification of erosion volume is important for rheumatoid arthritis diagnosis, and can add important information to evaluate disease progression and treatment effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) is well suited for this purpose, however analysis methods are not widely available. The purpose of this study was to develop an open-source software tool for the identification and quantification of bone erosions using images acquired by HR-pQCT. The collection of modules, Bone Analysis Modules (BAM) - Erosion, implements previously published erosion analysis techniques as modules in 3D Slicer, an open-source image processing and visualization tool. BAM includes a module to automatically identify cortical interruptions, from which erosions are manually selected, and a hybrid module that combines morphological and level set operations to quantify the volume of bone erosions. HR-pQCT images of the second and third metacarpophalangeal (MCP) joints were acquired in patients with RA (XtremeCT, n = 14, XtremeCTII, n = 22). The number of cortical interruptions detected by BAM-Erosion agreed strongly with the previously published cortical interruption detection algorithm for both XtremeCT (r2 = 0.85) and XtremeCTII (r2 = 0.87). Erosion volume assessment by BAM-Erosion agreed strongly (r2 = 0.95) with the Medical Image Analysis Framework. BAM-Erosion provides an open-source erosion analysis tool that produces comparable results to previously published algorithms, with improved options for visualization. The strength of the tool is that it implements multiple image processing algorithms for erosion analysis on a single, widely available, open-source platform that can accommodate future updates.

Multiscale Strain Transfer in Cartilage.

The transfer of stress and strain signals between the extracellular matrix (ECM) and cells is crucial for biochemical and biomechanical cues that are required for tissue morphogenesis, differentiation, growth, and homeostasis. In cartilage tissue, the heterogeneity in spatial variation of ECM molecules leads to a depth-dependent non-uniform strain transfer and alters the magnitude of forces sensed by cells in articular and fibrocartilage, influencing chondrocyte metabolism and biochemical response. It is not fully established how these nonuniform forces ultimately influence cartilage health, maintenance, and integrity. To comprehend tissue remodelling in health and disease, it is fundamental to investigate how these forces, the ECM, and cells interrelate. However, not much is known about the relationship between applied mechanical stimulus and resulting spatial variations in magnitude and sense of mechanical stimuli within the chondrocyte's microenvironment. Investigating multiscale strain transfer and hierarchical structure-function relationships in cartilage is key to unravelling how cells receive signals and how they are transformed into biosynthetic responses. Therefore, this article first reviews different cartilage types and chondrocyte mechanosensing. Following this, multiscale strain transfer through cartilage tissue and the involvement of individual ECM components are discussed. Finally, insights to further understand multiscale strain transfer in cartilage are outlined.

SPHARM-PDM based image preprocessing pipeline for quantitative morphometric analysis (QMA) for in situ joint assessment in rabbit and rat models.

The accessibility of quantitative measurements of joint morphometry depends on appropriate tibial alignment and volume of interest (VOI) selection of joint compartments; often a challenging and time-consuming manual task. In this work, we developed a novel automatic, efficient, and model-invariant image preprocessing pipeline that allows for highly reproducible 3D quantitative morphometric analysis (QMA) of the joint. The pipeline addresses the problem by deploying two modules: an alignment module and a subdivision module. Alignment is achieved by representing the tibia in its basic form using lower degree spherical harmonic basis functions and aligning using principal component analysis. The second module subdivides the joint into lateral and medial VOIs via a watershedding approach based on persistence homology. Multiple repeated micro-computed tomography scans of small (rat) and medium (rabbit) animal knees were processed using the pipeline to demonstrate model invariance. Existing QMA was performed to evaluate the pipeline's ability to generate reproducible measurements. Intraclass correlation coefficient and mean-normalised root-mean-squared error of more than 0.75 and lower than 9.5%, respectively, were achieved for joint centre of mass, joint contact area under virtual loading, joint space width, and joint space volume. Processing time and technical requirements were reduced compared to manual processing in previous studies.

Contrast-Enhanced Micro-Computed Tomography for 3D Visualization and Quantification of Glycosaminoglycans in Different Cartilage Types.

OBJECTIVE: To compare CA4+-enhanced micro-computed tomography (microCT) of bovine articular, meniscal, nasal, and auricular cartilage, each of which possesses a different extracellular matrix (ECM) composition and structure. DESIGN: The diffusion kinetics of CA4+ in different native cartilage types were assessed over 20 hours. The feasibility of CA4+-enhanced microCT to visualize and quantify glycosaminoglycans (GAGs) in these different tissues was tested using safranin-O staining and 1,9-dimethylmethylene blue assay. RESULTS: The diffusion kinetics of CA4+ in auricular cartilage are significantly slower compared with all other cartilage types. Total GAG content per volume correlates to microCT attenuation with an R2 value of 0.79 for all cartilage types. Three-dimensional contrast-enhanced microCT images of spatial GAG distribution reflect safranin-O staining and highlight the differences in ECM structure, with heterogeneous regions with higher GAG concentrations highlighted by the contrast agent. CONCLUSIONS: CA4+-enhanced microCT enables assessment of 3-dimensiona distribution and GAG content in different types of cartilage and has promise as an ex vivo diagnostic technique to monitor matrix development in different tissues over time as well as tissue-engineered constructs.

Macromolecular Interactions in Cartilage Extracellular Matrix Vary According to the Cartilage Type and Location.

OBJECTIVE: To investigate GAG-ECM (glycosaminoglycan-extracellular matrix) interactions in different cartilage types. To achieve this, we first aimed to determine protocols for consistent calculation of GAG content between cartilage types. DESIGN: Auricular cartilage containing both collagen and elastin was used to determine the effect of lyophilization on GAG depletion activity. Bovine articular, auricular, meniscal, and nasal cartilage plugs were treated using different reagents to selectively remove GAGs. Sulfated glycosaminoglycan (sGAG) remaining in the sample after treatment were measured, and sGAG loss was compared between cartilage types. RESULTS: The results indicate that dry weight of cartilage should be measured prior to cartilage treatment in order to provide a more accurate reference for normalization. Articular, meniscal, and nasal cartilage lost significant amounts of sGAG for all reagents used. However, only hyaluronidase was able to remove significant amount of sGAG from auricular cartilage. Furthermore, hyaluronidase was able to remove over 99% of sGAG from all cartilage types except auricular cartilage where it only removed around 76% of sGAG. The results indicate GAG-specific ECM binding for different cartilage types and locations. CONCLUSIONS: In conclusion, lyophilization can be performed to determine native dry weight for normalization without affecting the degree of GAG treatment. To our knowledge, this is the first study to compare GAG-ECM interactions of different cartilage types using different GAG extraction methods. Degree of GAG depletion not only varied with cartilage type but also the same type from different anatomic locations. This suggests specific structure-function roles for GAG populations found in the tissues.

Quantitative measures of bone shape, cartilage morphometry and joint alignment are associated with disease in an ACLT and MMx rat model of osteoarthritis.

Multi-scale, subject-specific quantitative methods to characterize and monitor osteoarthritis in animal models and therapeutic treatments could help reveal causal relationships in disease development and distinguish treatment strategies. In this work, we demonstrate a reproducible and sensitive quantitative image analysis to characterize bone, cartilage and joint measures describing a rat model of post-traumatic osteoarthritis. Eleven 3-month-old male Wistar rats underwent medial anterior cruciate ligament (ACL) transection and medial meniscectomy on the right knee to destabilise the right tibiofemoral joint. They were sacrificed 6 weeks post-surgery and a silicon-based micro-bead contrast agent was injected in the joint space, before scanning with micro-computed tomography (microCT). Subsequently, 3D quantitative morphometric analysis (QMA), previously developed for rabbit joints, was performed. This included cartilage, subchondral cortical and epiphyseal bone measures, as well as novel tibiofemoral joint metrics. Semi-quantitative evaluation was performed on matching two-dimensional (2D) histology and microCT images. Reproducibility of the QMA was tested on eleven age-matched additional joints. The results indicate the QMA method is accurate and reproducible and that microCT-derived cartilage measurements are valid for the analysis of rat joints. The pathologic changes caused by transection of the ACL and medial meniscectomy were reflected in measurements of bone shape, cartilage morphology, and joint alignment. Furthermore, we were able to identify model-specific predictive parameters based on morphometric parameters measured with the QMA.

Reliability and Change in Erosion Measurements by High-resolution Peripheral Quantitative Computed Tomography in a Longitudinal Dataset of Rheumatoid Arthritis Patients.

OBJECTIVE: The aim of this multireader exercise was to assess the reliability and change over time of erosion measurements in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: HR-pQCT scans of 23 patients with RA were assessed at baseline and 12 months. Four experienced readers examined the dorsal, palmar, radial, and ulnar surfaces of the metacarpal head (MH) and phalangeal base (PB) of the second and third digits, blinded to time order. In total, 368 surfaces (23 patients´ 16 surfaces) were evaluated per timepoint to characterize cortical breaks as pathological (erosion) or physiological, and to quantify erosion width and depth. Reliability was evaluated by intraclass correlation coefficients (ICC), percentage agreement, and Light k; change over time was defined by means ± SD of erosion numbers and dimensions. RESULTS: ICC for the mean measurements of width and depth of the pathological breaks ranged between 0.819-0.883, and 0.771-0.907, respectively. Most physiological cortical breaks were found at the palmar PB, whereas most pathological cortical breaks were located at the radial MH. There was a significant increase in both the numbers and the dimensions of erosions between baseline and follow-up (P = 0.0001 for erosion numbers, width, and depth in axial plane; P = 0.001 for depth in perpendicular plane). CONCLUSION: This exercise confirmed good reliability of HR-pQCT erosion measurements and their ability to detect change over time.

Molecular Signaling Interactions and Transport at the Osteochondral Interface: A Review.

Articular joints are comprised of different tissues, including cartilage and bone, with distinctive structural and mechanical properties. Joint homeostasis depends on mechanical and biological integrity of these components and signaling exchanges between them. Chondrocytes and osteocytes actively sense, integrate, and convert mechanical forces into biochemical signals in cartilage and bone, respectively. The osteochondral interface between the bone and cartilage allows these tissues to communicate with each other and exchange signaling and nutritional molecules, and by that ensure an integrated response to mechanical stimuli. It is currently not well known how molecules are transported between these tissues. Measuring molecular transport in vivo is highly desirable for tracking cartilage degeneration and osteoarthritis progression. Since transport of contrast agents, which are used for joint imaging, also depend on diffusion through the cartilage extracellular matrix, contrast agent enhanced imaging may provide a high resolution, non-invasive method for investigating molecular transport in the osteochondral unit. Only a few techniques have been developed to track molecular transport at the osteochondral interface, and there appear opportunities for development in this field. This review will describe current knowledge of the molecular interactions and transport in the osteochondral interface and discuss the potential of using contrast agents for investigating molecular transport and structural changes of the joint.