Cartilage Volume Research Articles

Reliability and concurrent validity of three-dimensional ultrasound for quantifying knee cartilage volume

ObjectiveThe goal of this study was to test the reliability and validity of a handheld mechanical three-dimensional (3D) ultrasound (US) device for quantifying femoral articular cartilage (FAC) against the current clinical standard of magnetic resonance imaging (MRI). DesignBilateral knee images of 25 healthy volunteers were acquired with 3D US and 3.0 T MRI. The trochlear FAC was segmented by two raters who repeated segmentations on five cases during separate sessions. MRI and 3D US segmentations were registered using a semi-automated surface-based registration algorithm, and MRI segmentations were trimmed to match the FAC region from 3D US. Intra- (n = 5) and inter-rater (n = 25) reliabilities were assessed using intraclass correlation coefficients (ICCs) calculated from FAC volumes. Relationships between MRI and 3D US were assessed using Spearman correlation and linear regression (n = 25). ResultsMRI intra-rater ICCs were 0.97 (0.79, 1.00) and 0.90 (0.25, 0.99) for each rater with an inter-rater ICC of 0.83 (0.48, 0.94). 3D US intra-rater ICCs were 1.00 (0.98, 1.00) and 0.98 (0.84, 1.00) for each rater with an inter-rater ICC of 0.96 (0.90, 0.98). Spearman correlation and linear regression revealed a strong correlation ρ = 0.884 (0.746, 0.949) and regression R2 = 0.848 (0.750, 0.950). ConclusionThese results suggest 3D US demonstrates excellent intra- and inter-rater reliabilities and strong concurrent validity with MRI when quantifying healthy trochlear FAC volume. 3D US may reduce imaging costs and greatly improve feasibility of quantifying knee cartilage volume during knee arthritis clinical trials and patient care.

Relationship between medial meniscus extrusion and cartilage measurements in the knee by fully automatic three-dimensional MRI analysis

BackgroundWe developed a fully automatic three-dimensional knee MRI analysis software that can quantify meniscus extrusion and cartilage measurements, including the projected cartilage area ratio (PCAR), which represents the ratio of the subject’s actual cartilage area to their ideal cartilage area. We also collected 3D MRI knee data from 561 volunteers (aged 30–79 years) from the “Kanagawa Knee Study.” Our purposes were to verify the accuracy of the software for automatic cartilage and meniscus segmentation using knee MRI and to examine the relationship between medial meniscus extrusion measurements and cartilage measurements from Kanagawa Knee Study data.MethodsWe constructed a neural network for the software by randomly choosing 10 healthy volunteers and 103 patients with knee pain. We validated the algorithm by randomly selecting 108 of these 113 subjects for training, and determined Dice similarity coefficients from five other subjects. We constructed a neural network using all data (113 subjects) for training. Cartilage thickness, cartilage volume, and PCAR in the medial femoral, lateral femoral, medial tibial, and lateral tibial regions were quantified by using the trained software on Kanagawa Knee Study data and their relationship with subject height was investigated. We also quantified the medial meniscus coverage ratio (MMCR), defined as the ratio of the overlapping area between the medial meniscus area and the medial tibial cartilage area to the medial tibial cartilage area. Finally, we examined the relationship between MMCR and PCAR at middle central medial tibial (mcMT) subregion located in the center of nine subregions in the medial tibial cartilage.ResultsDice similarity coefficients for cartilage and meniscus were both approximately 0.9. The femoral and tibial cartilage thickness and volume at each region correlated with height, but PCAR did not correlate with height in most settings. PCAR at the mcMT was significantly correlated with MMCR.ConclusionsOur software showed high segmentation accuracy for the knee cartilage and meniscus. PCAR was more useful than cartilage thickness or volume since it was less affected by height. Relations ips were observed between the medial tibial cartilage measurements and the medial meniscus extrusion measurements in our cross-sectional study.Trial registrationUMIN, UMIN000032826; 1 September 2018,

Lingzhi and San-Miao-San with hyaluronic acid gel mitigate cartilage degeneration in anterior cruciate ligament transection induced osteoarthritis.

SummaryObjectiveTo investigate the mitigate efficacy of Chinese medicine Lingzhi (LZ) and San-Miao-San (SMS) combined with hyaluronic acid (HA)-gel in attenuating cartilage degeneration in traumatic osteoarthritis (OA).MethodsThe standardized surgery of anterior cruciate ligament transection (ACLT) was made from the medial compartment of right hind limbs of 8-week-old female SD rats and resulted in a traumatic OA. Rats (n ​= ​5/group) were treated once intra-articular injection of 50 ​μl HA-gel, 50 ​μl HA-gel+50 ​μg LZ-SMS, 50 ​μl of saline+50 ​μg LZ-SMS and null (ACLT group) respectively, except sham group. Limbs were harvested for μCT scan and histopathological staining 3-month post-treatment. Inflammatory cytokines from plasma and synovial fluid were detected using Immunology Multiplex Assay kit. The putative targets of active compounds in LZ-SMS and known therapeutic targets for OA were combined to construct protein–protein interaction network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was adopted to predict the potential targets and signaling pathway of LZ-SMS in OA through the tool of DAVID Bioinformatics.ResultsIn vivo, HA-gel ​+ ​LZ-SMS treatment resulted in a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (total volume of cartilage), compared to ACLT and HA-gel groups. In addition, histological results showed the elevated cartilage matrix, chondrogenic and osteoblastic signals in HA-gel ​+ ​LZ-SMS treatment. Treatment also significantly altered subchondral bone (SCB) structure including an increase in BV/TV, Tb.Th, BMD, Conn.Dn, Tb.N, and DA, as well as a significant decrease in Tb.Sp and Po(tot), which implied a protective effect on maintaining the stabilization of tibial SCB microstructure. Furthermore, there was also a down-regulated inflammatory cytokines and upregulated anti-inflammatory cytokine IL-10 in HA+LZ-SMS group. Finally, 64 shared targets from 37 active compounds in LZ-SMS related to the core genes for the development of OA. LZ-SMS has a putative role in regulating inflammatory circumstance through influencing the MAPK signaling pathway.ConclusionOur study elucidated a protective effect of HA-gel ​+ ​LZ-SMS in mitigating cartilage degradation and putative interaction with targets and signaling pathway for the development of traumatic OA.The translational potential of this articleOur results provide a biological rationale for the use of LZ-SMS as a potential candidate for OA treatment.

Quantitative measurement of cartilage volume with automatic cartilage segmentation in knee osteoarthritis.

To determine the reproducibility of the automatic cartilage segmentation method using a prototype KneeCaP software (version 1.3; Siemens Healthcare, Erlangen, Germany) and to compare the difference in cartilage volume (CV) between the normal knee joint and knee osteoarthritis (KOA) of different degrees by using the above software. The study included 62 subjects with knee OA and 29 healthy control subjects. The cartilage lesion patients were divided into a mild-to-moderate OA group (n = 29) and severe OA group (n = 33). Automatic cartilage segmentation was performed on all the subjects, and among them, 19 knee cases were randomly selected to also do the manual cartilage segmentation. Statistical significance was determined with one-way analysis of variance (ANOVA), intraclass correlation coefficient (ICC), and Pearson correlation coefficient. Automatic segmentation was compared with the manual one. The relative cartilage volume percentages of the femur, tibia, and patella in the normal control/mild-to-moderate/severe OA groups were assessed. Comparing the cartilage volumes derived by manual and automatic segmentation, the ICC value for the knee joint, patella, femur, or tibia was 0.784, 0.815, 0.740, and 0.797. The relative cartilage volume percentages of the femur, tibia, and patella in the normal control/mild-to-moderate/severe OA groups were 57.28%/59.30%/62.45% (femur), 25.35%/23.46%/21.84% (tibia), and 17.37%/17.24%/15.71% (patella), respectively. Compared with the normal control group, the relative tibia cartilage volume percentage was lower in the mild-to-moderate OA group and the severe OA group. Corresponding index showed a similar difference between the mild-to-moderate OA group and the severe OA group (p < 0.001). This study demonstrated that the relative cartilage volume percentage is correlated with the semi-quantitative systems and may be a preferred outcome measure in clinical studies of OA. Automatic cartilage segmentation using KneeCaP delivered reliable results on high-spatial-resolution 3 T MR images for the healthy, mild-moderate OA patients. Key Points • The cartilage automatic segmentation has excellent reproducibility and was not affected by inter-observer variation. • The relative cartilage volume percentage is correlated with the semi-quantitative systems and may be a preferred outcome measure in clinical studies of OA.

Effect of Stem Cell Injections on Osteoarthritis-related Structural Outcomes: A Systematic Review.

To systematically review the evidence for the efficacy of mesenchymal stem cell (MSC) injections in improving osteoarthritis (OA)-related structural outcomes. Ovid Medline and EMBASE were searched from their inceptions to April 2020 using MeSH terms and key words. Independent reviewers extracted data and assessed methodological quality. Qualitative evidence synthesis was performed due to the heterogeneity of interventions and outcome measures. Thirteen randomized controlled trials (phase I or II) were identified: 10 in OA populations and 3 in populations at risk of OA, with low (n = 9), moderate (n = 3), or high (n = 1) risk of bias. Seven studies used allogeneic MSCs (4 bone marrow, 1 umbilical cord, 1 placenta, 1 adipose tissue), 6 studies used autologous MSCs (3 adipose tissue, 2 bone marrow, 1 peripheral blood). Among the 11 studies examining cartilage outcomes, 10 found a benefit of MSCs on cartilage volume, morphology, quality, regeneration, and repair, assessed by magnetic resonance imaging, arthroscopy, or histology. The evidence for subchondral bone was consistent in all 3 studies in populations at risk of OA, showing beneficial effects. Sixteen unpublished, eligible trials were identified by searching trial registries, including 8 with actual or estimated completion dates before 2016. Our systematic review of early-phase clinical trials demonstrated consistent evidence of a beneficial effect of intraarticular MSC injections on articular cartilage and subchondral bone. Due to the heterogeneity of MSCs, modest sample sizes, methodological limitations, and potential for publication bias, further work is needed before this therapy is recommended in the management of OA.

Reproducibility of an Automated Quantitative MRI Assessment of Low-Grade Knee Articular Cartilage Lesions.

ObjectiveThe goal of this study was to assess the reproducibility of an automated knee cartilage segmentation of 21 cartilage regions with a model-based algorithm and to compare the results with manual segmentation.DesignThirteen patients with low-grade femoral cartilage defects were included in the study and were scanned twice on a 7-T magnetic resonance imaging (MRI) scanner 8 days apart. A 3-dimensional double-echo steady-state (3D-DESS) sequence was used to acquire MR images for automated cartilage segmentation, and T2-mapping was performed using a 3D triple-echo steady-state (3D-TESS) sequence. Cartilage volume, thickness, and T2 and texture features were automatically extracted from each knee for each of the 21 subregions. DESS was used for manual cartilage segmentation and compared with automated segmentation using the Dice coefficient. The reproducibility of each variable was expressed using standard error of measurement (SEM) and smallest detectable change (SDC).ResultsThe Dice coefficient for the similarity between manual and automated segmentation ranged from 0.83 to 0.88 in different cartilage regions. Test-retest analysis of automated cartilage segmentation and automated quantitative parameter extraction revealed excellent reproducibility for volume measurement (mean SDC for all subregions of 85.6 mm3), for thickness detection (SDC = 0.16 mm) and also for T2 values (SDC = 2.38 ms) and most gray-level co-occurrence matrix features (SDC = 0.1 a.u.).ConclusionsThe proposed technique of automated knee cartilage evaluation based on the segmentation of 3D MR images and correlation with T2 mapping provides highly reproducible results and significantly reduces the segmentation effort required for the analysis of knee articular cartilage in longitudinal studies.

Calcified cartilage in patients with osteoarthritis of the hip compared to that of healthy subjects. A design-based histological study

Calcified cartilage is suggested to be involved in the pathogenesis of osteoarthritis (OA) by facilitating endochondral ossification at the bone-cartilage unit. Therefore, the objective was to quantify the volume and surface area of the calcified cartilage in the femoral head in OA patients and healthy subjects. We used design-based stereological principles, i.e., systematic uniform random sampling and vertical uniform random sections of the entire femoral head. We investigated the articular and calcified cartilage and femoral head surface area and volume, excluding fovea capitis and marginal osteophytes, in 20 patients with OA and 15 healthy subjects. The volume of the calcified cartilage was significantly larger for the patients with OA compared with the healthy subjects (mean difference [95% CI]) (284 [110,457] mm3, p=0.002). The upper and lower surface area of the calcified cartilage, i.e. the tidemark and cement line, were both significantly larger for OA patients compared with the healthy subjects (17.8 [8.4,27.3] cm2, p<0.001) and (38.7 [20.8,56.7] cm2, p=0.002), respectively. The volume of the calcified cartilage and the volume of the femoral head were significantly correlated for the patients with OA (Spearman's ρ=0.51, p=0.021), but not for the healthy subjects (ρ=0.41, p=0.123). Patients with OA had a larger femoral head surface area and more calcified cartilage compared to healthy subjects. The volume of the calcified cartilage correlated positively with the volume of the femoral head for patients with OA, but not for healthy subjects. This strongly supports the existing view that bone growth in OA is associated with endochondral ossification.

Colony housing promotes structural and functional changes during surgically induced osteoarthritis in rats

The aim of the study was to investigate how social housing with high locomotion activity affects experimental osteoarthritis (OA) in rats. Rats were housed either conventionally in type IV cages in pairs or in rat colony cages (RCC) on 4 levels interconnected by jump holes or staircase in groups of 48. OA was induced by anterior cruciate ligament transection and resection of the medial meniscus (ACLT+tMx), medial meniscal tear (MMT) or destabilization of the medial meniscus (DMM). Functional changes were characterized by continues tracking of individual activity and catwalk gait analysis. Cartilage volume and bone structure were investigated at week 20 after surgery by histology and micro-CT. In the RCC, healthy rats changed cage levels 82±15 times daily, reduced by 30% after ACLT+tMx (p<0.0001). In both housing systems, the order of severity of the investigated models was ACLT+tMx>MMT>DMM in all outcome measures. Compared to Type IV, RCC housed rats developed stronger gait disturbance symptoms (ACLT+tMx; 95%CI=-15-2; p<0.004), the cartilage volume was reduced (ACLT+tMx: 95%CI=-0.1-0.5; p<0.0001), serum levels of the cartilage remodeling marker AGNx1 were higher (MMT; 95%CI=-53-(-6); p=0.001), bone was denser with increased volume (ACLT+tMx; 95%CI=0.8-7.5; p=0.004) and joints were less flexible (ACLT+tMx; 95%CI=3.6-14; p<0.0001). Housing rats in an environment allowing increased locomotion and socialization promotes structural and functional alterations during joint instability-induced OA. This increases the assay window, improves the relevance for the human disease and enables to discriminate the models in structural and behavioral parameters.

Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice.

To characterize tracheal cartilage morphology in mouse models of fibroblast growth factor receptor (Fgfr2)-related craniosynostosis syndromes. To establish relationships between specific Fgfr2 mutations and tracheal cartilaginous sleeve (TCS) phenotypes in these mouse models. Postnatal day 0 knock-in mouse lines with disease-specific genetic variations in the Fgfr2 gene (Fgfr2C342Y/C342Y , Fgfr2C342Y/+ , Fgfr2+/Y394C , Fgfr2+/S252W , and Fgfr2+/P253R ) as well as line-specific controls were utilized. Tracheal cartilage morphology as measured by gross analyses, microcomputed tomography (μCT), and histopathology were compared using Chi-squared and single-factor analysis of variance statistical tests. A greater proportion of rings per trachea were abnormal in Fgfr2C342Y/+ tracheas (63%) than Fgfr2+/S252W (17%), Fgfr2+/P253R (17%), Fgfr2+/Y394C (12%), and controls (10%) (P < .001 for each vs. Fgfr2C342Y/+ ). TCS segments were found only in Fgfr2C342Y/C342Y (100%) and Fgfr2C342Y/+ (72%) tracheas. Cricoid and first-tracheal ring fusion was noted in all Fgfr2C342Y/C342Y and 94% of Fgfr2C342Y/+ samples. The Fgfr2C342Y/C342Y and Fgfr2C342Y/+ groups were found to have greater areas and volumes of cartilage than other lines on gross analysis and μCT. Histologic analyses confirmed TCS among the Fgfr2C342Y/C342Y and Fgfr2C342Y/+ groups, without appreciable differences in cartilage morphology, cell size, or density; no histologic differences were observed among other Fgfr2 lines compared to controls. This study found TCS phenotypes only in the Fgfr2C342Y mouse lines. These lines also had increased tracheal cartilage compared to other mutant lines and controls. These data support further study of the Fgfr2 mouse lines and the investigation of other Fgfr2 variants to better understand their role in tracheal development and TCS formation. NA Laryngoscope, 131:E1349-E1356, 2021.

Intra-articular corticosteroid knee injection induces a reduction in meniscal thickness with no treatment effect on cartilage volume: a case\u2013control study

Although intra-articular corticosteroid injections (IACI) are commonly used for the treatment of knee osteoarthritis (OA), there is controversy regarding possible deleterious effects on joint structure. In this line, this study investigates the effects of IACI on the evolution of knee OA structural changes and pain. Participants for this nested case–control study were from the Osteoarthritis Initiative. Knees of participants who had received an IACI and had magnetic resonance images (MRI) were named cases (n = 93), and each matched with one control (n = 93). Features assessed at the yearly visits and their changes within the follow-up period were from MRI (cartilage volume, meniscal thickness, bone marrow lesions, bone curvature, and synovial effusion size), X-ray (joint space width), and clinical (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain score) data. Participants who received IACI experienced a transient and significantly greater rate of loss of the meniscal thickness (p = 0.006) and joint space width (p = 0.011) in the knee medial compartment in the year they received the injection, compared to controls. No significant effect of the IACI was found on the rate of cartilage loss nor on any other knee structural changes or WOMAC pain post-treatment. In conclusion, a single IACI in knee OA was shown to be safe with no negative impact on structural changes, but there was a transient meniscal thickness reduction, a phenomenon for which the clinical relevance is at present unknown.

Two- and three-dimensional optical coherence tomography to differentiate degenerative changes in a rat meniscectomy model.

Optical coherence tomography (OCT) is an attractive tool for evaluating cartilage. We developed an OCT system that reconstructs and analyzes a three-dimensional (3D) OCT image by determining the cartilage surface and cartilage-bone boundary from the image taken with currently available OCT devices. We examined the usefulness of 3D renderings of OCT images. In a rat meniscectomized model, the tibia was harvested after 0, 2, 4, or 8 weeks (n = 6). We scanned 300 slices in the y-plane to cover a 4 × 3 × 6-mm section (x-plane; 10 µm × 400 pixels, y-plane; 10 µm × 300 pixels, z-plane; 12.66 µm × 500 pixels) of the medial tibial cartilage. The cartilage surface line and the cartilage-bone boundary were plotted semi-automatically. Slices from 300 two-dimensional (2D) sequential images were systematically and visually checked and corrected, as necessary. We set a region of interest in the cartilage and quantified the cartilage volume in the 3D image. The Osteoarthritis Research Society International (OARSI) histological score was also obtained. The cartilage volume determined using 3D OCT images was 0.291 ± 0.022 mm3 in the normal, 0.264 ± 0.009 mm3 at 2 weeks, 0.210 ± 0.012 mm3 at 4 weeks, and 0.205 ± 0.011 mm3 at 8 weeks. The cartilage volume significantly decreased at 4 and 8 weeks and was significantly correlated with the OARSI histological score (r = -0.674; P = .002). Although the 3D image information could be obtained from the 2D images, the 3D OCT images provided easier-to-understand information because the 3D reconstructed cartilage provided information about the smoothness of the surface, the area, and depth of the defect at a glance.

Finite Element Analysis of the Septal Cartilage L-Strut.

Importance: Septoplasty is one of the most commonly performed operations in the head and neck. However, the reasons for septoplasty failure and the additional stress of performing a chondrotomy on the septal cartilage are not well understood. Design, Setting, and Participants: A finite element model of the nasal septum was created using a microcomputed tomography scan of the nasoseptal complex that was reconstructed into a three-dimensional model in silico. Testing included four common chondrotomy designs: traditional L-strut, double-cornered chondrotomy (DCC), curved L-strut, and the C-curve. Tip displacement was applied in a vector parallel to the caudal strut to simulate nasal tip palpation. Main Outcomes and Measures: With finite element analysis, the maximum principal stress (MPS), von Mises stress (VMS), harvested cartilage volume, and surface area were recorded. Results: The highest MPS for the L-strut, DCC, curved L-strut, and C-curve was identified at the corner of the chondrotomy. The MPS at the corner of the chondrotomy was reduced 44% when comparing the C-curve with the traditional L-strut. The VMS patterns showed compressive stress along the caudal septum in all models, but at the corner, the stresses were highest in the chondrotomies designed with sharp-angled corners. The VMS showed a 76% decrease when comparing the C-curve with the traditional L-strut. The stress across the anterior septal angle is also higher in models with sharp-angled corners. Cartilage harvest volumetric and surface area assessments did not show meaningful differences between shapes. Conclusions and Relevance: The highest area of stress is near the transition of the dorsal to caudal septum in all models. Stresses are relatively higher in chondrotomy shapes that contain sharp-angled corners. The relative reduction in MPS and VMS utilizing a C-curve instead of an L-strut may decrease the likelihood that the septum will deform or fail in this region. The volume and surface area of the C-curve are similar to that of the L-strut technique. Avoiding sharp-angled corners reduces the stresses at the corner of the chondrotomy and across the anterior septal angle. Using a C-curve may be an improved septoplasty design.

Leukocyte-dependent effects of platelet-rich plasma on cartilage loss and thermal hyperalgesia in a mouse model of post-traumatic osteoarthritis

Platelet-rich plasma (PRP) is an emerging therapeutic strategy for treatment of osteoarthritis (OA); however, there is a lack of preclinical and clinical evidence for its efficacy and its mechanism of action is unclear. In the current study, we utilized leukocyte poor-PRP (LP-PRP) and leukocyte rich-PRP (LR-PRP) to mimic clinical point of care formulations and assessed their potential to alter disease progression in a mouse model of post-traumatic OA. Three-month-old wild-type male FVB/N mice received destabilization of the medial meniscus (DMM) surgery to induce OA. To assess the efficacy of LP-PRP and LR-PRP, mice were given intraarticular injections at 2-, 7- and 28-days post-surgery. Mice were then assessed at 5-, 9-, and 13-weeks post-surgery for changes in chronic pain using the hot plate nociceptive assay. At 14-weeks, OA pathogenesis was evaluated using histology and phase-contrast μCT. Treatment with LP-PRP and to a lesser extent LR-PRP preserved cartilage volume and surface area compared to phosphate-buffered saline (PBS) as measured by phase-contrast μCT. However, both treatments had higher Osteoarthritis Research Society International (OARSI) and synovitis scores compared to sham, and neither substantially improved scores compared to PBS controls. With respect to thermal hyperalgesia, PBS-treated mice displayed reduced latency to response compared to sham, and LR-PRP but not LP-PRP improved latency to response at 5-, 9- and 13-weeks post-surgery compared to PBS. The results of this study suggest that effects of PRP therapy on OA progression and disease-induced hyperalgesia may be leukocyte-dependent. And while LP-PRP and to a lesser extent LR-PRP protect from volume and surface loss, significant pathology is still seen within OA joints. Future work is needed to understand how the different components of PRP effect OA pathogenesis and pain, and how these could be modified to achieve greater therapeutic efficacy.

LPS-Induced Inflammation Prior to Injury Exacerbates the Development of Post-Traumatic Osteoarthritis in Mice.

ABSTRACTOsteoarthritis (OA) is a debilitating and painful disease characterized by the progressive loss of articular cartilage. Post‐traumatic osteoarthritis (PTOA) is an injury‐induced type of OA that persists in an asymptomatic phase for years before it becomes diagnosed in ~50% of injured individuals. Although PTOA is not classified as an inflammatory disease, it has been suggested that inflammation could be a major driver of PTOA development. Here we examined whether a state of systemic inflammation induced by lipopolysaccharide (LPS) administration 5‐days before injury would modulate PTOA outcomes. RNA‐seq analysis at 1‐day post‐injury followed by micro‐computed tomography (μCT) and histology characterization at 6 weeks post‐injury revealed that LPS administration causes more severe PTOA phenotypes. These phenotypes included significantly higher loss of cartilage and subchondral bone volume. Gene expression analysis showed that LPS alone induced a large cohort of inflammatory genes previously shown to be elevated in synovial M1 macrophages of rheumatoid arthritis (RA) patients, suggesting that systemic LPS produces synovitis. This synovitis was sufficient to promote PTOA in MRL/MpJ mice, a strain previously shown to be resistant to PTOA. The synovium of LPS‐treated injured joints displayed an increase in cellularity, and immunohistological examination confirmed that this increase was in part attributable to an elevation in type 1 macrophages. LPS induced the expression of Tlr7 and Tlr8 in both injured and uninjured joints, genes known to be elevated in RA. We conclude that inflammation before injury is an important risk factor for the development of PTOA and that correlating patient serum endotoxin levels or their state of systemic inflammation with PTOA progression may help develop new, effective treatments to lower the rate of PTOA in injured individuals. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

FRI0417 IDENTIFICATION OF THE MOST IMPORTANT FEATURES OF KNEE OSTEOARTHRITIS PROGRESSORS USING MACHINE LEARNING METHODS

Background:Knee osteoarthritis (OA), a leading cause of disability worldwide, can be difficult to define as its development is often insidious and involves different subgroups. We still lack robust prediction models that are able to guide clinical decisions and stratify OA patients according to risk of disease progression.Objectives:This study aimed at identifying the most important features of knee OA progressors. To this end, we used machine learning (ML) algorithms on a large set of subjects and features to develop advanced prediction models that provide high classification and prediction performance.Methods:Participants, features and outcomes were from the Osteoarthritis Initiative. Features were from baseline (1107), including articular knee tissues (135) assessed by quantitative MRI. OA progressors were ascertained by four outcomes: cartilage volume loss in medial plateau at 48 and 96 months (Prop_CV_48M, 96M); Kellgren-Lawrence (KL) grade ≥2; and medial joint space narrowing (JSN) ≥1 at 48 months. Subjects’ numbers were as follows: 1598 for the outcome Prop_CV_96M, 1044 for the Prop_CV_48M, and 1468 for each KL grade ≥2 at 48 months and JSN ≥1 at 48 months. Six feature selection models were used to identify the common features in each outcome. Six classification methods were applied to measure the accuracy of the selected features in classifying the subjects into progressors and non-progressors. Classification of the best features was done using auto-ML interface and the area under the curve (AUC). To prioritize the top features, Sparse Partial Least Square (sPLS) method was used.Results:For the classification of the best common features in each outcome, Multi-Layer Perceptron (MLP) achieved the highest AUC in Prop_CV_96M, KL, and JSN (0.80, 0.88, 0.95), and Gradient Boosting Machine (GBM) for Prop_CV_48M (0.70). sPLS revealed that the baseline top five features to predict knee OA progressors are the joint space width (JSW), mean cartilage thickness of peripheral, medial, and central tibial plateau, and JSN.Conclusion:This is the first time that such a comprehensive study was performed for identifying the best features and classification methods for knee OA progressors. Data revealed that early prediction of knee OA progression can be done with high accuracy and based on only a few features. This study identifies the baseline X-ray and MRI-based features as the most important for predicting knee OA progressors. These results could be used for the development of a tool enabling prediction of knee OA progressors.Acknowledgments:This work was supported in part by the Osteoarthritis Research Unit of the University of Montreal Hospital Research Centre; the Chair in Osteoarthritis, University of Montreal, (both from Montreal, Quebec, Canada); and the Computational Biology Laboratory, Laval University Hospital Research Center, (Québec, Quebec, Canada). A Jamshidi received a bursary from the Canada First Research Excellence Fund through TransMedTech Institute, (Montreal, Quebec, Canada).Disclosure of Interests:Afshin Jamshidi: None declared, Mickaël Leclercq: None declared, Aurelie Labbe: None declared, Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica, Speakers bureau: TRB Chemedica and Mylan, François Abram Employee of: ArthroLab Inc., Arnaud Droit: None declared, Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica

Associations of Joint Line Tenderness and Patellofemoral Grind With Long-Term Knee Joint Outcomes: Data From the Osteoarthritis Initiative.

To examine whether joint line tenderness and patellofemoral grind from physical examination were associated with cartilage volume loss, worsening of radiographic osteoarthritis, and the risk of total knee replacement. This study examined 4,353 Osteoarthritis Initiative participants. For each measurement of joint line tenderness and patellofemoral grind, the patterns were defined as no (none at baseline and at 1 year), fluctuating (present at either time point), and persistent (present at both time points). Cartilage volume loss and worsening of radiographic osteoarthritis over 4 years were assessed using magnetic resonance imaging and radiographs, and total knee replacement over 6 years was assessed. A total of 35.0% of participants had joint line tenderness, and 15.8% had patellofemoral grind. Baseline patellofemoral grind, but not joint line tenderness, was associated with increased cartilage volume loss (1.08% per year versus 0.96% per year; P = 0.02) and an increased risk of total knee replacement (odds ratio [OR] 1.55 [95% confidence interval (95% CI) 1.11-2.17]; P = 0.01). While the patterns of joint line tenderness were not significantly associated with joint outcomes, participants with persistent patellofemoral grind had an increased rate of cartilage volume loss (1.30% per year versus 0.90% per year; P < 0.001) and an increased risk of total knee replacement (OR 2.10 [95% CI 1.30-3.38]; P = 0.002) compared with those participants without patellofemoral grind. Patellofemoral grind, but not joint line tenderness, may represent a clinical marker associated with accelerated cartilage volume loss over 4 years and an increased risk of total knee replacement over 6 years. This simple clinical examination may provide clinicians with an inexpensive way to identify those at higher risk of disease progression who should be targeted for surveillance and management.

Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups

Hutchinson-Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Microcomputed tomography and CT-based rigidity analyses were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess strength. Contrast-enhanced µCT imaging of mouse femurs was performed to measure glycosaminoglycan content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness, and modulus of the HGPS G608G mouse model may increase the risk for bending and deformation, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble changes observed in the age-matched WT controls, including early loss of glycosaminoglycans, and decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly. Lonafarnib monotherapy did not improve bone or cartilage parameters, but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which ameliorate the musculoskeletal phenotype of the disease.

Comparison of radiographic and MRI osteoarthritis definitions and their combination for prediction of tibial cartilage loss, knee symptoms and total knee replacement: a longitudinal study

To describe the value of radiographic- and magnetic resonance imaging (MRI)-defined tibiofemoral osteoarthritis (ROA and MRI-OA, respectively) and in combination for predicting tibial cartilage loss, knee pain and disability and total knee replacement (TKR) in a population-based cohort. A radiograph and 1.5T MRI of the right knee was performed. ROA and MRI-OA at baseline were defined according to the Osteoarthritis Research Society International atlas and a published Delphi exercise, respectively. Tibial cartilage volume was measured over 2.6 and 10.7 years. Knee pain and disability were assessed at baseline, 2.6, 5.1 and 10.7 years. Right-sided TKRs were assessed over 13.5 years. Of 574 participants (mean 62 years, 49% female), 8% had ROA alone, 15% had MRI-OA alone, 13% had both ROA and MRI-OA. Having ROA (vs. no ROA) and MRI-OA (vs. no MRI-OA) predicted greater tibial cartilage loss over 2.6 years (-75.9 and-86.4mm3/year) and higher risk of TKR over 13.5 years (Risk Ratio [RR]: 15.0 and 10.9). Only MRI-OA predicted tibial cartilage loss over 10.7 years (-7.1mm3/year) and only ROA predicted onset and progression of knee symptoms (RR: 1.32-1.88). In participants with both MRI-OA and ROA, tibial cartilage loss was the greatest (over 2.6 years:-116.1mm3/year; over 10.7 years:-11.2mm3/year), and the onset and progression of knee symptoms (RR: 1.75-2.89) and risk of TKR (RR: 50.9) were the highest. The Delphi definition of MRI-OA is not superior to ROA for predicting structural or symptomatic OA progression but, combining MRI-OA and ROA has much stronger predictive validity.

A review on segmentation of knee articular cartilage: from conventional methods towards deep learning.

In this paper, we review the state-of-the-art approaches for knee articular cartilage segmentation from conventional techniques to deep learning (DL) based techniques. Knee articular cartilage segmentation on magnetic resonance (MR) images is of great importance in early diagnosis of osteoarthritis (OA). Besides, segmentation allows estimating the articular cartilage loss rate which is utilised in clinical practice for assessing the disease progression and morphological changes. It has been traditionally applied in quantifying longitudinal knee OA progression pattern to detect and assess the articular cartilage thickness and volume. Topics covered include various image processing algorithms and major features of different segmentation techniques, feature computations and the performance evaluation metrics. This paper is intended to provide researchers with a broad overview of the currently existing methods in the field, as well as to highlight the shortcomings and potential considerations in the application at clinical practice. The survey showed that state-of-the-art techniques based on DL outperform the other segmentation methods. The analysis of the existing methods reveals that integration of DL-based algorithms with other traditional model-based approaches has achieved the best results (mean Dice similarity coefficient (DSC) between 85.8% and 90%).

Intra-Articular Injections of Allogeneic Human Adipose-Derived Mesenchymal Progenitor Cells in Patients with Symptomatic Bilateral Knee Osteoarthritis: A Phase I pilot study

Aim: This study investigated the safety and clinical outcomes of expanded allogeneic human adipose-derived mesenchymal progenitor cells injected into patients with symptomatic, bilateral knee osteoarthritis. Design: In this single-site, randomized, double-blind, dose-ranging, Phase I study, patients were randomized to three treatment groups (low dose, 1×107 cells; medium dose, 2×107 cells; high dose, 5×107 cells). All patients received two bilateral intra-articular injections: week 0 (baseline) and week 3. The primary end point was adverse events within 48 weeks. Secondary end points were measured with Western Ontario and McMaster Universities Osteoarthritis index, visual analog scale, short form-36 at weeks 12, 24 and 48. Quantitative MRI measurements of cartilage volume were compared from baseline and week 48. Results:A total of22 subjects were enrolled of which19 (86%) completed the study. Adverse events were transient, including mild to moderate pain and swelling of injection site. Improvements from baseline were measured in the secondary end points. MRI assessments showed slight improvements in the low-dose group. Conclusion: Safety and improvements in pain and function after intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells into arthritic patients was demonstrated.