Alterations in DNA methylation machinery in a rat model of osteoarthritis of the hip.

BACKGROUND: This study aimed to validate alterations in the gene expression of DNA methylation-related enzymes and global methylation in the peripheral blood mononuclear cell (PBMC) and synovial tissues of animal hip osteoarthritis (OA) models. METHODS: Animals were assigned to the control (no treatment), sham (25 µL of sterile saline), and OA (25 µL of sterile saline and 2 mg of monoiodoacetate) groups. Microcomputed tomography scan, histopathological assessment and pain threshold measurement were performed after induction. The mRNA expression of the DNA methylation machinery genes and global DNA methylation in the PBMC and hip synovial tissue were evaluated. RESULTS: The OA group presented with hip joint OA histopathologically and radiologically and decreased pain threshold. The mRNA expression of DNA methyltransferase (Dnmt 3a), ten-eleven translocation (Tet) 1 and Tet 3 in the synovial tissue of the OA group was significantly upregulated. Global DNA methylation in the synovial tissue of the OA group was significantly higher than that of the control and sham groups. CONCLUSIONS: The intra-articular administration of monoiodoacetate induced hip joint OA and decreased pain threshold. The DNA methylation machinery in the synovial tissues of hip OA was altered.

A systematic review and cross-database analysis of single nucleotide polymorphisms underlying hip morphology and osteoarthritis reveals shared mechanisms.

OBJECTIVE: Understanding the mechanisms of hip disease, such as osteoarthritis (OA), is crucial to advance their treatment. Such hip diseases often involve specific morphological changes. Genetic variations, called single nucleotide polymorphisms (SNPs), influence various hip morphological parameters. This study investigated the biological relevance of SNPs correlated to hip morphology in genome-wide association studies (GWAS). The SNP-associated genes were compared to genes associated with OA in other joints, aiming to see if the same genes play a role in both hip development and the risk of OA in other lower limb joints. METHODOLOGY: A systematic literature review was conducted to identify SNPs correlated with hip morphology, based on the Population, Intervention, Comparison, Outcome, and Study (PICOS) framework. Afterwards, Gene Ontology (GO) analysis was performed, using EnrichR, on the SNP-associated genes and compared with non-hip OA-associated genes, across different databases. RESULTS: Reviewing 49 GWAS identified 436 SNPs associated with hip joint morphology, encompassing variance in bone size, structure and shape. Among the SNP-associated genes, SOX9 plays a pivotal role in size, GDF5 impacts bone structure, and BMP7 affects shape. Overall, skeletal system development, regulation of cell differentiation, and chondrocyte differentiation emerged as crucial processes influencing hip morphology. Eighteen percent of GWAS-identified genes related to hip morphology were also associated with non-hip OA. CONCLUSION: Our findings indicate the existence of multiple shared genetic mechanisms across hip morphology and OA, highlighting the necessity for more extensive research in this area, as in contrast to the hip, the genetic background on knee or foot morphology remains largely understudied.

Distinctiveness of Femoral and Acetabular Mesenchymal Stem and Progenitor Populations in Patients with Primary and Secondary Hip Osteoarthritis Due to Developmental Dysplasia.

Primary hip osteoarthritis (pOA) develops without an apparent underlying reason, whereas secondary osteoarthritis arises due to a known cause, such as developmental dysplasia of the hips (DDH-OA). DDH-OA patients undergo total hip arthroplasty at a much younger age than pOA patients (50.58 vs. 65 years in this study). Recently, mesenchymal stem and progenitor cells (MSPCs) have been investigated for the treatment of osteoarthritis due to their immunomodulatory and regenerative potential. This study identified cells in subchondral bone expressing common MSPC markers (CD10, CD73, CD140b, CD146, CD164, CD271, GD2, PDPN) in vivo and compared the proportions of these populations in pOA vs. DDH-OA, further correlating them with clinical, demographic, and morphological characteristics. The differences in subchondral morphology and proportions of non-hematopoietic cells expressing MSPC markers were noted depending on OA type and skeletal location. Bone sclerosis was more prominent in the pOA acetabulum (Ac) in comparison to the DDH-OA Ac and in the pOA Ac compared to the pOA femoral head (Fh). Immunophenotyping indicated diagnosis-specific differences, such as a higher proportion of CD164+ cells and their subsets in DDH-OA, while pOA contained a significantly higher proportion of CD10+ and GD2+ cells and subsets, with CD271+ being marginally higher. Location-specific differences showed that CD271+ cells were more abundant in the Fh compared to the Ac in DDH-OA patients. Furthermore, immunohistochemical characterization of stromal bone-adjacent cells expressing MSPC markers (CD10, CD164, CD271, GD2) in the Ac and Fh compartments was performed. This research proved that immunophenotype profiles and morphological changes are both location- and disease-specific. Furthermore, it provided potentially effective targets for therapeutic strategies. Future research should analyze the differentiation potential of subsets identified in this study. After proper characterization, they can be selectively targeted, thus enhancing personalized medicine approaches in joint disease management.

Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis.

The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans' heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

Automated evaluation of hip abductor muscle quality and size in hip osteoarthritis: Localized muscle regions are strongly associated with overall muscle quality.

Limited information exists regarding abductor muscle quality variation across its length and which locations are most representative of overall muscle quality. This is exacerbated by time-intensive processes for manual muscle segmentation, which limits feasibility of large cohort analyses. The purpose of this study was to develop an automated and localized analysis pipeline that accurately estimates hip abductor muscle quality and size in individuals with mild-to-moderate hip osteoarthritis (OA) and identifies regions of each muscle which provide best estimates of overall muscle quality. Forty-four participants (age 52.7 ± 16.1 years, BMI 23.7 ± 3.4 kg/m2, 14 males) with and without mild-to-moderate radiographic hip OA were recruited for this study. Unilateral hip magnetic resonance (MR) images were acquired on a 3.0 T MR scanner and included axial T1-weighted fast spin echo and 3D axial Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL-IQ) spoiled gradient-recalled echo (SPGR) with multi-peak fat spectrum modeling and single T2* correction. A three dimensional (3D) V-Net convolutional neural network was trained to automatically segment the gluteus medius (GMED), gluteus minimus (GMIN), and tensor fascia lata (TFL) on axial IDEAL-IQ. Agreement between manual and automatic segmentation and associations between axial fat fraction (FF) estimated from IDEAL-IQ and overall muscle FF were evaluated. Dice scores for automatic segmentation were 0.94, 0.87, and 0.91 for GMED, GMIN, and TFL, respectively. GMED, GMIN, and TFL volumetric and FF measures were strongly correlated (r: 0.92-0.99) between automatic and manual segmentations, where all values fell within the 95% limits of agreement of [-9.79 cm3, 17.43 cm3] and [-1.99%, 2.89%], respectively. Axial FF was significantly associated with overall FF with the strongest correlations at 50%, 50%, and 65% the length of the GMED, GMIN, and TFL muscles, respectively (r: 0.93-0.97). An automated and localized analysis can provide efficient and accurate estimates of hip abductor muscle quality and size across muscle length. Specific regions of the muscle may be used to estimate overall muscle quality in an abbreviated evaluation of muscle quality.

Are there gender-specific differences in hip and knee cartilage composition and degeneration? A systematic literature review.

The aim of the present review is to systematically analyse the current literature about gender differences in hip or knee cartilage composition and degeneration, to help explaining how and why osteoarthritis affects women more often and more severely than men. A systematic review of the literature in English was performed. Eleven studies on 1962 patients (905 females and 787 males) that reported differences on cartilage composition between males and females were included. Nine evaluated the knee, one the hip, and one both. They were heterogeneous in their methods: one conducted histological analyses, and all the others evaluated cartilage characteristics (volume, width, and composition) through magnetic resonance imaging. All authors reported gender differences in both volume and morphology of the cartilage, from infancy to menopause. In fact, a study on 92 healthy children statistically showed significant gender differences in cartilage thickness at all sites, even after adjustment for age, body, and bone size. Gender differences become more evident after menopause, when women have a lower cartilage volume and a higher cartilage loss. Men show significantly higher knee and hip cartilage volumes than women, and women carry a significantly greater risk to develop osteoarthritis. This is in part due to body and bone size, but also depends on qualitative and quantitative differences in the composition of cartilage and its degeneration rate after menopause. Structural changes in cartilage that occur between genders during ageing have significance in the development of osteoarthritis.

Association Between Osteoarthritis Burden and Intervertebral Disk Degeneration in Patients Undergoing Lumbar Spine Surgery for Degenerative Lumbar Spondylolisthesis.

STUDY DESIGN: A retrospective analysis of prospectively collected data. OBJECTIVE: To assess the association between intervertebral disk degeneration and hip and knee osteoarthritis (OA) in patients with degenerative lumbar spondylolisthesis. BACKGROUND: The co-occurrence of hip OA and degenerative spinal pathologies was first described as the "hip-spine syndrome" and has also been observed in knee OA. It remains unclear whether both pathologies share an underlying connection beyond demographic factors. MATERIALS AND METHODS: Intervertebral disk degeneration was classified by the Pfirrmann Classification and intervertebral vacuum phenomenon. Intervertebral vacuum phenomenon was classified into mild (1 point), moderate (2 points), and severe (3 points) at each level and combined into a lumbar vacuum score (0-15 points). Similarly, a lumbar Pfirrmann grade was calculated (5-25 points). Patients with previous hip or knee replacement surgery were classified as having an OA burden. We used multivariable regression to assess the association between OA and disk degeneration, adjusted for age, body mass index, and sex. RESULTS: A total of 246 patients (58.9% female) were included in the final analysis. Of these, 22.3% had OA burden. The multivariable linear regression showed an independent association between OA burden and lumbar vacuum (ß = 2.1, P <0.001) and Pfirrmann grade (ß = 2.6, P <0.001). Representing a 2.1 points higher lumbar vacuum and 2.6 points higher lumbar Pfirrmann grade after accounting for demographic differences. CONCLUSIONS: Our study showed that OA burden was independently associated with the severity of the intervertebral disk degeneration of the lumbar spine. These findings give further weight to a shared pathology of OA of large joints and degenerative processes of the lumbar spine. LEVEL OF EVIDENCE: 3.

Increase in TPSB2 and TPSD1 Expression in Synovium of Hip Osteoarthritis Patients Who Are Overweight.

While research suggests that increasing body mass index (BMI) is a risk factor for hip osteoarthritis (HOA), the mechanisms of this effect are not fully understood. Tryptases are among the main proteases found in mast cells (MCs) and contribute to OA pathology. TPSB2, which encodes ß-tryptase, is increased in the synovium of overweight and obese knee OA patients. However, it remains unclear whether tryptase in the synovium of HOA is increased with increasing BMI. Here, we investigated tryptase genes (TPSB2 and TPSD1) in the synovium of overweight HOA patients. Forty-six patients radiographically diagnosed with HOA were allocated to two groups based on BMI, namely normal (<25 kg/m2) and overweight (25-29.99 kg/m2). TPSB2 and TPSD1 expression in the synovium of the two groups was compared using real-time polymerase chain reaction. To compare TPSB2 and TPSD1 expression in MCs between the groups, we isolated the MC-rich fraction (MC-RF) and MC-poor fraction (MC-PF), extracted using magnetic isolation. TPSB2 and TPSD1 expression was increased in the overweight group compared with the normal group. Expression of both genes in the MC-RF was significantly higher than that in MC-PF in both groups. However, TPSB2 and TPSD1 expression levels in the MC-RF did not differ between the groups. Tryptase genes were highly expressed in the synovium of overweight HOA patients. Further investigation to reveal the role of tryptase in the relationship between increasing BMI and HOA pathology is required.

What is new in pharmacological treatment for osteoarthritis?

Osteoarthritis (OA) is a degenerative joint disease in which structural changes of hyaline articular cartilage, subchondral bone, ligaments, capsule, synovium, muscles, and periarticular changes are involved. The knee is the most commonly affected joint, followed by the hand, hip, spine, and feet. Different pathological mechanisms are at play in each of these various involvement sites. Although systemic inflammation is more prominent in hand OA, knee and hip OA have been associated with excessive joint load and injury. As OA has varied phenotypes and the primarily affected tissues differ, treatment options must be tailored accordingly. In recent years, ongoing efforts have been made to develop disease-modifying options that halt or slow disease progression. Many are still in clinical trials, and as insights into the pathogenesis of OA evolve, novel therapeutic strategies will be developed. In this chapter, we provide an overview of the novel and emerging strategies in the management of OA.

Hip muscle activity in people with hip-related pain compared to asymptomatic controls: A systematic review.

BACKGROUND: Altered hip and thigh muscle activity have been observed across a spectrum of articular hip pathologies, including hip osteoarthritis, femoroacetabular impingement syndrome, and labral pathology. No systematic reviews have examined muscle activity associated with hip pathology and hip-related pain across the life span. A greater understanding of impairments in hip and thigh muscle activity during functional tasks may assist in the development of targeted treatment strategies. METHODS: We conducted a systematic review using the PRISMA guidelines. A literature search was performed in five databases (MEDLINE, CINAHL, EMBASE, Sports Discuss, and PsychINFO). Studies were included that (i) investigated people with hip-related pain (femoroacetabular impingement syndrome, labral tears) or hip osteoarthritis; and (ii) reported on muscle activity using electromyography of hip and thigh muscles during functional tasks such as walking, stepping, squatting, or lunging. Two independent reviewers performed data extraction and assessed risk of bias using a modified version of the Downs and Black checklist. RESULTS: Non-pooled data demonstrated a limited level of evidence. Overall, differences in muscle activity appeared to be more prevalent in people with more advanced hip pathology. CONCLUSIONS: We found that impairments in muscle activity in those with intra-articular hip pathology measured using electromyography were variable but appeared to be greater in severe hip pathology (e.g., hip OA).

Microstructural and cellular characterisation of the subchondral trabecular bone in human knee and hip osteoarthritis using synchrotron tomography.

OBJECTIVE: It is unclear if different factors influence osteoarthritis (OA) progression and degenerative changes characterising OA disease in hip and knee. We investigated the difference between hip OA and knee OA at the subchondral bone (SCB) tissue and cellular level, relative to the degree of cartilage degeneration. DESIGN: Bone samples were collected from 11 patients (aged 70.4 ± 10.7years) undergoing knee arthroplasty and 8 patients (aged 62.3 ± 13.4years) undergoing hip arthroplasty surgery. Trabecular bone microstructure, osteocyte-lacunar network, and bone matrix vascularity were evaluated using synchrotron micro-CT imaging. Additionally, osteocyte density, viability, and connectivity were determined histologically. RESULTS: The associations between severe cartilage degeneration and increase of bone volume fraction (%) [- 8.7, 95% CI (-14.1, -3.4)], trabecular number (#/mm) [- 1.5, 95% CI (-0.8, -2.3)], osteocyte lacunar density (#/mm3) [4714.9; 95% CI (2079.1, 7350.6)] and decrease of trabecular separation (mm) [- 0.07, 95% CI (0.02, 0.1)] were found in both knee and hip OA. When compared to knee OA, hip OA was characterised by larger (µm3) but less spheric osteocyte lacunae [47.3; 95% CI (11.2, 83.4), - 0.04; 95% CI (-0.06, -0.02), respectively], lower vascular canal density (#/mm3) [- 22.8; 95% CI (-35.4, -10.3)], lower osteocyte cell density (#/mm2) [- 84.2; 95% CI (-102.5, -67.4)], and less senescent (#/mm2) but more apoptotic osteocytes (%) [- 2.4; 95% CI (-3.6, -1.2), 24.9; 95% CI (17.7, 32.1)], respectively. CONCLUSION: SCB from hip OA and knee OA exhibits different characteristics at the tissue and cellular levels, suggesting different mechanisms of OA progression in different joints.

Magnetic resonance-based hip muscles retrospective analysis shows deconditioning and recovery after total hip arthroplasty surgery.

PURPOSE: The purpose of this study is to estimate the effect of unilateral hip osteoarthritis (OA) on hip muscle volume and fatty infiltration and to evaluate changes of muscles after total hip arthroplasty (THA) surgery. METHODS: A retrospective analysis was conducted on patients with unilateral hip OA subjected to THA with perioperative pelvic girdle 1.5 T magnetic resonance imaging (MRI). Thirty-five patients were included. Ten of these have also postoperative MRIs. Medius gluteus (MG) and iliopsoas (IP) muscles were manually segmented on the MRI scans, the corresponding 3D muscle geometries were reconstructed, and the volumes extracted. Muscle quality was assessed using the Goutallier classification on coronal MRI images. Volume and muscle quality differences were calculated between healthy and affected side. RESULTS: Pre-operatively, MG and IP on the affected side presented a mean muscle volume 17.5 ± 18% (p < 0.001) and 14.4 ± 15.8% (p < 0.001) smaller than the healthy counterpart, respectively. Muscles on the affected side showed a significant higher grade of fatty infiltration compared to the healthy side (p < 0.05 for MG; p < 0.001 for IP). At an average follow-up of 13 ± 5.3 months after THA, MG, and IP muscles of the affected hip showed an average 22.8% (p < 0.001) and 28.2% (p < 0.001) volume increase after THA. Also, the healthy side showed a significant increase of muscle volume for IP (17.1% p < 0.001). No significant change for MG muscle was observed. CONCLUSIONS: The study demonstrated preoperative reduced muscle volume and higher fatty infiltration at the muscles of the OA hip compared to the contralateral healthy one. A significant positive effect of THA on hip muscle volume was observed. These findings give an interesting insight on muscle deconditioning and recovery in patients undergoing THA.

Hip Labral Morphological Changes in Patients with Femoroacetabular Impingement Speed Up the Onset of Early Osteoarthritis.

Over the last decade, evidence has mounted for a prominent etiologic role of femoroacetabular impingement (FAI) in the development of early hip osteoarthritis (OA). The aim of this study was to compare the ultrastructure and tissue composition of the hip labrum in healthy and pathological conditions, as FAI and OA, to provide understanding of structural changes which might be helpful in the future to design targeted therapies and improve treatment indications. We analyzed labral tissue samples from five healthy multi-organ donors (MCDs) (median age, 38 years), five FAI patients (median age, 37 years) and five late-stage OA patients undergoing total hip replacement (median age, 56 years). We evaluated morpho-functional by histology and transmission electron microscopy. Extracellular matrix (ECM) structure changes were similar in specimens from FAI compared to those from patients with OA (more severe in the latter) showing disorganization of collagen fibers and increased proteoglycan content. In FAI and in OA nuclei the chromatin was condensed, organelle degenerated and cytoplasm vacuolized. Areas of calcification were mainly observed in FAI and OA labrum, as well as apoptotic-like features. We showed that labral tissue of patients with FAI had similar pathological alterations of tissue obtained from OA patients, suggesting that FAI patients might have high susceptibility to develop OA.

Effect of spinal fusion on joint space narrowing of the hip: comparison among non-fusion, short fusion, and middle or long fusion.

BACKGROUND: Lumbar fusion corrects spinal deformities and improves spinal complications. Hip osteoarthritis (OA) is strongly correlated with spinal mobility, and joint space narrowing of the hip after spinal fusion has gained attention. This study aimed to elucidate the effect of spinal fusion on hip joint space narrowing. MATERIALS AND METHODS: We retrospectively examined 530 hips of 270 patients who underwent spinal surgery. All the patients underwent whole-spine radiography before and at the final follow-up. Patients were divided into three groups (N group: non-spinal fusion, S group: up to three interbody fusions, and L group: more than four interbody fusions). The rates of joint space narrowing, spinal parameters (sagittal vertical axis, thoracic kyphosis, lumbar lordosis, sacral slope, pelvic tilt, and pelvic incidence), and limb length discrepancy at the final follow-up were compared. A multilinear regression analysis was performed to identify the risk factors for the rate of joint space narrowing. RESULTS: The rate of joint space narrowing was significantly higher in the L group than in the N and S groups (P < 0.001). No significant difference in the rate of joint space narrowing was observed between the N and S groups. Multiple linear regression analysis revealed that the number of fusion levels (p < 0.05) and follow-up period (p < 0.001) were independent risk factors for joint space narrowing. Spinal parameters at the final follow-up were not independent risk factors. CONCLUSIONS: Long spinal fusion (more than four levels) led to significantly greater joint space narrowing of the hip than short (up to three levels) or no fusion. Spinal alignment did not affect joint space narrowing of the hip. Surgeons should be aware that more than four interbody fusions may result in worse joint space narrowing of the hip. LEVEL OF EVIDENCE: IV, retrospective study.

Mechanical stretching induces calcification and cartilage matrix metabolism, causing degeneration of the acetabular labrum.

PURPOSE: The acetabular labrum plays an important role in joint lubrication, and damage to this structure leads to osteoarthritis. This study aimed to histologically classify the degree of degeneration of the acetabular labrum and to investigate the changes in gene expression induced by mechanical stretching. METHODS: We obtained acetabular labrum cells from patients with hip osteoarthritis during total hip arthroplasty (n = 25). The labrum was stained with safranin O, and images were histologically evaluated using a new parameter, the red/blue (R/B) value. The samples were divided into the degenerated group (D group: n = 18) and the healthy group (H group: n = 7) in accordance with the Kellgren-Lawrence (KL) grade. The cultured acetabular labral cells were subjected to loaded uniaxial cyclic tensile strain (CTS). After CTS, changes in gene expression were examined in both groups. RESULTS: Spearman's correlation analysis revealed that the R/B value was significantly correlated with the KL grade and the Krenn score. The expression levels of genes related to cartilage metabolism, osteogenesis and angiogenesis significantly increased after CTS in the H group, while gene expression in the D group showed weaker changes after CTS than that in the H group compared to the nonstretched control group. CONCLUSIONS: The degree of labral degeneration could be classified histologically using the R/B value and the KL grade. Mechanical stretching caused changes in gene expression that support the pathological features of labral degeneration.

Effects of a targeted resistance intervention compared to a sham intervention on gluteal muscle hypertrophy, fatty infiltration and strength in people with hip osteoarthritis: analysis of secondary outcomes from a randomised clinical trial.

BACKGROUND: People with hip osteoarthritis are typically offered a combination of education and exercise to address muscle atrophy and weakness. Limited evidence exists to assess the efficacy of exercise programs on muscle structure or function in this population. The aim of this study was to evaluate the effects of targeted resistance exercise on gluteal muscle hypertrophy and strength in people with mild-to-moderate hip osteoarthritis. METHODS: Twenty-seven participants with radiologically confirmed hip osteoarthritis recruited from a single site of a multi-site, double-blind clinical trial were randomly allocated to receive a 12-week targeted gluteal intervention or sham intervention. Magnetic resonance imaging and hand-held dynamometry were used to determine change in gluteal muscle volume, fatty infiltration and hip muscle strength. For gluteal muscle volume and strength outcomes mixed model analyses of variance (ANOVA) were conducted. A general linear model (ANOVA) analysis with fixed effects parameter estimates was used to assess the impact of sex on gluteal muscle size and strength of the affected limb only. For muscle fat index a mixed method ANOVA was used to assess the differences between groups and over time. RESULTS: In the targeted intervention group, gluteus minimus volume increased from baseline to post-intervention in both limbs (pooled mean difference: 0.06 cm3/kg, 95% confidence interval: 0.01 to 0.11) while no change occurred in the sham group (time x group effect: P = 0.025). Gluteus medius, gluteus maximus and tensor fascia lata volume did not change significantly over time. Hip strength (abduction, adduction, flexion, extension, external and internal rotation) improved similarly in both groups (time main effect: P ≤ 0.042). There was a consistent, albeit non-significant, pattern of reduced fatty infiltration after the targeted intervention. CONCLUSION: Targeted resistance exercise resulted in gluteus minimus hypertrophy, but improvements in hip strength occurred in both groups. Clinicians delivering hip osteoarthritis rehabilitation programs might consider implementing a targeted exercise program to attenuate disease associated changes within gluteal muscles. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ID: ACTRN12617000970347. Registered prospectively on 5 July 2017.

High bone mass and cam morphology are independently related to hip osteoarthritis: findings from the High Bone Mass cohort.

BACKGROUND: High bone mass (HBM, BMD Z-score ≥ + 3.2) and cam morphology (bulging of lateral femoral head) are associated with greater odds of prevalent radiographic hip osteoarthritis (rHOA). As cam morphology is itself a manifestation of increased bone deposition around the femoral head, it is conceivable that cam morphology may mediate the relationship between HBM and rHOA. We therefore aimed to determine if individuals with HBM have increased odds of prevalent cam morphology. In addition, we investigated whether the relationship between cam and prevalent and incident osteoarthritis was preserved in a HBM population. METHODS: In the HBM study, a UK based cohort of adults with unexplained HBM and their relatives and spouses (controls), we determined the presence of cam morphology using semi-automatic methods of alpha angle derivation from pelvic radiographs. Associations between HBM status and presence of cam morphology, and between cam morphology and presence of rHOA (or its subphenotypes: osteophytes, joint space narrowing, cysts, and subchondral sclerosis) were determined using multivariable logistic regression, adjusting for age, sex, height, weight, and adolescent physical activity levels. The association between cam at baseline and incidence of rHOA after an average of 8 years was determined. Generalised estimating equations accounted for individual-level clustering. RESULTS: The study included 352 individuals, of whom 235 (66.7%) were female and 234 (66.5%) had HBM. Included individuals contributed 694 hips, of which 143 had a cam deformity (20.6%). There was no evidence of an association between HBM and cam morphology (OR = 0.97 [95% CI: 0.63-1.51], p = 0.90) but a strong relationship was observed between cam morphology and rHOA (OR = 3.96 [2.63-5.98], p = 5.46 × 10-11) and rHOA subphenotypes joint space narrowing (OR = 3.70 [2.48-5.54], p = 1.76 × 10-10), subchondral sclerosis (OR = 3.28 [1.60-6.60], p = 9.57 × 10-4) and osteophytes (OR = 3.01 [1.87-4.87], p = 6.37 × 10-6). Cam morphology was not associated with incident osteoarthritis (OR = 0.76 [0.16-3.49], p = 0.72). CONCLUSIONS: The relationship between cam morphology and rHOA seen in other studies is preserved in a HBM population. This study suggests that the risk of OA conferred by high BMD and by cam morphology are mediated via distinct pathways.

Structural features of subchondral bone cysts and adjacent tissues in hip osteoarthritis.

OBJECTIVE: Focal lesions within the subchondral bone, termed subchondral bone cysts (SBCs), are clinically accepted radiographic markers of advanced osteoarthritis (OA), but their etiology in the hip is not well understood. DESIGN: This study used micro-computed tomography (µCT), and histological and immunocytological analysis to examine the prevalence, size, location, and morphological and cellular features of SBCs found within 34 femoral heads (14 male, 20 female; age range = 43-80 years) obtained from total hip arthroplasty procedures. RESULTS: SBCs were common-present in 91% of the femoral heads examined-and frequently commuted with the surface of the femoral head, but otherwise showed no preferred anatomical location. Few associations were found between SBC features and patient characteristics such as BMI, age and sex. SBCs were also heterogenous in composition, ranging from fibrous (most common) to predominantly fatty (least common) and often containing vasculature, nerve fibers, cartilage islands, and bony spicules. Despite this heterogeneity, focal abnormalities in bone density and cartilage thickness were consistently observed. Bone adjacent to SBCs was denser than that in the primary compressive group, and cartilage thickness in regions overlying SBCs was lower than in non-overlying regions. In contrast to these local bony changes, µCT-based finite element analyses indicated that the stiffness of the primary compressive group was only mildly affected by SBCs. CONCLUSIONS: These findings indicate that SBCs in the femoral head involve extensive perturbations in cellular activity, culminating in myriad skeletal tissue types and spatially heterogenous changes in bone and cartilage morphology that are likely to affect OA progression.

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses.

Changes in cellular metabolism have been implicated in mediating the activated fibroblast phenotype in a number of chronic inflammatory disorders, including pulmonary fibrosis, renal disease and rheumatoid arthritis. The aim of this study was therefore to characterise the metabolic profile of synovial joint fluid and synovial fibroblasts under both basal and inflammatory conditions in a cohort of obese and normal-weight hip OA patients. Furthermore, we sought to ascertain whether modulation of a metabolic pathway in OA synovial fibroblasts could alter their inflammatory activity. Synovium and synovial fluid was obtained from hip OA patients, who were either of normal-weight or obese and were undergoing elective joint replacement surgery. The synovial fluid metabolome was determined by 1H NMR spectroscopy. The metabolic profile of isolated synovial fibroblasts in vitro was characterised by lactate secretion, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XF Analyser. The effects of a small molecule pharmacological inhibitor and siRNA targeted at glutaminase-1 (GLS1) were assessed to probe the role of glutamine metabolism in OA synovial fibroblast function. Obese OA patient synovial fluid (n = 5) exhibited a different metabotype, compared to normal-weight patient fluid (n = 6), with significantly increased levels of 1, 3-dimethylurate, N-Nitrosodimethylamine, succinate, tyrosine, pyruvate, glucose, glycine and lactate, and enrichment of the glutamine-glutamate metabolic pathway, which correlated with increasing adiposity. In vitro, isolated obese OA fibroblasts exhibited greater basal lactate secretion and aerobic glycolysis, and increased mitochondrial respiration when stimulated with pro-inflammatory cytokine TNFα, compared to fibroblasts from normal-weight patients. Inhibition of GLS1 attenuated the TNFα-induced expression and secretion of IL-6 in OA synovial fibroblasts. These findings suggest that altered cellular metabolism underpins the inflammatory phenotype of OA fibroblasts, and that targeted inhibition of glutamine-glutamate metabolism may provide a route to reducing the pathological effects of joint inflammation in OA patients who are obese.

Otto Aufranc Award: Identification of Key Molecular Players in the Progression of Hip Osteoarthritis Through Transcriptomes and Epigenetics.

BACKGROUND: This study aimed: (1) to compare the transcriptome profile of articular cartilage in cam-FAI (early stage) to advanced OA secondary to cam-FAI (late stage) and (2) to investigate epigenetic changes through the expression of DNA methylation enzymes DNMT3B, DNMT1, and DNMT3A and peroxisome proliferator-activated receptor gamma (PPARγ) in human cartilage samples during the progression of hip OA. METHODS: Full-thickness cartilage samples were collected from the anterolateral head-neck junction (impingement zone) of 22 patients (9 early-FAI and 13 late-FAI). RNA sequencing and in vitro cartilage cultures with histological analysis and immunohistochemistry staining for PPARγ and DNMT3B were performed. Target gene validation was confirmed with RT-PCR. RESULTS: Fifty genes and 42 pathways were identified differentially between early and late-FAI (fold change <-1.5 or >1.5, P < .01). PPARγ and DNMT3B were gradually suppressed with disease progression. Contrarily, disease progression induced expression of DNMT1/3A. CONCLUSION: By comparing comprehensive gene expression in early and late stage hip degeneration at the whole-genome level, distinct transcriptome profiles for early and late stage disease were identified along with key molecular contributors to the progression of hip OA. Preservation of endogenous PPARγ may have therapeutic potential to delay or prevent hip OA.