Osteophyte Volume Research Articles

Cell-recruited microspheres for OA treatment by dual-modulating inflammatory and chondrocyte metabolism

Osteoarthritis (OA) is a degenerative disease potentially exacerbated due to inflammation, cartilage degeneration, and increased friction. Both mesenchymal stem cells (MSCs) and pro-inflammatory macrophages play important roles in OA. A promising approach to treating OA is to modify multi-functional hydrogel microspheres to target the OA microenvironment and structure. Arginyl-glycyl-aspartic acid (RGD) is a peptide widely used in bioengineering owing to its cell adhesion properties, which can recruit BMSCs and macrophages. We developed TLC-R, a microsphere loaded with TGF-β1-containing liposomes. The recruitment effect of TLC-R on macrophages and BMSCs was verified by in vitro experiments, along with its function of promoting chondrogenic differentiation of BMSCs. And we evaluated the effect of TLC-R in balancing OA metabolism in vitro and in vivo. When TLC-R was co-cultured with BMSCs and lipopolysaccharide (LPS)-treated macrophages, it showed the ability to recruit both cells in substantial numbers. As the microspheres degraded, TGF-β1 and chondroitin sulfate (ChS) were released to promote chondrogenic differentiation of the recruited BMSCs, modulate chondrocyte metabolism and inhibit inflammation induced by the macrophages. Furthermore, in vivo analysis showed that TLC-R restored the narrowed space, reduced osteophyte volume, and improved cartilage metabolic homeostasis in OA rats. Altogether, TLC-R provides a comprehensive and novel solution for OA treatment by dual-modulating inflammatory and chondrocyte metabolism.

Establishment of a Posttraumatic Osteoarthritis Model in Mice Induced by Noninvasive Anterior Cruciate Ligament Tear

Background: Animal models that use open surgical transection of the anterior cruciate ligament (ACL) do not accurately simulate the clinical condition regarding the pivot-shift mechanism and the associated inflammatory response that occurs before reconstruction. Purpose/Hypothesis: The purpose was to characterize a reproducible manual, nonsurgical method to mimic an isolated ACL tear in a clinically relevant model and to evaluate the development of progressive posttraumatic osteoarthritis due to ACL injury. It was hypothesized that the ACL could be reproducibly torn with minimal damage to other ligaments and that there would be progressive development of degenerative joint disease after ACL injury. Study Design: Controlled laboratory study. Methods: A total of 37 mice (strain C57BL/6) were used to compare the manual procedure with sham surgery (sham group; n = 10) and with the established surgical ACL transection (ACLT) procedure (surgical group; n = 27). In the sham group, a closed manual procedure was performed on the right knee and sham surgery on the left knee. In the surgical group, the closed manual procedure was performed on the right knee and surgical ACLT on the left knee. Dissection using India ink, histological assessment with safranin O and hematoxylin-eosin staining, radiological evaluation through radiographs and microfocus computed tomography scans, and gait analyses were performed to assess cartilage/ligament status. Osteoarthritis Research Society International (OARSI) and synovitis scores, anterior tibial translation, range of motion, bone microstructure, osteophyte volume, and pain were assessed at 2, 4, and 8 weeks postoperatively. Results: The manual procedure successfully resulted in an ACL rupture and associated meniscal injury. The posterior cruciate, lateral collateral, and medial collateral ligaments were intact in all dissected knees. Two weeks after ACL tear, the surgical group showed a significantly higher synovitis score, whereas 8 weeks after ACL tear, the manual group showed a significantly higher volume of osteophytes. No significant differences were found between the groups in terms of OARSI score, anterior tibial translation, range of motion, bone microstructure computed tomography values, and stride distance/irregularity. Conclusion: This procedure can be used to create an ACL tear model without causing grossly evident injuries to other ligaments and avoiding the risk of cartilage damage from surgical instruments. Clinical Relevance: This procedure offers a more clinically relevant ACL tear model and facilitates simple, inexpensive, and reproducible development of posttraumatic osteoarthritis.

Characterizing Osteophyte Formation in Knee Osteoarthritis: Application of Machine Learning Quantification of a Computerized Tomography Cohort: Implications for Treatment

BackgroundOsteophytes are commonly used to diagnose and guide knee osteoarthritis (OA) treatment, but their causes are unclear. Although they are not typically the focus of knee arthroplasty surgeons, they can predict case difficulty and length. Furthermore, their extent and location may yield much information about the knee joint status. The aims of this computed tomography–based study in patients awaiting total or partial knee arthroplasty were to: (1) measure osteophyte volume in anatomical subregions and relative change as total volume increases; (2) determine whether medial and/or lateral OA affects osteophyte distribution; and (3) explore relationships between osteophytes and OA severity. MethodsData were obtained from 4,928 computed tomography scans. Machine-learning-based imaging analyses enabled osteophyte segmentation and quantification, divided into anatomical regions. Mean three-dimensional joint space narrowing was assessed in medial and lateral compartments. A Bayesian model assessed the uniformity of osteophyte distribution. We correlated femoral osteophyte volumes with B-scores, a validated OA status measure. ResultsTotal tibial (25%) and femoral osteophyte volumes (75%) within each knee correlated strongly (R2 = 0.85). Medial osteophytes (65.3%) were larger than lateral osteophytes (34.6%), with similar proportions in both the femur and tibia. Osteophyte growth was found in all compartments, and as total osteophyte volume increased, the relative distribution of osteophytes between compartments did not markedly change. No evidence of variation was found in the regional distribution of osteophyte volume between knees with medial, lateral, both, or no three-dimensional joint space narrowing in the femur or tibia. There was a direct relationship between osteophyte volume and OA severity. ConclusionsOsteophyte volume increased in both medial and lateral compartments proportionally with total osteophyte volume, regardless of OA location. The peripheral position of femoral osteophytes does not appear to contribute to load-bearing. This suggests that osteophytic growth represents a ‘whole-knee’/global response. This work may have broad applications for knee OA, both surgically and nonoperatively.

Numerical study of osteophyte effects on preoperative knee functionality in patients undergoing total knee arthroplasty.

Osteophytes are routinely removed during total knee arthroplasty, yet the preoperative planning currently relies on preoperative computed tomography (CT) scans of the patient's osteoarthritic knee, typically including osteophytic features. This complicates the surgeon's ability to anticipate the exact biomechanical effects of osteophytes and the consequences of their removal before the operation. The aim of this study was to investigate the effect of osteophytes on ligament strains and kinematics, and ascertain whether the osteophyte volume and location determine the extent of this effect. We segmented preoperative CT scans of 21 patients, featuring different osteophyte severity, using image-based active appearance models trained to identify the osteophytic and preosteophytic bone geometries and estimate the cartilage thickness in the segmented surfaces. The patients' morphologies were used to scale a template musculoskeletal knee model. Osteophytes induced clinically relevant changes to the knee's functional behavior, but these were variable and patient-specific. Generally, severe osteophytic knees significantly strained the oblique popliteal ligament (OPL) and posterior capsule (PC) relative to the preosteophytic state. Furthermore, there was a marked effect on the lateral collateral ligament and anterolateral ligament (ALL) strains compared to mild and moderate osteophytic knees, and concurrent alterations in the tibial lateral-medial translation and external-internal rotation. We found a strong correlation between the OPL, PC, and ALL strains and posterolateral condylar and tibial osteophytes, respectively. Our findings may have implications for the preoperative planning in total knee arthroplasty, toward reproducing the physiological knee biomechanics as close as feasibly possible.

Mild exercise expedites joint clearance and slows joint degradation in a joint instability model of osteoarthritis in male rats

ObjectiveExercise remains a hallmark treatment for post-traumatic osteoarthritis (PTOA) and may maintain joint homeostasis in part by clearing inflammatory cytokines, cells, and particles. It remains largely unknown whether exercise-induced joint clearance can provide therapeutic relief of PTOA. In this study, we hypothesized that exercise could slow progression of preclinical PTOA in part by enhancing knee joint clearance. DesignSurgical medial meniscal transection was used to induce PTOA in 3-month-old male Lewis rats. A sham surgery was used as a control. Mild treadmill walking was introduced 3 weeks post-surgery and maintained to 6 weeks post-surgery. Gait and isometric muscle torque were measured at the study endpoint. Near-infrared imaging tracked how exercise altered lymphatic and venous knee joint clearance during discrete time points of PTOA progression. ResultsExercise mitigated joint degradation associated with PTOA by preserving glycosaminoglycan content and reducing osteophyte volume (effect size (95% CI); 1.74 (0.71-2.26). PTOA increased hind step widths (0.57 (0.18-0.95) cm), but exercise corrected this gait dysfunction (0.54 (0.16-0.93) cm), potentially indicating pain relief. Venous, but not lymphatic, clearance was quicker 1-, 3-, and 6-weeks post-surgery compared to baseline. The mild treadmill walking protocol expedited lymphatic clearance rate in moderate PTOA (3.39 (0.20-6.59) hrs), suggesting exercise may play a critical role in restoring joint homeostasis. ConclusionsWe conclude that mild exercise has the potential to slow disease progression in part by expediting joint clearance in moderate PTOA.

Unveiling the distinctive ossification patterns of diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis using computed tomography three-dimensional reconstruction.

To quantitatively analyze the morphological characteristics of osteophytes in DISH and syndesmophytes in AS, and summarize different ossification patterns to help identify the two diseases. Associated factors for new bone formation would be investigated. Fifty patients with DISH and 50 age-, sex-, CT examination site- matched patients with AS were enrolled. Radiographic and clinical data were reviewed. Osteophytes (syndesmophytes) in front of each vertebral body and the corresponding intervertebral disc space were defined as vertebral osteophytes unit (VOU). The volume, angle and location (contralateral, ipsilateral, bilateral) of osteophytes in each VOU were measured and compared between DISH and AS groups. In each VOU, the volume and angle of osteophytes in DISH were significantly larger. The best osteophytes volume and angle cutoff value in predicting DISH was 0.59 cm3 and 40.15°. Contralateral, bilateral, ipsilateral osteophytes were recorded in 59.32%, 36.38%, 4.3% of assessed VOUs in patients with DISH and 64.78%, 29.31%, 5.91% in AS (p‹0.001), respectively. As to ipsilateral osteophytes, the volume was inversely correlated with the center of the vertebral body to the center of the descending aorta (DISH: r = -0.45, p= 0.01; AS: r = -0.83, p‹0.001). Advanced age, disease duration, smoking and overweight contribute to the progression of osteophytes and syndesmophytes. Morphological features of osteophytes are helpful to distinguish DISH with AS. Aortic pulsations inhibit or hinder new bone formation in both DISH and AS. Maintaining normal BMI could postpone osteophytes formation.

Tranexamic Acid Attenuates the Progression of Posttraumatic Osteoarthritis in Mice

Background: Posttraumatic osteoarthritis (OA) is a common disorder associated with a high socioeconomic burden, particularly in young, physically active, and working patients. Tranexamic acid (TXA) is commonly used in orthopaedic trauma surgery as an antifibrinolytic agent to control excessive bleeding. Previous studies have reported that TXA modulates inflammation and bone cell function, both of which are dysregulated during posttraumatic OA disease progression. Purpose: To evaluate the therapeutic effects of systemic and topical TXA treatment on the progression of posttraumatic OA in the knee of mice. Study Design: Controlled laboratory study. Methods: OA was induced via anterior cruciate ligament (ACL) transection on the right knee of female mice. Mice were treated with TXA or vehicle intraperitoneally daily or intra-articularly weekly for 4 weeks, starting on the day of surgery. Articular cartilage degeneration, synovitis, bone erosion, and osteophyte formation were scored histologically. Micro−computed tomography evaluation was conducted to measure the subchondral bone microstructure and osteophyte volume. Cartilage thickness and bone remodeling were assessed histomorphometrically. Results: Both systemic and topical TXA treatment significantly reduced cartilage degeneration, synovitis, and bone erosion scores and increased the ratio of hyaline to calcified cartilage thickness in posttraumatic OA. Systemic TXA reversed ACL transection-induced subchondral bone loss and osteophyte formation, whereas topical treatment had no effect. Systemic TXA decreased the number and surface area of osteoclasts, whereas those of osteoblasts were not affected. No effect of topical TXA on osteoblast or osteoclast parameters was observed. Conclusion: Both systemic and topical TXA exerted protective effects on the progression of posttraumatic OA. Drug repurposing of TXA may, therefore, be useful for the prevention or treatment of posttraumatic OA, particularly after ACL surgery. Clinical Relevance: TXA might be beneficial in patients with posttraumatic OA of the knee.

Sexual dimorphism of the synovial transcriptome underpins greater PTOA disease severity in male mice following joint injury

Osteoarthritis is a disease with sex-dependent prevalence and severity in both humans and animal models. We sought to elucidate sex differences in synovitis, mechanical sensitization, structural damage, bone remodeling, and the synovial transcriptome in the anterior cruciate ligament rupture (ACLR) mouse model of post-traumatic osteoarthritis (PTOA). Male and female 12-week-old C57/BL6J mice were randomized to Sham or noninvasive ACLR with harvests at 7d or 28d post-ACLR (n=9 per sex in each group - Sham, 7d ACLR, 28d ACLR). Knee hyperalgesia, mechanical allodynia, and intra-articular MMP activity (via intravital imaging) were measured longitudinally. Trabecular and subchondral bone remodeling and osteophyte formation were assessed by µCT. Histological scoring of PTOA and synovitis and anti-MMP13 immunostaining were performed. NaV1.8-Cre;tdTomato mice were used to document localization and sprouting of nociceptors. Bulk RNA-seq of synovium in Sham, 7d, and 28d post-ACLR, and contralateral joints (n=6 per group per sex) assessed injury-induced and sex-dependent gene expression. Male mice exhibited more severe joint damage at 7d and 28d and more severe synovitis at 28d, accompanied by 19% greater MMP activity, 8% lower knee hyperalgesia threshold, and 43% lower hindpaw withdrawal threshold in injured limbs compared to female injured limbs. Females had injury-induced catabolic responses in trabecular and subchondral bone, whereas males exhibited 133% greater normalized osteophyte volume relative to females and sclerotic remodeling of trabecular and subchondral bone. NaV1.8+ nociceptor sprouting in subchondral bone and medial synovium was induced by injury and comparable between sexes. RNA-seq of synovium demonstrated similar injury-induced transcriptomic programs between the sexes at 7d, but only female mice exhibited a transcriptomic signature indicative of synovial inflammatory resolution by 28d, whereas males had persistent pro-inflammatory, pro-fibrotic, pro-neurogenic, and pro-angiogenic gene expression. Male mice exhibited more severe overall joint damage and pain behavior after ACLR, which was associated with persistent activation of synovial inflammatory, fibrotic, and neuroangiogenic processes, implicating persistent synovitis in driving sex differences in murine PTOA.

Validation of a Low-Cost Portable Device for Inducing Noninvasive Anterior Cruciate Ligament Injury in Mice.

Noninvasive compression-induced anterior cruciate ligament rupture (ACL-R) is an easy and reproducible model for studying post-traumatic osteoarthritis (PTOA) in mice. However, equipment typically used for ACL-R is expensive, immobile, and not available to all researchers. In this study, we compared PTOA progression in mice injured with a low-cost custom ACL-rupture device (CARD) to mice injured with a standard system (ElectroForce 3200). We quantified anterior-posterior (AP) joint laxity immediately following injury, epiphyseal trabecular bone microstructure, and osteophyte volume at 2 and 6 weeks post injury using micro-computed tomography, and osteoarthritis progression and synovitis at 2 and 6 weeks post injury using whole-joint histology. We observed no significant differences in outcomes in mice injured with the CARD system compared to mice injured with the Electroforce (ELF) system. However, AP joint laxity data and week 2 micro-CT and histology outcomes suggested that injuries may have been slightly more severe and PTOA progressed slightly faster in mice injured with the CARD system compared to the ELF system. Altogether, these data confirm that ACL-R can be successfully and reproducibly performed with the CARD system and that osteoarthritis (OA) progression is mostly comparable to that of mice injured with the ELF system, though potentially slightly faster. The CARD system is low cost and portable, and we are making the plans and instructions freely available to all interested investigators in the hopes that they will find this system useful for their studies of OA in mice.

Posterior Compartment Debridement and Varus Deformity Correction in Total Knee Arthroplasty

BackgroundRestoration of joint-line position and deformity correction remain important tenets for preserving stability and function after total knee arthroplasty (TKA). We sought to characterize the role of posterior osteophytes in the correction of alignment deformity during TKA. MethodsWe evaluated 57 patients (57 TKAs) who participated in a trial of robotic-arm assisted TKA outcomes. Weight-bearing and fixed preoperative alignment was measured using long-standing radiographs and tools of the robotic-arm tracking system, respectively. Total volume (cm3) of posterior osteophytes was quantified using preoperative planning computed tomography scans. Joint-line position was evaluated using bone resection thicknesses measured using a caliper. ResultsThe mean (minimum to maximum) initial fixed deformity was 4 degrees (range, 0 to 11) of varus. All patients showed asymmetric posterior osteophytes. Mean total osteophyte volume was 3 cm3 (range, 1 to 9). Total osteophyte volume was positively correlated with severity of fixed deformity (r = 0.48, P = .0001). Removal of osteophytes allowed for the correction of functional alignment to within 3 degrees of neutral in all cases (mean 0 degree), with none requiring release of the superficial medial collateral ligament. Tibial joint-line position was restored to within 3 millimeters in all but 2 cases (mean increase of height, 0.6 [range, −4 to +5]). ConclusionIn the end-stage diseased knee, posterior osteophytes typically occupy space in the posterior capsule on the concave side of the deformity. Thorough debridement of posterior osteophytes may help facilitate management of modest varus deformity with decreased need for soft-tissue releases or adjustments to planned bone resection.

Dorsal Subluxation of the First Metacarpal During Thumb Flexion is an Indicator of Carpometacarpal Osteoarthritis Progression.

Dorsal Subluxation of the First Metacarpal During Thumb Flexion is an Indicator of Carpometacarpal Osteoarthritis Progression.

Bone morphological changes of the trapezium and first metacarpal with early thumb osteoarthritis progression.

Thumb carpometacarpal osteoarthritis is characterized by osteophyte growth and changes in the curvature of the articular surfaces of the trapezium and first metacarpal. The aim of this longitudinal study was to quantify in-vivo bone morphology changes with osteoarthritis progression. The study analyzed an observational dataset of 86 subjects with early thumb osteoarthritis and 22 age-matched asymptomatic controls. CT scans of subjects' affected hands were acquired at enrollment (year 0), and at 1.5, 3, 4.5, and 6-year follow-up visits. Osteoarthritic subjects were classified into stable and progressive groups, as defined by osteophyte volume and the rate of osteophyte growth. Trapezium height, width, and volar facet recession, along with first metacarpal volar beak recession and recession angle, were quantified. Mean trapezium width increased 12% over six years in the progressive osteoarthritis group. Trapezium volar recession of the progressive osteoarthritis group was significantly greater than stable at enrollment (P<0.0001) and year 6 (P<0.0001). The first metacarpal volar beak of the progressive osteoarthritis group recessed significantly faster than stable (P=0.0004) and control (P=0.0003). In year 6, volar beak surfaces in subjects with progressive osteoarthritis were flatter with reduced curvature, measuring -8.7±4.0 degrees, compared to the stable osteoarthritis (P<0.0001) and control groups (P=0.0003), which maintained nominal curvatures, measuring 0.7±2.5 and 0.2±3.2 degrees, respectively. Our results demonstrate significant recession and reduction in the angle of the first metacarpal volar beak in progressive osteoarthritis. Flattening of the first metacarpal volar beak may have important associations with carpometacarpal joint contact and loading migrations, further propagating osteophyte formation and bony remodeling. This work highlights the volar beak of the first metacarpal as a region of morphology change with disease.

Predicting robotic-assisted total knee arthroplasty operating time : benefits of machine-learning and 3D patient-specific data.

AimsNo predictive model has been published to forecast operating time for total knee arthroplasty (TKA). The aims of this study were to design and validate a predictive model to estimate operating time for robotic-assisted TKA based on demographic data, and evaluate the added predictive power of CT scan-based predictors and their impact on the accuracy of the predictive model.MethodsA retrospective study was conducted on 1,061 TKAs performed from January 2016 to December 2019 with an image-based robotic-assisted system. Demographic data included age, sex, height, and weight. The femoral and tibial mechanical axis and the osteophyte volume were calculated from CT scans. These inputs were used to develop a predictive model aimed to predict operating time based on demographic data only, and demographic and 3D patient anatomy data.ResultsThe key factors for predicting operating time were the surgeon and patient weight, followed by 12 anatomical parameters derived from CT scans. The predictive model based only on demographic data showed that 90% of predictions were within 15 minutes of actual operating time, with 73% within ten minutes. The predictive model including demographic data and CT scans showed that 94% of predictions were within 15 minutes of actual operating time and 88% within ten minutes.ConclusionThe primary factors for predicting robotic-assisted TKA operating time were surgeon, patient weight, and osteophyte volume. This study demonstrates that incorporating 3D patient-specific data can improve operating time predictions models, which may lead to improved operating room planning and efficiency.Cite this article: Bone Jt Open 2022;3(5):383–389.

Quantitative high-resolution 7T MRI to assess longitudinal changes in articular cartilage after anterior cruciate ligament injury in a rabbit model of post-traumatic osteoarthritis

ObjectiveTo demonstrate an ultra-high field (UHF) 7 ​T delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) protocol for quantitative post-traumatic osteoarthritis (PTOA) detection and monitoring in a rabbit anterior cruciate ligament transection (ACLT) model. DesignACL transections were performed unilaterally in 5 rabbits (33-weeks-old, 3.5 ​± ​0.5 ​kg) to induce PTOA. MRI exams were performed at 7 ​T prior to and 2, 4, 7 and 10-weeks after ACLT using a modified dGEMRIC protocol. Voxel-based T1 and T2 maps were created over manually drawn femoral cartilage ROIs from the center of the tibial plateau to the posterior meniscus. Femoral, tibial, and patellar epiphyses were harvested 10-weeks post-surgery and processed for μCT imaging and histology. ResultsQuantitative analysis revealed a 35% and 39% decrease in dGEMRIC index in the medial ACLT knee compartment 7- and 10-weeks post-surgery, respectively (p ​= ​0.009 and p ​= ​0.006) when compared to baseline. There was no significant change in the lateral ACLT compartment or in either compartment of the control knees. Visual inspection of histology confirmed PTOA in the ACLT knees. Osteophytes were found only in ACLT knees (osteophyte volume in femur: 94.53 ​± ​44.08 ​mm3, tibia: 29.35 ​± ​13.79 ​mm3, and patella: 3.84 ​± ​0.92 ​mm3) and were significantly larger in the medial compartments of the femur than lateral (p ​= ​0.0312). ConclusionThe dGEMRIC technique quantitatively applied at 7 ​T UHF-MRI demonstrates site-specific cartilage degeneration in a large animal PTOA model. This should encourage further investigation, with potential applications in drug and therapeutic animal trials as well as human studies.

NSAIDs Reduce Therapeutic Efficacy of Mesenchymal Stromal Cell Therapy in a Rodent Model of Posttraumatic Osteoarthritis

Background: Intra-articular injections of human mesenchymal stromal cells (hMSCs) have shown promise in slowing cartilage degradation in posttraumatic osteoarthritis (PTOA). Clinical use of cell therapies for osteoarthritis has accelerated in recent years without sufficient scientific evidence defining best-use practices. Common recommendations advise patients to avoid nonsteroidal anti-inflammatory drug (NSAID) use before and after cell injection over concerns that NSAIDs may affect therapeutic efficacy. Recommendations to restrict NSAID use are challenging for patients, and it is unclear if patients are compliant. Hypothesis: NSAIDs will reduce the efficacy of hMSC therapy in treating a preclinical model of PTOA. Study Design: Controlled laboratory study. Methods: Lewis rats underwent medial meniscal transection (MMT) surgery to induce PTOA or a sham (sham group) surgery that did not progress to PTOA. Rats received naproxen solution orally daily before (Pre-NSAID group) or after (Post-NSAID group) hMSC treatment, throughout the course of the experiment (Full-NSAID group), or received hMSCs without NSAIDs (No NSAID). Cartilage morphology and composition were quantified using contrast-enhanced micro–computed tomography and histology. Pain (secondary allodynia) was measured using a von Frey filament. Results: Injection of hMSCs attenuated cartilage degeneration associated with MMT. hMSCs prevented proteoglycan loss, maintained smooth cartilage surfaces, reduced cartilage lesions, reduced mineralized osteophyte formation, and reduced pain by week 7. The Pre-NSAID group had decreased proteoglycan levels compared with the hMSC group, although there were no other significant differences. Thus, pretreatment with NSAIDs had minimal effects on the therapeutic benefits of hMSC injections. The Post-NSAID and Full-NSAID groups, however, exhibited significantly worse osteoarthritis than the hMSC-only group, with greater proteoglycan loss, surface roughness, osteophyte volume, and pain. Conclusion: Use of NSAIDs before hMSC injection minimally reduced the therapeutic benefits for PTOA, which included preservation of cartilage surface integrity as well as a reduction in osteophytes. Use of NSAIDs after injections, however, substantially reduced the therapeutic efficacy of cellular treatment. Clinical Relevance: Our data support the clinical recommendation of avoiding NSAID use after hMSC injection but suggest that using NSAIDs before treatment may not substantially diminish the therapeutic efficacy of cell treatment.

Association of Bone Erosions and Osteophytes With Systemic Bone Involvement on High-Resolution Peripheral Quantitative Computed Tomography in Premenopausal Women With Longstanding Rheumatoid Arthritis.

To evaluate premenopausal women with longstanding rheumatoid arthritis (RA) for potential associations between parameters of localized bone involvement and parameters of systemic bone involvement in the affected joints. Eighty consecutively evaluated premenopausal women with RA were included in the study, along with 160 healthy female control subjects who were matched to the patients by age and body mass index. Volumetric bone mineral density (vBMD), bone microarchitecture, and finite elements of biomechanical bone strength (bone stiffness and estimated failure load) at the distal radius and distal tibia were analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with RA compared to healthy controls. In addition, in patients with RA, localized bone involvement in the metacarpophalangeal and proximal interphalangeal joints was analyzed by HR-pQCT, to identify bone erosions and osteophytes. Among the 80 premenopausal women with longstanding RA, the mean ± SD age was 39.4 ± 6.7 years and mean ± SD disease duration was 9.8 ± 5.3 years. Trabecular and cortical bone parameters and bone strength at the distal radius and distal tibia were all impaired in patients with RA compared to healthy controls (each P < 0.05). In total, 75% of RA patients had evidence of bone erosions, and 41.3% of RA patients had detectable osteophytes on HR-pQCT. RA patients with bone erosions, as compared to RA patients without bone erosions, had lower cortical vBMD (at the distal radius, mean ± SD 980 ± 72 mg HA/cm3 versus 1,021 ± 47 mg HA/cm3 [P=0.03]; at the distal tibia, 979 ± 47 mg HA/cm3 versus 1,003 ± 34 mg HA/cm3 [P=0.04]) and higher cortical bone porosity (at the distal radius, mean ± SD 2.8 ± 2.5% versus 1.8 ± 1.6% [P=0.04]; at the distal tibia, 3.7 ± 1.6% versus 2.7 ± 1.6% [P=0.01]). In patients with RA, osteophyte volume at the distal radius was positively correlated with trabecular vBMD (r=0.392, P=0.02), trabecular number (r=0.381, P=0.03), and trabecular stiffness (r=0.411, P=0.02), and negatively correlated with trabecular separation (r=-0.364, P=0.04), as determined by Pearson's or Spearman's correlation test. The findings show that premenopausal women with longstanding RA have systemic bone fragility at peripheral joint sites. Moreover, the presence of bone erosions is mainly associated with cortical bone fragility at the distal radius and tibia, and presence of osteophytes is associated with repair of trabecular bone at the distal radius.

Post-traumatic osteoarthritis progression is diminished by early mechanical unloading and anti-inflammatory treatment in mice

Post-traumatic osteoarthritis (PTOA) is a degenerative joint disease initiated by injury. Early phase (0-7 days) treatments often include rest (unloading) and anti-inflammatory medications, but how those early interventions impact PTOA progression is unknown. We hypothesized that early unloading and anti-inflammatory treatment would diminish joint inflammation and slow PTOA progression. Mice were injured with non-invasive ACL rupture followed by hindlimb unloading (HLU) or normal cage activity (ground control: GC) for 7 days, after which all mice were allowed normal cage activity. HLU and GC mice were treated with daily celecoxib (CXB; 10mg/kg IP) or vehicle. Protease activity was evaluated using in vivo fluorescence imaging, osteophyte formation and epiphyseal trabecular bone were quantified using micro-computed tomography, and synovitis and articular cartilage were evaluated using whole-joint histology at 7, 14, 21, and 28 days post-injury. HLU significantly reduced protease activity (-22-30% compared to GC) and synovitis (-24-50% relative to GC) at day 7 post-injury (during unloading), but these differences were not maintained at later timepoints. Similarly, trabecular bone volume was partially preserved in HLU mice at during unloading (-14-15% BV/TV for HLU mice, -21-22% for GC mice relative to uninjured), but these differences were not maintained during reloading. Osteophyte volume was reduced by both HLU and CXB, but there was not an additive effect of these treatments (HLU:-46%, CXB:-30%, HLU+CXB:-35% relative to vehicle GC at day 28). These data suggest that early unloading following joint injury can reduce inflammation and potentially slow PTOA progression.

Proximal tibial osteophyte volumes are correlated spatially and with knee alignment: a quantitative analysis suggesting the influence of biochemical and mechanical factors in the development of osteophytes

To characterize the differences and correlations in osteophyte volumes between and within proximal tibial compartments, and to assess the correlations between osteophyte volumes and the femorotibial angle. CT scans of 73 knees with predominantly medial femorotibial osteoarthritis (21K/L2, 28K/L3, 24K/L4) were retrospectively analyzed using a new, reproducible method measuring total and subregional osteophyte volumes in the medial and lateral compartments. Non-parametric statistics was used for comparison and correlation analyses. Total osteophyte volumes were larger in the medial than in the lateral compartment for all severity groups (p<0.05). Additionally, statistically significant differences were observed among subregions of the lateral compartment in K/L3 and K/L4 knees. Statistically significant positive correlations were found between the medial and lateral total osteophyte volumes in K/L3 and K/L4 knees (ρ≥0.44, p=0.03), and among most subregional osteophyte volumes within each compartment in K/L3 knees. Markedly fewer statistically significant correlations were present in K/L2 and K/L4 knees. In K/L3 knees, the femorotibial angle was statistically significantly positively correlated with the total osteophyte volume in the medial compartment (ρ=0.50, p=0.01), with osteophyte volumes in most medial subregions, and with the osteophyte volume in the lateral posterior subregion (ρ=0.40, p=0.05). Quantitative assessment of osteophytes may bring insight on factors influencing their development. Positive correlations of osteophyte volumes found between and within compartments suggest the influence of biochemical mediators acting on the entire joint, while positive correlations between the femorotibial angle and osteophyte volumes suggest a role of mechanical factors. These hypotheses are to be further confirmed.

Calcified cartilage revealed in whole joint by X-ray phase contrast imaging

ObjectiveX-ray Phase Contrast Imaging (PCI) is an emerging modality that will be in the next few years available in a wider range of preclinical set-ups. In this study, we compare this imaging technique with conventional preclinical modalities in an osteoarthritis mouse model. MethodPhase contrast technique was performed on 6 post-mortem, monoiodoacetate-induced osteoarthritis knees and 6 control knees. The mice knees were then imaged using magnetic resonance imaging and conventional micro computed tomography. Examples of imaging surrogate markers are reported: local distances within the articular space, cartilage surface roughness, calcified cartilage thickness, number, volume and locations of osteophytes. ResultsThanks to PCI, we can show in 3D calcified cartilage without contrast agent by a non-invasive technique. The phase contrast images reveal more details than conventional imaging techniques, especially at smaller scales, with for instance a higher number of micro-calcifications detected (57, 314 and 329 for MRI, conventional micro-CT and phase contrast imaging respectively). Calcified cartilage thickness was measured with a significant difference (p ​< ​0.01) between the control (23.4 ​± ​17.2 ​μm) and the osteoarthritis induced animal (46.9 ​± ​19.0 ​μm). ConclusionsX-ray phase contrast imaging outperforms the conventional imaging modalities for assessing the different tissue types (soft and hard). This new imaging modality seems to bring new relevant surrogate markers for following-up small animal models even for low-grade osteoarthritis.

Metformin attenuates traumatic osteoarthritis in obese mice induced by high-fat diet partly by reducing leptin

Purpose: Obesity is one of the main risk factors for osteoarthritis (OA), and evidence is accumulating that proinflammatory adipokines such as leptin play an important role in OA. Metformin (Met) has been shown to reduce weight and relieve inflammation. Here, we combine surgical joint damage with high-fat diet (HFD) in mice to investigate the effect of metformin on OA and its potential mechanism. Methods: Mice were fed with HFD or normal diet (ND) from 3 weeks old and destabilization of the medial meniscus (DMM) surgery was performed at 12 weeks old. Metformin was administrated in drinking water immediately after DMM and the joint structural changes were observed at 5 and 10 weeks after the surgery. OA was evaluated by Osteoarthritis Research Society International (OARSI) score, synovitis score, and osteophyte volume reconstructed by micro-computed tomography. Macrophage infiltration in synovium and leptin expression in adipose tissue were detected by immunofluorescence. In vitro, the apoptosis of primary human chondrocytes and the subtypes of macrophages were detected by flow cytometry. Murine chondrogenic cell line ATDC5 and macrophage cell line RAW264.7 were incubated in fat conditioned medium (FCM) from mouse abdominal fat, and the metabolic changes were detected by western blot and ELISA. Results: The OARSI score, synovitis score and osteophyte volume of ND + DMM + Met mice and HFD + DMM + Met mice were significantly lower than that of ND + DMM mice and HFD + DMM mice, respectively. Importantly, the interaction between diet and Met on OARSI score was statistically significant at 5 weeks (F = 6.364, P = 0.020) and 10 weeks (F = 4.949, P = 0.038) after DMM. The mean difference of OARSI score in HFD mice (2.08 at 5 weeks and 3.17 at 10 weeks) was greater than that in ND mice (0.8 at 5 weeks and 2 at 10 weeks). Metformin reduced the expression of ADAMTS-5 and MMP13 in articular chondrocytes, and increased the expression of autophagy marker LC3. The M1 macrophage marker iNOS was decreased and the M2 macrophage marker CD206 was increased in synovium of metformin- treated mice. Interestingly, metformin reduced the leptin levels in abdominal fat and articular chondrocytes in HFD mice but not ND mice. The expression of MMP-13, ADAMTS-5 and p-S6 of ATDC5 cells in HFD + DMM + Met FCM was significantly lower than that in HFD + DMM FCM. The content of TNF-α and IL-1β of RAW264.7 cells in HFD + DMM + Met FCM was significantly lower than that in HFD + DMM FCM. Furthermore, the expression of ADAMTS-5 and p-S6 in ATDC5 and the secretion of TNF-α and IL-1β in RAW264.7 was significantly reduced after neutralization of leptin in HFD + DMM FCM. Conclusions: Metformin showed a therapeutic effect on OA both in ND mice and in HFD mice. The therapeutic effect of metformin on OA in HFD mice is better than that in ND mice, which may be related to decreasing leptin levels.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)