Association of subchondral bone marrow lesion localization with weight-bearing pain in people with knee osteoarthritis: data from the Osteoarthritis Initiative

© 2021, The Author(s). Background: Subchondral bone marrow lesions (BMLs) detected on MRI in knee osteoarthritis (OA) are associated with knee pain. The prevalence and progression of subchondral BMLs are increased by mechanical knee load. However, associations of subchondral BML location with weight-bearing knee pain are currently unknown. In this study, we aim to demonstrate associations of subchondral BML location and size with weight-bearing knee pain in knee OA. Methods: We analyzed 1412 and 582 varus knees from cross-sectional and longitudinal Osteoarthritis Initiative datasets, respectively. BML scores were semi-quantitatively analyzed with the MRI Osteoarthritis Knee Score for 4 subchondral regions (median and lateral femorotibial, medial and lateral patellofemoral) and subspinous region. Weight-bearing and non-weight-bearing pain scores were derived from WOMAC pain items. Correlation and negative binomial regression models were used for analysis of associations between the BML scores and pain at baseline and changes in the BML scores and changes in pain after 24-month follow-up. Results: Greater BML scores at medial femorotibial and lateral patellofemoral compartments were associated with greater weight-bearing pain scores, and statistical significance was retained after adjusting for BML scores at the other 4 joint compartments and other OA features, as well as for non-weight-bearing pain, age, sex, and body mass index (BMI) (medial femorotibial; B = 0.08, p = 0.02. patellofemoral; B = 0.13, p = 0.01). Subanalysis revealed that greater medial femorotibial BML scores were associated with greater pain on walking and standing (B = 0.11, p = 0.01, and B = 0.10, p = 0.04, respectively). Lateral patellofemoral BML scores were associated with pain on climbing, respectively (B = 0.14, p = 0.02). Increases or decreases over 24 months in BML score in the medial femorotibial compartment were significantly associated with increases or decreases in weight-bearing pain severity after adjusting for non-weight-bearing pain, age, sex, baseline weight-bearing pain, BMI, and BML at the other 4 joint compartments (B = 0.10, p = 0.01). Conclusions: Subchondral BML size at the medial femorotibial joint compartment was specifically associated with the severity and the change in weight-bearing pain, independent of non-weight-bearing pain, in knee OA. Specific associations of weight-bearing pain with subchondral BMLs in weight-bearing compartments of the knee indicate that BMLs in subchondral bone contribute to biomechanically induced OA pain

Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain

Objective: Chronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH–driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. Methods: Potential associations of chronic knee pain with single-nucleotide polymorphisms (SNPs) in the gene-encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N-[1-(1-oxopropy)-4-piperidinyl]-N′-(trifluoromethoxy)phenyl]-urea (TPPU) on weight-bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs. Results: In human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9-DHET and 14,15-DHET. EET levels were unchanged by TPPU administration. Conclusion: Our novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain

Refining surgical models of osteoarthritis in mice and rats alters pain phenotype but not joint pathology.

The relationship between osteoarthritis (OA) structural change and pain is complex. Surgical models of OA in rodents are often rapid in onset, limiting mechanistic utility and translational validity. We aimed to investigate the effect of refining surgical small rodent models of OA on both joint pathology and pain behaviour. Adult male C57BL/6 mice (n = 76, 10-11 weeks of age at time of surgery) underwent either traditional (transection of the medial meniscotibial ligament [MMTL]) or modified (MMTL left intact, transection of the coronary ligaments) DMM surgery, or sham surgery. Adult male Sprague Dawley rats (n = 76, weight 175-199g) underwent either modified meniscal transection (MMNX) surgery (transection of the medial meniscus whilst the medial collateral ligament is left intact) or sham surgery. Pain behaviours (weight bearing asymmetry [in mice and rats] and paw withdrawal thresholds [in rats]) were measured pre-surgery and weekly up to 16 weeks post-surgery. Post-mortem knee joints were scored for cartilage damage, synovitis, and osteophyte size. There was a significant increase in weight bearing asymmetry from 13 weeks following traditional, but not modified, DMM surgery when compared to sham operated mice. Both traditional and modified DMM surgery led to similar joint pathology. There was significant pain behaviour from 6 weeks following MMNX model compared to sham operated control rats. Synovitis was significant 4 weeks after MMNX surgery, whereas significant chondropathy was first evident 8 weeks post-surgery, compared to sham controls. Pain behaviour is not always present despite significant changes in medial tibial plateau cartilage damage and synovitis, reflecting the heterogeneity seen in human OA. The development of a slowly progressing surgical model of OA pain in the rat suggests that synovitis precedes pain behaviour and that chondropathy is evident later, providing the foundations for future mechanistic studies into the disease

620 - The rat Osteoarthritis Bone Score: a new histological system for scoring subchondral pathology in rat knees analogous to histological correlates of human OA bone marrow lesions

Purpose (the aim of the study): Bone marrow lesions (BMLs) are detected by MRI in the in human osteoarthritis (OA) subchondral bone and associated with pain. We previously described 7 histological features associated with BMLs from which we developed the Osteoarthritis Bone Score (OABS) for human subchondral bone. We now describe parallel histopathological features in rat OA, and validate a rat version of the OABS (rOABS).Methods: Histological features contributing to the human OABS system were identified knees from rats with OA induced by intra-articular injection with sodium monoiodoacetate (MIA, n=10), or by meniscal transection (MNX, n=10). Controls were vehicle injected (n=10) injected, or sham-operated (n=8). Pain behaviour (weightbearing asymmetry and paw withdrawal threshold) were analysed from during the final 7 days of each model before sample collection (MIA: 28 days, MNX 42 days after model induction). Coronal knee sections were stained using haemotoxylin and eosin, or safranin-O, fast green and haemotoxylin. Scoring criteria from human OABS were adapted for rat knees. Optimal numbers of sections were determined by comparing the variances of averages from 1, 2 or 3 sections. Reliability of rOABS was assessed between observers using intraclass correlation coefficients. rOABS was compared between OA models and their respective controls (MIA vs vehicle; MNX vs sham operation) using Mann-Whitney U-tests. Associations of rOABS with pain behaviour, and with histological scores for cartilage involvement, synovitis or osteophytes, were evaluated using Spearman’s rho.Results: Features of human OABS were found in rat models of OA. The MNX and MIA models displayed similar rOABS features. One section per knee permitted reliable assessment of rOABS. The rOABS scores were higher in each model than their controls; MIA vs vehicle 4 (2 to 4) vs 0 (0 to 0) respectively, and MNX vs sham 4 (2 to 5) vs 0 (0 to 0) respectively. Reliability from 2 raters for rOABS was good with intra-class correlation coefficient = 0.79 (0.63 to 0.88), p<0.001. The rOABS was positively associated with OA scores for cartilage involvement (rho = 0.77, p <0.001), synovial inflammation (rho = 0.80, p<0.001) and osteophyte (rho = 0.60, p <0.001). Moderate associations were detected between rOABS and pain behaviour (weight-bearing asymmetry: rho = 0.32, p=0.05, paw withdraw threshold: rho = -0.30, p=0.07).Conclusions: The rOABS is a reliable measure of subchondral pathology in two rat models of knee which reflects changes associated with bone marrow lesions in humans. Significant associations with cartilage involvement, synovitis and osteophytes underline the nature of OA as a `whole joint’ disease. Although subchondral pathology may contribute to OA pain, other factors likely also contribute to pain behaviour in rat OA models. Scoring of subchondral pathology by rOABS opens the door to preclinical testing of interventions aiming to reduce pain or joint damage by targeting bone marrow lesions

Synthesis of Molecularly Imprinted Polymer as a Solid Phase Sorbent for Pesticide Dursban

This study describes the synthesis of molecularly imprinted polymers (MIPs) by using an Anti-ChE OPs, namely dursban, as a template. Non-covalent bulk polymerization was successfully applied to synthesis different imprinted and non-imprinted polymers with MAA, MMA, AA, and 4-vpy as monomer in selected porogens (chloroform, toluene, and acetonitrile). In order to evaluate the template binding of the polymers, equilibrium binding experiments was carried out. High binding amount of imprinted polymers compared to non-imprinted polymer was due to effective imprinting or encoding of dursban template shape in the polymer matrixes. From this study, the dursban imprinted polymers prepared using acidic MAA as a functional monomer showed excellent molecular binding ability for dursban. This is because the hydrogen binding interaction between dursban and MAA may be formed between sulfur, oxygen, chlorine, and nitrogen groups of dursban and carboxyl group of MAA. The results shows the use of chloroform as porogen, with a poor hydrogen binding power, significantly affects the binding extend of the MIPs. MAA and chloroform were found to be the most suitable monomer and porogen for the preparation of appropriate dursban molecularly imprinted polymers. This study has shown the possibility of synthesizing and using molecularly imprinted polymers as sorbent for an Anti-ChE OPs

Tehran environmental and neurodevelopmental disorders (TEND) cohort study : Phase I, feasibility assessment

Purpose: To advance knowledge about childhood neurodevelopmental disorders and study their environmental determinants, we conducted a study in Tehran, Iran to assess the feasibility of prospective birth cohort study. Methods: We evaluated participation of pregnant women, feasibility of sampling biological material, and health care services availability in Tehran in four steps: (1) first trimester of pregnancy; (2) third trimester of pregnancy; (3) at delivery; and (4) two to three months after delivery. We collected related data through questionnaires, also various biological samples were obtained from mothers (blood, urine, milk and nails—hands and feet) and newborns (umbilical cord blood, meconium, and urine samples) from February 2016 to October 2017. Results: overall 838 eligible pregnant women were approached. The participation rate was 206(25%) in our study and about 185(90%) of subjects were recruited in hospitals. Out of 206 participants in the first trimester, blood, urine, hand nail, and foot nail samples were collected from 206(100%),193(93%), 205(99%), and 205(99%), respectively. These values dropped to 65(54%), 83(69%), 84(70%), and 84(70%) for the remaining participants 120(58%) in the third trimester, respectively. Also, we gathered milk samples from 125(60%) of mothers at two to three months after delivery. Conclusion: Our findings suggest that hospitals were better places for recruitment of subjects in a birth cohort in Tehran. We further concluded that birth cohort study recruitment can be improved by choosing appropriate gestational ages. Obtaining the newborn’s urine, meconium, and umbilical cord blood were challenging procedures and require good collaboration between hospital staff and researchers.</p

Tehran environmental and neurodevelopmental disorders (TEND) cohort study: Phase I, feasibility assessment

Purpose: To advance knowledge about childhood neurodevelopmental disorders and study their environmental determinants, we conducted a study in Tehran, Iran to assess the feasibility of prospective birth cohort study. Methods: We evaluated participation of pregnant women, feasibility of sampling biological material, and health care services availability in Tehran in four steps: (1) first trimester of pregnancy; (2) third trimester of pregnancy; (3) at delivery; and (4) two to three months after delivery. We collected related data through questionnaires, also various biological samples were obtained from mothers (blood, urine, milk and nails�hands and feet) and newborns (umbilical cord blood, meconium, and urine samples) from February 2016 to October 2017. Results: overall 838 eligible pregnant women were approached. The participation rate was 206(25) in our study and about 185(90) of subjects were recruited in hospitals. Out of 206 participants in the first trimester, blood, urine, hand nail, and foot nail samples were collected from 206(100),193(93), 205(99), and 205(99), respectively. These values dropped to 65(54), 83(69), 84(70), and 84(70) for the remaining participants 120(58) in the third trimester, respectively. Also, we gathered milk samples from 125(60) of mothers at two to three months after delivery. Conclusion: Our findings suggest that hospitals were better places for recruitment of subjects in a birth cohort in Tehran. We further concluded that birth cohort study recruitment can be improved by choosing appropriate gestational ages. Obtaining the newborn�s urine, meconium, and umbilical cord blood were challenging procedures and require good collaboration between hospital staff and researchers. © 2020, Springer Nature Switzerland AG