Articular damages in multi-generational female offspring due to prenatal caffeine exposure correlates with H3K9 deacetylation of TGFß signaling pathway.

Adverse environment during pregnancy could lead to maternal glucocorticoid overexposure in utero, and then induce the intrauterine growth retardation (IUGR) and the programmed change in cartilage development. The transforming growth factor ß (TGFß) signaling pathway plays a crucial role in the process of chondrogenesis, cartilage growth, development, maturation, and phenotype maintenance. Our previous results had shown that prenatal caffeine exposure (PCE) could result in the damaged articular cartilage in offspring rats. However, whether this change could transmit to multiple generations was still unknown. In this study, pregnant Wistar rats received either saline or caffeine (120 mg/kg, i.g.) once daily from gestational day 9-20 (GD9-20). The female offspring mated with normal male rats to generate the following generations. We obtained the articular cartilages in subsequent F1 to F3 female offspring. The H3K9 acetylation and expression of the TGFß signaling pathway were detected; the content of the cartilage matrix was detected. The results showed that PCE reduced the H3K9 acetylation and the expression of the TGFß signaling pathway, then reduced the extracellular matrix in F1, F2, and F3 generations. in vitro, corticosterone could induce the H3K9 deacetylation of the TGFß signaling pathway, thus inhibiting the expression of the TGFß signaling pathway and extracellular matrix. The overall results revealed that PCE induced a multi-generational damaged articular cartilage in female offspring rats, which was partially related to the maternal high glucocorticoid-induced H3K9 hypoacetylation of TGFß signaling pathway.

Plasma and synovial fluid concentrations and cartilage toxicity of bupivacaine following intra-articular administration of a liposomal formulation to horses.

BACKGROUND: The use of intra-articular (IA) local anaesthetics has proven to be an effective means to treat post-operative pain. The effects of local anaesthetics on equine chondrocytes are mixed with some studies reporting chondrodestruction and others no adverse effects. A liposomal formulation of bupivacaine is used in people and dogs by intra- and peri-articular administration to provide up to 72 h of analgesia. The potential uses, side effects including chondrotoxicity, and likelihood of abuse (long-term analgesic effects) has not been evaluated in horses. OBJECTIVES: Describe bupivacaine concentrations following IA administration and assess biomarkers as indicators of the effects of liposomal bupivacaine on chondrocytes in vivo. STUDY DESIGN: Parallel design. METHODS: Sixteen exercised horses received a single IA administration of 0.12 mg/kg liposomal bupivacaine or 0.9% saline. Blood and urine samples were collected for 96 h post-drug administration. Six horses treated with bupivacaine and those receiving saline, underwent daily arthrocentesis. Six additional bupivacaine treated horses underwent arthrocentesis at 96 h. Drug concentrations were measured using LC-MS/MS and pharmacokinetic analyses performed. Immunoassays were used to measure markers of collagen degradation (C2C, C12C) and cartilage matrix synthesis (CPII, CS846) in synovial fluid. RESULTS: The bupivacaine plasma elimination half-life was 17.8 ± 5.42 and 11.9 ± 5.17 h for horses from which synovial fluid was collected daily and at 96 h respectively. Bupivacaine concentrations in the joint were still detectable at 96 h. Significant increases in C12C and C2C were noted at 96 h in horses undergoing arthrocentesis at 96 h only. CPII was increased at 48 h and CS846 at 24 and 48 h in horses sampled daily. MAIN LIMITATIONS: Limited number of animals and absence of liposome control group. CONCLUSIONS: Sustained concentrations of IA bupivacaine suggest viability of this medication as an intra-articular analgesic. Effects on equine chondrocytes need further study.

Notoginseng Radix and Rehmanniae Radix Preparata Extract Combination (YH23537) Reduces Pain and Cartilage Degeneration in Rats with Monosodium Iodoacetate-Induced Osteoarthritis.

Notoginseng Radix and Rehmanniae Radix Preparata have been widely used traditionally for treating inflammatory diseases. This research studies the therapeutic effects of YH23537, the extracts of Notoginseng Radix and Rehmanniae Radix Preparata, on pain and cartilage degeneration in an experimental osteoarthritis (OA) model. Male Wistar rats were inoculated intra-articularly with 3 mg of monosodium iodoacetate (MIA) in the right intra-articular. Four days later, the animals were administrated orally with YH23537 daily for 24 days. Tactile allodynia and weight bearing were measured. Macroscopic and microscopic observations for articular cartilage were performed at the end of the experiment. Protein expression in the joint was determined by immunohistochemistry. The effects of YH23537 on mRNA levels in chondrocytes stimulated with interleukin (IL)-1ß were analyzed using random polymerase chain reaction. OA induction was confirmed by significant decrease of paw withdrawal latency, paw withdrawal threshold, and weight bearing compared with the normal group at 3 days after MIA injection. The YH23537-treated groups displayed significant increases in pain thresholds and weight bearing throughout the observation period. The damage to articular cartilage was significantly lessened visually and histopathologically by YH23537 treatment. YH23537 suppressed the expression of metalloproteinase-3, nitrotyrosine, IL-1ß and IL-6 increased in OA joints. YH23537 upregulated tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 in IL-1ß-stimulated human OA chondrocytes. The protein levels of the NF-κBp65 and HIF-2α in the joint tissues were reduced by YH23537. YH23537 exerted antinociceptive effects and cartilage protective effects in experimental OA rats by suppressing oxidative injury, inflammatory mediators, and inducing anabolic factors. We suggest that YH23537 may have efficacy for treating OA in humans.

Models of Disease.

Osteochondral (OC) lesions are a major cause of chronic musculoskeletal pain and functional disability, which reduces the quality of life of the patients and entails high costs to the society. Currently, there are no effective treatments, so in vitro and in vivo disease models are critically important to obtain knowledge about the causes and to develop effective treatments for OC injuries. In vitro models are essential to clarify the causes of the disease and the subsequent design of the first barrier to test potential therapeutics. On the other hand, in vivo models are anatomically more similar to humans allowing to reproduce the pattern and progression of the lesion in a controlled scene and offering the opportunity to study the symptoms and responses to new treatments. Moreover, in vivo models are the most suitable preclinical model, being a fundamental and a mandatory step to ensure the successful transfer to clinical trials. Both in vitro and in vitro models have a number of advantages and limitation, and the choice of the most appropriate model for each study depends on many factors, such as the purpose of the study, handling or the ease to obtain, and cost, among others. In this chapter, we present the main in vitro and in vivo OC disease models that have been used over the years in the study of origin, progress, and treatment approaches of OC defects.

Different doses of strontium ranelate and mechanical vibration modulate distinct responses in the articular cartilage of ovariectomized rats.

OBJECTIVE: To investigate the effects of different strontium ranelate (SrR) doses alone or in combination with low-intensity and high-frequency mechanical vibration (MV) on articular cartilage in ovariectomized rats. DESIGN: Fifty 6-month-old female Wistar rats underwent ovariectomy (OVX) and after 3 months were divided into: control group (Control); SrR 300 mg/kg/day (SrR300); SrR 625 mg/kg/day (SrR625); MV; SrR 625 mg/kg/day plus MV (SrR625 + MV). The vehicle and the SrR were administered by gavage 7 days/week and vibration (0.6 g/60 Hz) was performed for 20 min/day, 5 days/week. Bone mineral density (BMD) and body composition were evaluated by densitometry. Changes in cartilage were assessed 90 days after treatment by histomorphometry; immunohistochemistry analysis evaluating cell death (caspase-3), tumor necrosis factor-α (TNF-α), metalloproteinase 9 (MMP-9) and type II collagen; Osteoarthritis Research Society International (OARSI) grading system and glycosaminoglycans (GAGs) analyses. RESULTS: SrR-treated groups exhibited a lower OARSI grade, a smaller number of chondrocyte clusters, increased levels of chondroitin sulfate (CS) and decreased expression of caspase-3. Additionally, compared to all the groups, SrR300 exhibited increased levels of hyaluronic acid (HA). Vibration applied alone or in combination accelerated cartilage degradation, as demonstrated by increased OARSI grade, reduced number of chondrocytes, increased number of clusters, elevated expression of type II collagen and cell death, and was accompanied by decreased amounts of CS and HA; however, MV alone was able to reduce MMP-9. CONCLUSIONS: SrR and vibration modulate distinct responses in cartilage. Combined treatment accelerates degeneration. In contrast, SrR treatment at 300 mg/kg/day attenuates osteoarthritis (OA) progression, improving cartilage matrix quality and preserving cell viability in ovariectomized rats.

Does chondrolysis occur after corticosteroid-analgesic injections? An analysis of patients treated for adhesive capsulitis of the shoulder.

BACKGROUND: Clinical studies using continuous infusions of local anesthetics and basic science studies that model injections of local anesthetics have shown chondrotoxicity. However, clinical studies do not exist that have assessed for the risk of chondrolysis in nonarthritic joints exposed to single or intermittent corticosteroid or analgesic injections. Currently, there are no data available to guide the clinician on the safety of using these injections in clinical practice. MATERIALS AND METHODS: A retrospective review of patients treated for adhesive capsulitis of the shoulder with at least 1 intra-articular injection of a corticosteroid and anesthetic was performed. The inclusion criteria were a diagnosis of adhesive capsulitis and a minimum 2-year follow-up. Prospective follow-up was performed to obtain patient-determined outcome scores, range of motion, and radiographs to determine the presence of chondrolysis. RESULTS: Fifty-six patients with a mean age of 52.5 ± 7.2 years were enrolled at a mean follow-up of 54 months. The mean number of injections performed was 1.5 ± 0.7 (range, 1-4). At final follow-up, the mean Western Ontario Osteoarthritis of the Shoulder score was 91.4% ± 14.2%; Disabilities of the Arm, Shoulder and Hand score, 6.7 ± 9.6; Shoulder Pain and Disability Index score, 7.4 ± 11.4; and Single Assessment Numeric Evaluation score, 92.7% ± 10.1%. The Shoulder Activity Score was 8.3 ± 4.7. Passive and active forward elevation, external rotation, internal rotation, and cross-body adduction showed no significant differences compared with the unaffected contralateral shoulder. There was no radiographic evidence of chondrolysis in any patient. CONCLUSIONS: This study did not show chondrolysis in patients treated with an intra-articular corticosteroid and local anesthetic for adhesive capsulitis. The findings of this study do not support the cessation of using intra-articular analgesic-corticosteroid injections for the treatment of adhesive capsulitis. LEVEL OF EVIDENCE: Level IV; Case Series; Treatment Study.

Surgical Modification of the Murine Calvaria Osteolysis Model.

The murine calvaria model has been adopted for evaluation of osteolysis and inflammation induced by polyethylene (PE) or metal wear debris. However, this model suffers from several complications. The purpose of our study is to introduce a surgical modification with lower complication rates, thus providing more accurate results. Forty C57/BL6 mice were divided into two groups, both receiving polyethylene particles. Surgical modifications were performed in group 1, and group 2 underwent traditional surgeries. The incidence of fluid leakage was recorded on the operative day. Curst formation, wound dehiscence, and bone exposure were recorded on day 7. Histological osteolysis was demonstrated by HE staining of tissue slices. Micro-CT was used for quantifying evaluation of osteolysis in two groups. Intraoperative fluid leakage was significantly reduced in group 1. Postoperative crust formation, wound dehiscence, and bone exposure were also significantly decreased in group 1. HE staining results revealed obvious osteolysis in group 1 and more obvious osteolysis in group 2. Bone volume fraction (BVF) was (0.32 ± 0.03) in group 1 compared to group 2 (0.24 ± 0.05). Bone mineral density (BMD) was (1.11 ± 0.03) in group 1 compared to group 2 (1.01 ± 0.02). Surgical modifications provide a reliable way for establishment of the murine calvaria osteolysis model.

Assessment of musculoskeletal toxicity 5 years after therapy with levofloxacin.

BACKGROUND: Safety concerns for fluoroquinolones exist from animal studies demonstrating cartilage injury in weight-bearing joints, dependent on dose and duration of therapy. For children treated with levofloxacin or comparator in randomized, prospective, comparative studies for acute otitis media and community-acquired pneumonia, this 5-year follow-up safety study was designed to assess the presence/absence of cartilage injury. METHODS: Children enrolled in treatment studies were also enrolled in a 1-year follow-up safety study, which; focused on musculoskeletal adverse events (MSAE). Those with persisting MSAEs, protocol-defined musculoskeletal disorders, or of concern to the Data Safety and Monitoring Committee were requested to enroll in four additional years of follow-up, the subject of this report. RESULTS: Of the 2233 subjects participating in the 12-month follow-up study, 124 of 1340 (9%) of the levofloxacin subjects, and 83 of 893 (9%) of the comparator subjects were continued for 5-year posttreatment assessment. From children identified with an MSAE during years 2 through 5 posttreatment, the number that were "possibly related" to drug therapy was equal for both arms: 1 of 1340 for levofloxacin and 1 of 893 for comparator. Of all cases of MSAE assessed by the Data Safety and Monitoring Committee at 5 years' posttreatment, no case was assessed as "likely related" to study drug. CONCLUSIONS: With no clinically detectable difference between levofloxacin- and comparator-treated children in MSAEs presenting between 1 and 5 years in these safety studies, risks of cartilage injury with levofloxacin appear to be uncommon, are clinically undetectable during 5 years, or are reversible.

Published evidence demonstrating the causation of glenohumeral chondrolysis by postoperative infusion of local anesthetic via a pain pump.

BACKGROUND: Glenohumeral chondrolysis is the irreversible destruction of previously normal articular cartilage, occurring most commonly after shoulder surgery in young individuals. The reported incidence of this complication has risen rapidly since the early 2000s. As chondrolysis cannot be reversed, its occurrence can only be prevented by establishing and avoiding its causes. METHODS: We analyzed all published cases of glenohumeral chondrolysis, including the relevant published laboratory data, to consolidate the available evidence on the causation of this complication by the postoperative intra-articular infusion of local anesthetic via a pain pump. RESULTS: Analysis of the published evidence demonstrated a causal relationship between the infusion of local anesthetic and the development of glenohumeral chondrolysis. The risk of this complication in shoulders receiving intra-articular infusions via a pain pump was significantly greater with higher doses of local anesthetic: twenty of forty-eight shoulders receiving high-flow infusions developed chondrolysis, whereas only two of twenty-five shoulders receiving low-flow infusions developed this complication (p = 0.0029). Eleven of twenty-two shoulders receiving 0.5% bupivacaine developed chondrolysis, whereas none of six shoulders receiving 0.25% bupivacaine developed this complication (p = 0.05). Of twenty-two shoulders infused with 0.5% bupivacaine, the eleven that developed chondrolysis had a mean pain pump delivery volume of 377 mL, whereas the eleven that did not develop chondrolysis had a mean volume of 187 mL (p = 0.003). Among shoulders in which an intra-articular pain pump was used, the risk of chondrolysis was significantly greater when suture anchors were placed in the glenoid for labral repair (p < 0.001). CONCLUSIONS: The published evidence indicates that the preponderance of cases of glenohumeral chondrolysis can be prevented by the avoidance of the intra-articular infusion of local anesthetic via a pain pump.

Histopathology of chondronecrosis development in knee articular cartilage in a rat model of Kashin-Beck disease using T-2 toxin and selenium deficiency conditions.

The objective of this study is to observe pathogenic lesions of joint cartilages in rats fed with T-2 toxin under a selenium deficiency nutrition status in order to determine possible etiological factors causing Kashin-Beck disease (KBD). Sprague-Dawley rats were fed selenium-deficient or control diets for 4 weeks prior to their being exposed to T-2 toxin. Six dietary groups were formed and studied 4 weeks later, i.e., controls, selenium-deficient, low T-2 toxin, high T-2 toxin, selenium-deficient diet plus low T-2 toxin, and selenium-deficient diet plus high T-2 toxin. Selenium deficiencies were confirmed by the determination of glutathione peroxidase activity and selenium levels in serum. The morphology and pathology (chondronecrosis) of knee joint cartilage of experimental rats were observed using light microscopy and the expression of proteoglycans was determined by histochemical staining. Chondronecrosis in deep zone of articular cartilage of knee joints was seen in both the low and high T-2 toxin plus selenium-deficient diet groups, these chondronecrotic lesions being very similar to chondronecrosis observed in human KBD. However, the chondronecrosis observed in the rat epiphyseal growth plates of animals treated with T-2 toxin alone or T-2 toxin plus selenium-deficient diets were not similar to that found in human KBD. Our results indicate that the rat can be used as a suitable animal model for studying etiological factors contributing to the pathogenesis (chondronecrosis) observed in human KBD. However, those changes seen in epiphyseal growth plate differ from those seen in human KBD probably because of the absence of growth plate closure in the rat.

Comparison of joint destruction between standard- and low-dose etanercept in rheumatoid arthritis from the Prevention of Cartilage Destruction by Etanercept (PRECEPT) study.

OBJECTIVE: To evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept (ETN) (25 mg/week) compared with standard-dose ETN (50 mg/week) in RA. METHODS: In this prospective, randomized, open-label study, 70 patients were assigned to receive ETN at either 50 or 25 mg/week for 52 weeks. The primary endpoint was the variation in modified total Sharp score (mTSS), and secondary endpoints were variations in disease activity score in 28 joints (DAS-28), modified HAQ and adverse event rate. Values of mTSS were calculated at baseline and after 52 weeks. Non-progression was estimated as ΔmTSS ≤0.5, and the non-progression rate was compared between groups. RESULTS: Mean values at baseline were as follows: disease duration 9.2 years; DAS-28 5.45; and annual progression of mTSS 26.1. No significant differences in background were seen between groups. At 52 weeks, the non-progression rate was significantly less in the 25 mg/week group (36.7%) than in the 50 mg/week group (67.7%) (P = 0.041). Mean ΔmTSS was higher at 25 mg/week (1.03) than at 50 mg/week (-0.13). DAS-28 was significantly improved at 4 weeks, and the effect of treatment lasted for 52 weeks in both groups. No differences in adverse event rates were seen between groups. CONCLUSION: Low-dose ETN is not inferior to standard-dose ETN in terms of effects on clinical manifestations. However, in terms of the radiographic non-progression rate, the effects of low-dose ETN may be inferior to the effects of standard-dose ETN. TRIAL REGISTRATION: UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/, UMIN000001798.

Thermal stress potentiates bupivacaine chondrotoxicity.

PURPOSE: The primary objective of this study was to determine whether thermal stress potentiates the chondrotoxic effect of bupivacaine, resulting in decreased articular chondrocyte viability compared with exposure to bupivacaine alone. METHODS: Bovine articular cartilage explants and cultured chondrocytes were treated with a range of thermal exposures (10 to 20 minutes at 37°C to 65°C) to create time/temperature viability curves and to determine threshold conditions for cell death. A second set of experiments was performed to determine whether subthreshold thermal stress potentiates bupivacaine toxicity. Explants were exposed to 37°C or 55°C for 10 or 20 minutes, and cultured chondrocytes were exposed to 37°C or 45°C for 10 or 20 minutes. Thirty minutes later, the explants and chondrocytes were treated with either 0.9% normal saline solution or 0.5% bupivacaine for 30 minutes. Chondrocyte viability was quantified 24 hours after treatment. RESULTS: There was a temperature- and time-dependent decrease in chondrocyte viability above the thermo-toxicity threshold in both intact cartilage explants and cultured chondrocytes (55°C and 45°C, respectively; P < .05). Chondrocyte viability in cartilage explants was significantly lower after treatment with thermal stress for 10 or 20 minutes followed by bupivacaine for 30 minutes compared with treatment with bupivacaine at 37°C (bupivacaine and 55°C for 10 minutes, 0.09% ± 0%; bupivacaine and 55°C for 20 minutes, 0.08% ± 0%; bupivacaine and 37°C for 10 minutes, 37.4% ± 1.2% [P < .001]; and bupivacaine and 37°C for 20 minutes, 47.1% ± 0.8% [P < .001]). A similar trend was seen in cultured chondrocytes, although it was not statistically significant (P > .05). CONCLUSIONS: Thermal stress potentiates the chondrotoxic effects of bupivacaine in intact cartilage, leading to decreased chondrocyte viability compared with exposure to bupivacaine alone. CLINICAL RELEVANCE: Intra-articular injection of bupivacaine after arthroscopic procedures during which cartilage is exposed to elevated temperatures, such as with prolonged use of radiofrequency probes, may increase the risk of chondrocyte toxicity.

Progressive osteolysis and surface chondrolysis of the proximal humerus following influenza vaccination.

Influenza vaccination is a common annual event among individuals in the United States. Complications, although infrequent, are usually mild and self-limiting. This article describes the case of a 46-year-old man who experienced progressive osteolysis and surface chondrolysis of the proximal humerus following routine influenza vaccination. The patient presented with shoulder pain and limited range of motion 3 weeks following vaccination in the deltoid area. No skin changes were noted, inflammatory markers were normal, and the patient's pain and disability persisted despite nonsteroidal anti-inflammatory drugs and occupational therapy. Plain radiographs revealed a small lytic area involving the greater tuberosity of the humeral head. Magnetic resonance imaging (MRI) showed abnormal uptake and cystic changes involving the greater tuberosity of the humeral head; repeat MRI at 5 months showed progression in the cystic changes. Diagnostic arthroscopy of the shoulder revealed a hyperemic joint capsule and extensive, full-thickness chondrolysis of the humeral head. Cystic biopsy demonstrated inflammatory cells and granulation tissue, consistent with foreign body response. Cultures were negative. Surgical debridement of the cystic areas and resurfacing of the humeral head yielded a good outcome. To our knowledge, this is the first reported complication of influenza vaccination requiring surgical intervention. Physicians need to be aware of the potential for osteolysis and chondrolysis, which may require aggressive forms of management.

Protocol on induction of TMJ articular disc degeneration in rats by utilization of botulinum toxin.

OBJECTIVE: To develop a model of experimental degeneration in the articular disc of the TMJ of rats through the use of botulinum toxin that can be used in future studies of degenerative diseases on fibrocartilage. METHODS: Aiming at the above-mentioned objective, 12 Lewis male rats were used and divided into two groups: CG, control group and DG, group of animals to which the botulinum toxin was administered (6 units/kg). The morphological analysis was carried out utilizing histological cuts stained with hematoxyline-eosine, toluidine blue and Picrosirius; the biochemical analysis was made by SDS-polyacrylamide gel electrophoresis. RESULTS: The DG showed peculiar characteristics regarding a degeneration joint disk, compatible with those described in literature as: reduction of cells number, general disorganization of cells direction and extracellular matrix, increase in glycosaminoglycans content and degradation of the tissue collagen. CONCLUSIONS: Based on the morphological and biochemical results, it was concluded that the proposed degeneration model showed to be satisfactory for futures studies of injuries and fibrocartilage regeneration processes.

Chondrotoxicity of low pH, epinephrine, and preservatives found in local anesthetics containing epinephrine.

BACKGROUND: Recent clinical and basic science investigations have revealed the chondrotoxicity of local anesthetics, especially those containing epinephrine, administered via an intra-articular pain pump. However, the exact mechanism of toxicity is unknown. This study evaluates the chondrotoxicity of low pH, epinephrine, and preservatives found in commonly used local anesthetics. HYPOTHESIS: The chondrotoxicity of local anesthetics containing epinephrine is due to low pH, epinephrine, or the preservative sodium metabisulfite. STUDY DESIGN: Controlled laboratory study. METHODS: Human chondrocytes were harvested and cultured in a custom bioreactor designed to simulate metabolism of medication. Pain pumps were used to infuse one of the following medications into the culture system: control media; media titrated to pH 4.5, 5.0, 5.5, 6.0, 6.5; media with 1:100000 or 1:200000 epinephrine only; media with 0.5 mg/mL of sodium metabisulfite preservative; media with 0.5 mg/mL of methylparaben preservative, 0.25% bupivacaine, 0.25% bupivacaine with epinephrine, 1% lidocaine, and 1% lidocaine with epinephrine. Cultures were perfused for 24 hours and then were stained with live/dead cell viability assay. The chondrocytes were then examined by fluorescence microscopy and counted, and the percentage of cell death was calculated. RESULTS: Cultures containing media titrated to pH 4.5 and 5.0 and local anesthetics containing epinephrine (pH 4.0-5.5) had high cell death rates compared with controls at all time points (P < .001), while cultures containing 1:100000 and 1:200000 epinephrine alone had no increased death rate. Also, 0.5 mg/mL sodium metabisulfite preservative had a significant effect on cell death (P < .034); however, the preservative methylparaben had no effect (P > .05). The percentage of cell death was not significant for 1% lidocaine (12.5%; P > .943) and 0.25% bupivacaine (16.5%; P > .609). CONCLUSION: The marked chondrotoxicity of local anesthetics containing epinephrine appears to be a combined effect of low pH, as these medications are titrated to pH 4.0 to 5.5 for product stability, and the preservative sodium metabisulfite. Extreme caution should be exercised when using intra-articular pain pumps with local anesthetics containing epinephrine. CLINICAL RELEVANCE: Understanding the causes of chondrotoxicity using local anesthetics containing epinephrine is critical to decrease complications associated with this class of medications.

Effects of moniliformin and selenium on human articular cartilage metabolism and their potential relationships to the pathogenesis of Kashin-Beck disease.

OBJECTIVE: To investigate the effects of mycotoxin moniliformin (MON) on the metabolism of aggrecan and type II collagen in human chondrocytes in vitro and the relationship between MON and Kashin-Beck disease (KBD). METHODS: Human chondrocytes were isolated and cultured on bone matrix gelatin to form an artificial cartilage model in vitro with or without MON toxin. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of aggrecan and type II collagen in the cartilage was determined using immunocytochemical staining. RESULTS: MON toxin inhibited chondrocyte viability in dose-dependent and time-dependent manners. MON reduced aggrecan and type II collagen syntheses in the tissue-engineered cartilage. MON also increased the expression of matrix metalloproteinase-1 (MMP-1), MMP-13, BC4 epitopes, and CD44 in cartilages. However, the expression of 3B3(-) epitopes in cartilages was inhibited by MON. Selenium partially alleviated the damage of aggrecan induced by MON toxin. CONCLUSION: MON toxin promoted the catabolism of aggrecan and type II collagen in human chondrocytes.

Case reports: two cases of glenohumeral chondrolysis after intraarticular pain pumps.

BACKGROUND: Acute idiopathic chondrolysis in young adults is rare. The etiology often is unknown and outcomes can be devastating owing to rapid development of painful secondary osteoarthritis. There have been some recent reports of chondrolysis after arthroscopic shoulder procedures. Animal and laboratory data suggest chondrolysis is related to the use of intraarticular pain pumps, although there is no conclusive evidence that this is causative in patients. CASE DESCRIPTION: We present two cases of young adults with chondrolysis of the humeral head after intraarticular pain pump use with humeral head resurfacing and biologic glenoid resurfacing. LITERATURE REVIEW: Several authors report glenohumeral chondrolysis after shoulder arthroscopy involving the use of bupivacaine pain pumps. In addition, experimental animal studies have confirmed the presence of chondrolysis after bupivacaine infusion. PURPOSES AND CLINICAL RELEVANCE: These cases provide additional evidence of an important association between postarthroscopic chondrolysis of the glenohumeral joint and the use of bupivacaine pain pumps.

Do NSAIDs affect longitudinal changes in knee cartilage volume and knee cartilage defects in older adults?

BACKGROUND: The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on knee osteoarthritis progression are unclear. The aim of this longitudinal study was to determine the associations between use of NSAIDs and changes in knee cartilage volume and knee cartilage defects over 2.9 years in older adults. METHODS: T(1)-weighted fat-suppressed magnetic resonance imaging on the right knee was performed in a total of 395 randomly selected subjects (mean age 62 years, range 51-80 years, and 50% female) to assess knee cartilage volume at tibial sites and knee cartilage defects (0-4 scale) at baseline and 2.9 years later. Medication use in the last month was recorded by questionnaire. RESULTS: Compared with nonusers of NSAIDs (n = 334), users of cyclooxygenase (COX)-2 inhibitors (n = 40) had decreased knee cartilage defect development in the medial tibiofemoral compartment (odds ratio [OR] 0.4, 95% confidence interval [CI], 0.2-0.99), whereas users of conventional NSAIDs (n = 21) had increased knee cartilage defect development in both medial (OR 3.1, 95% CI, 1.0-9.1) and lateral (OR 2.6, 95% CI, 1.0-6.7) tibiofemoral compartments. Comparing users of COX-2 inhibitors with users of conventional NSAIDs, the latter had higher knee cartilage volume loss (-5.3% vs -3.1% at medial tibia and -3.6% vs -1.1% at lateral tibia; all P <.05). All associations were adjusted for potential confounders including knee pain and radiographic osteoarthritis. CONCLUSIONS: This study suggests that nonselective NSAIDs may have deleterious effects, while selective COX-2 inhibitors might have beneficial effects on knee cartilage. Randomized controlled trials examining knee structure to confirm this finding are warranted.

Pain pump use after shoulder arthroscopy as a cause of glenohumeral chondrolysis.

Shoulder arthroscopy has become a routine outpatient surgery. Pain control is a limiting factor for patient discharge after surgery, and several modalities are used to provide continued analgesia postoperatively. Regional anesthetic blocks and shoulder pain pumps are common methods to provide short-term pain control. Shoulder pain pumps can be used either in the subacromial space or within the glenohumeral joint. Several clinical studies suggested--which was confirmed by a bovine and rabbit cartilage study--that there is significant chondrotoxicity from bupivacaine, a local anesthetic commonly used in pain pumps. Postarthroscopic glenohumeral chondrolysis is a noninfectious entity associated with factors including use of radiofrequency thermal instruments and intra-articular pain pumps that administer bupivacaine, but there have been no cases reported with subacromial pain pump placement. Treatment options are difficult in a young patient with postarthroscopic glenohumeral chondrolysis, and understanding the literature with regard to risk factors is paramount to counseling patients and preventing this devastating complication.