Human Osteoarthritic Chondrocytes Express Nineteen Different TRP-Genes-TRPA1 and TRPM8 as Potential Drug Targets.

Transient receptor potential (TRP) ion channels are expressed in neuronal and some non-neuronal cells and are involved particularly in pain and thermosensation. We previously showed that TRPA1 is functionally expressed in human osteoarthritic (OA) chondrocytes and mediates inflammation, cartilage degradation, and pain in monosodium-iodoacetate-induced experimental OA. In the present study, we explored the expression of TRP-channels in primary human OA chondrocytes and investigated whether drugs used in the treatment of OA, ibuprofen and glucocorticoids, have effects on TRP-channel expression. OA cartilage was obtained from knee replacement surgery and chondrocytes were isolated with enzyme digestion. NGS analysis showed the expression of 19 TRP-genes in OA chondrocytes, with TRPM7, TRPV4, TRPC1, and TRPM8 having the highest counts in unstimulated cells. These results were verified with RT-PCR in samples from a different group of patients. Interleukin-1ß (IL-1ß) significantly increased TRPA1 expression, while TRPM8 and TRPC1 expression was decreased, and TRPM7 and TRPV4 expression remained unaffected. Furthermore, dexamethasone attenuated the effect of IL-1ß on TRPA1 and TRPM8 expression. The TRPM8 and TRPA1 agonist menthol increased the expression of the cartilage-degrading enzymes MMP-1, MMP-3, and MMP-13 and the inflammatory factors iNOS and IL-6 in OA chondrocytes. In conclusion, human OA chondrocytes express 19 different TRP-genes, of which the significant TRPM8 expression is a novel finding. Dexamethasone attenuated IL-1ß-induced TRPA1 expression. Interestingly, the TRPM8 and TRPA1 agonist menthol increased MMP expression. These results support the concept of TRPA1 and TRMP8 as potential novel drug targets in arthritis.

Dexamethasone Attenuates the Expression of MMP-13 in Chondrocytes through MKP-1.

Mitogen-activated protein kinase phosphatase-1 (MKP-1) is upregulated in inflammation and reduces the activity of proinflammatory mitogen-activated protein kinases (MAP kinases) by dephosphorylation. MAP kinases are intracellular signaling pathways that mediate the cellular effects of proinflammatory cytokines. In the present study, we investigated the effects of the glucocorticoid dexamethasone on the expression of catabolic enzymes in chondrocytes and tested the hypothesis that these effects are mediated through MKP-1. Dexamethasone was found to significantly attenuate the expression of matrix metalloproteinase (MMP)-13 in human OA chondrocytes as well as in chondrocytes from MKP-1 WT mice, but not in chondrocytes from MKP-1 KO mice. Dexamethasone also increased the expression of MKP-1 in murine and human OA chondrocytes. Furthermore, p38 MAP kinase inhibitors significantly attenuated MMP-13 expression in human OA chondrocytes, while JNK MAP kinase inhibitors had no effect. The results indicate that the effect of dexamethasone on MMP-13 expression in chondrocytes was mediated by an MKP-1 and p38 MAP kinase-dependent manner. These findings, together with previous results, support the concept of MKP-1 as a protective factor in articular chondrocytes in inflammatory conditions and as a potential drug target to treat OA.

Is the Preoperative Use of Antidepressants and Benzodiazepines Associated with Opioid and Other Analgesic Use After Hip and Knee Arthroplasty?

BACKGROUND: Mental health disorders can occur in patients with pain conditions, and there have been reports of an increased risk of persistent pain after THA and TKA among patients who have psychological distress. Persistent pain may result in the prolonged consumption of opioids and other analgesics, which may expose patients to adverse drug events and narcotic habituation or addiction. However, the degree to which preoperative use of antidepressants or benzodiazepines is associated with prolonged analgesic use after surgery is not well quantified. QUESTION/PURPOSES: (1) Is the preoperative use of antidepressants or benzodiazepine medications associated with a greater postoperative use of opioids, NSAIDs, or acetaminophen? (2) Is the proportion of patients still using opioid analgesics 1 year after arthroplasty higher among patients who were taking antidepressants or benzodiazepine medications before surgery, after controlling for relevant confounding variables? (3) Does analgesic drug use decrease after surgery in patients with a history of antidepressant or benzodiazepine use? (4) Does the proportion of patients using antidepressants or benzodiazepines change after joint arthroplasty compared with before? METHODS: Of the 10,138 patients who underwent hip arthroplasty and the 9930 patients who underwent knee arthroplasty at Coxa Hospital for Joint Replacement, Tampere, Finland, between 2002 and 2013, those who had primary joint arthroplasty for primary osteoarthritis (64% [6502 of 10,138] of patients with hip surgery and 82% [8099 of 9930] who had knee surgery) were considered potentially eligible. After exclusion of another 8% (845 of 10,138) and 13% (1308 of 9930) of patients because they had revision or another joint arthroplasty within 2 years of the index surgery, 56% (5657 of 10,138) of patients with hip arthroplasty and 68% (6791 of 9930) of patients with knee arthroplasty were included in this retrospective registry study. Patients who filled prescriptions for antidepressants or benzodiazepines were identified from a nationwide drug prescription register, and information on the filled prescriptions for opioids (mild and strong), NSAIDs, and acetaminophen were extracted from the same database. For the analyses, subgroups were created according to the status of benzodiazepine and antidepressant use during the 6 months before surgery. First, the proportions of patients who used opioids and any analgesics (that is, opioids, NSAIDs, or acetaminophen) were calculated. Then, multivariable logistic regression adjusted with age, gender, joint, Charlson Comorbidity Index, BMI, laterality (unilateral/same-day bilateral), and preoperative analgesic use was performed to calculate odds ratios for any analgesic use and opioid use 1 year postoperatively. Additionally, the proportion of patients who used antidepressants and benzodiazepines was calculated for 2 years before and 2 years after surgery. RESULTS: At 1 year postoperatively, patients with a history of antidepressant or benzodiazepine use were more likely to fill prescriptions for any analgesics than were patients without a history of antidepressant or benzodiazepine use (adjusted odds ratios 1.9 [95% confidence interval 1.6 to 2.2]; p < 0.001 and 1.8 [95% CI 1.6 to 2.0]; p < 0.001, respectively). Similarly, patients with a history of antidepressant or benzodiazepine use were more likely to fill prescriptions for opioids than patients without a history of antidepressant or benzodiazepine use (adjusted ORs 2.1 [95% CI 1.7 to 2.7]; p < 0.001 and 2.0 [95% CI 1.6 to 2.4]; p < 0.001, respectively). Nevertheless, the proportion of patients who filled any analgesic prescription was smaller 1 year after surgery than preoperatively in patients with a history of antidepressant (42% [439 of 1038] versus 55% [568 of 1038]; p < 0.001) and/or benzodiazepine use (40% [801 of 2008] versus 55% [1098 of 2008]; p < 0.001). The proportion of patients who used antidepressants and/or benzodiazepines was essentially stable during the observation period. CONCLUSION: Surgeons should be aware of the increased risk of prolonged opioid and other analgesic use after surgery among patients who were on preoperative antidepressant and/or benzodiazepine therapy, and they should have candid discussions with patients referred for elective joint arthroplasty about this possibility. Further studies are needed to identify the most effective methods to reduce prolonged postoperative opioid use among these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Chondrocytes from Osteoarthritis Patients Adopt Distinct Phenotypes in Response to Central TH1/TH2/TH17 Cytokines.

Chronic low-grade inflammation plays a central role in the pathogenesis of osteoarthritis (OA), and several pro- and anti-inflammatory cytokines have been implicated to mediate and regulate this process. Out of these cytokines, particularly IFNγ, IL-1ß, IL-4 and IL-17 are associated with different phenotypes of T helper (TH) cells and macrophages, both examples of cells known for great phenotypic and functional heterogeneity. Chondrocytes also display various phenotypic changes during the course of arthritis. We set out to study the hypothesis of whether chondrocytes might adopt polarized phenotypes analogous to TH cells and macrophages. We studied the effects of IFNγ, IL-1ß, IL-4 and IL-17 on gene expression in OA chondrocytes with RNA-Seq. Chondrocytes were harvested from the cartilage of OA patients undergoing knee replacement surgery and then cultured with or without the cytokines for 24 h. Total RNA was isolated and sequenced, and GO (Gene Ontology) functional analysis was performed. We also separately investigated genes linked to OA in recent genome wide expression analysis (GWEA) studies. The expression of more than 2800 genes was significantly altered in chondrocytes treated with IL-1ß [in the C(IL-1ß) phenotype] with a fold change (FC) > 2.5 in either direction. These included a large number of genes associated with inflammation, cartilage degradation and attenuation of metabolic signaling. The profile of genes differentially affected by IFNγ (the C(IFNγ) phenotype) was relatively distinct from that of the C(IL-1ß) phenotype and included several genes associated with antigen processing and presentation. The IL-17-induced C(IL-17) phenotype was characterized by the induction of a more limited set of proinflammatory factors compared to C(IL-1ß) cells. The C(IL-4) phenotype induced by IL-4 displayed a differential expression of a rather small set of genes compared with control, primarily those associated with TGFß signaling and the regulation of inflammation. In conclusion, our results show that OA chondrocytes can adopt diverse phenotypes partly analogously to TH cells and macrophages. This phenotypic plasticity may play a role in the pathogenesis of arthritis and open new therapeutic avenues for the development of disease-modifying treatments for (osteo)arthritis.

Novel adipokine associated with OA: retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients.

OBJECTIVE: Retinol binding protein 4 (RBP4) is a member of the lipocalin family and a vitamin A carrier in the blood. More recently, RBP4 has been described as an adipokine that is involved in insulin resistance and metabolic syndrome (MetS). As obesity, MetS and some adipokines contribute to the pathogenesis of osteoarthritis (OA), we investigated RBP4 in patients with OA. MATERIALS AND METHODS: Cartilage, synovial fluid and blood samples were collected from 100 OA patients undergoing total knee replacement surgery. Primary chondrocytes and cartilage tissue were cultured to measure the RBP4 expression. The concentrations of RBP4, other adipokines (adipsin, adiponectin, leptin and resistin) and biomarkers of OA (COMP, MMP-1, MMP-3 and YKL-40) were measured by immunoassay, and gene expression was measured by next-generation RNA sequencing. RESULTS: The OA cartilage samples released RBP4 into the culture medium, and the levels correlated positively with the expression of the adipokines adipsin, adiponectin, leptin and resistin. RBP4 was the most prominently expressed of these adipokines in the OA chondrocytes, and the expression of the RBP4 receptors STRA6 (stimulated by retinoic acid gene homologue 6) and TLR4 (Toll-like receptor 4) was also detected. Within the cartilage culture medium, RBP4 showed a positive correlation with MMP-1, MMP-3 and YKL-40. RBP4 was also present in the synovial fluid from the OA patients and correlated positively with the concentrations of RBP4 found in the plasma and the cartilage culture medium. Plasma RBP4 concentrations also showed a positive correlation with MMP-3 and adipsin. CONCLUSIONS: We show here, for the first time, that RBP4 is produced within OA joints and that it is associated with increased levels of adipokines and MMPs. The results suggest a role for RBP4 in the pathogenesis of OA and as a possible target for the disease-modifying drugs for the treatment of OA.

Transient Receptor Potential Ankyrin 1 (TRPA1) Is Involved in Upregulating Interleukin-6 Expression in Osteoarthritic Chondrocyte Models.

Transient receptor potential ankyrin 1 (TRPA1) is a membrane-bound ion channel found in neurons, where it mediates nociception and neurogenic inflammation. Recently, we have discovered that TRPA1 is also expressed in human osteoarthritic (OA) chondrocytes and downregulated by the anti-inflammatory drugs aurothiomalate and dexamethasone. We have also shown TRPA1 to mediate inflammation, pain, and cartilage degeneration in experimental osteoarthritis. In this study, we investigated the role of TRPA1 in joint inflammation, focusing on the pro-inflammatory cytokine interleukin-6 (IL-6). We utilized cartilage/chondrocytes from wild-type (WT) and TRPA1 knockout (KO) mice, along with primary chondrocytes from OA patients. The results show that TRPA1 regulates the synthesis of the OA-driving inflammatory cytokine IL-6 in chondrocytes. IL-6 was highly expressed in WT chondrocytes, and its expression, along with the expression of IL-6 family cytokines leukemia inhibitory factor (LIF) and IL-11, were significantly downregulated by TRPA1 deficiency. Furthermore, treatment with the TRPA1 antagonist significantly downregulated the expression of IL-6 in chondrocytes from WT mice and OA patients. The results suggest that TRPA1 is involved in the upregulation of IL-6 production in chondrocytes. These findings together with previous results on the expression and functions of TRPA1 in cellular and animal models point to the role of TRPA1 as a potential mediator and novel drug target in osteoarthritis.

Use of prescription analgesic drugs before and after hip or knee replacement in patients with osteoarthritis.

BACKGROUND: Analgesic drugs are recommended to treat pain caused by osteoarthritis, and joint replacement should decrease the need for them. We aimed to determine the user rates of analgesic drugs before and after joint replacement. METHODS: All patients who underwent a primary hip or knee replacement for osteoarthritis from 2002 to 2013 in a region of 0.5 million people were identified. Patients with revision or other joint replacements during the study period (operation date +/- two years) were excluded, leaving 6238 hip replacements (5657 patients) and 7501 knee replacements (6791 patients) for analyses. Medication data were collected from a nationwide Drug Prescription Register and the prevalence (with its 95% confidence intervals) of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), mild opioids, strong opioids, and medications used for neuropathic pain was calculated in three-month periods two years before and after surgery. RESULTS: Between two years and three months preoperatively, the proportion of patients who redeemed at least one type of analgesic drug increased from 28% (95% CI, 27-30%) to 48% (47-50%) on hip replacement patients and from 33% (32-34%) to 41% (40-42%) on knee replacement patients. Postoperatively, the proportions decreased to 23% (22-24%) on hip and to 30% (29-31%) on knee patients. Hip replacement patients used more NSAIDs (34% (32-35%) hip vs 26% (25-27%) knee, p < 0.001), acetaminophen (14% (13-15%) vs 12% (11-13%), p < 0.001), and mild opioids (14% (13-15%) vs 9% (8-9%), p < 0.001) than knee patients preoperatively, but postoperatively hip patients used less NSAIDs (12% (11-13%) vs 16% (15-16%), p < 0.001), acetaminophen (9% (8-10%) vs 11% (11-12%), p < 0.001), and mild opioids (5% (5-6%) vs 8% (7-8%), p < 0.001). CONCLUSION: Use of analgesic drugs increases prior to joint replacement, and is reduced following surgery. However, a considerable proportion of patients continue to use analgesics in two-year follow-up.

IL-6 in Osteoarthritis: Effects of Pine Stilbenoids.

Interleukin-6 (IL-6) is involved in the pathogenesis of various inflammatory diseases, like rheumatoid arthritis (RA). In the present study, we investigated the role of IL-6 in osteoarthritis (OA) patients and the effects of the stilbenoids monomethyl pinosylvin and pinosylvin on the expression of the cartilage matrix components aggrecan and collagen II and the inflammatory cytokine IL-6 in human OA chondrocytes. Synovial fluid and plasma samples were obtained from 100 patients with severe OA [BMI 29.7 (8.3) kg/m², age 72 (14) years, median (IQR); 62/38 females/males] undergoing total knee replacement surgery. IL-6 and matrix metalloproteinase (MMP) concentrations in synovial fluid and plasma were measured by immunoassay. The effects of pinosylvin on the expression of IL-6, aggrecan, and collagen II were studied in primary cultures of human OA chondrocytes. IL-6 levels in synovial fluid from OA patients [119.8 (193.5) pg/mL, median (IQR)] were significantly increased as compared to the plasma levels [3.1 (2.7) pg/mL, median (IQR)] and IL-6 levels in synovial fluid were associated with MMPs and radiographic disease severity. Natural stilbenoids monomethyl pinosylvin and pinosylvin increased aggrecan expression and suppressed IL-6 production in OA chondrocytes. The results propose that IL-6 is produced within OA joints and has an important role in the pathogenesis of OA. Stilbenoid compounds monomethyl pinosylvin and pinosylvin appeared to have disease-modifying potential in OA chondrocytes.

Factors Associated With Trunnionosis in the Metal-on-Metal Pinnacle Hip.

BACKGROUND: Trunnionosis of the tapered head-stem junction of total hip arthroplasties, either through corrosion or mechanical wear, has been implicated in early implant failure. Retrieval analysis of large numbers of failed implants can help us better understand the factors that influence damage at this interface. METHODS: In this study, we examined 120 retrieved total hip arthroplasties of one bearing design, the 36-mm diameter metal-on-metal, DePuy Pinnacle, that had been paired with 3 different stems. We measured material loss of the bearing and head-trunnion taper surfaces and collected clinical and component data for each case. We then used multiple linear regression analysis to determine which factors influenced the rate of taper material loss. RESULTS: We found 4 significant variables: (1) longer time to revision (P = .004), (2) the use of a 12/14 taper for the head-trunnion junction (P < .001), (3) decreased bearing surface wear (P = .003), and (4) vertical femoral offset (P = .05). These together explained 29% of the variability in taper material loss. CONCLUSION: Our most important finding is the effect of trunnion design. Of the 3 types studied, we found that S-ROM design was the most successful at minimizing trunnionosis.

Higher Blood Cobalt and Chromium Levels in Patients With Unilateral Metal-on-Metal Total Hip Arthroplasties Compared to Hip Resurfacings.

BACKGROUND: Adverse soft tissue reactions in metal-on-metal (MoM) hip replacements are associated with cobalt (Co) and chromium (Cr) ions in blood. We report the prevalence and risk factors for elevated blood Co and Cr levels in patients with a unilateral MoM hip. METHODS: From a single institution, blood Co and Cr levels were analyzed in 1748 patients (692 hip resurfacings and 1056 total hip arthroplasties [THAs]). Concentrations exceeding 7 ppb were considered elevated, and the risk factors for elevated levels were calculated with binary logistic regression. RESULTS: Elevated blood metal ion levels were more common in MoM THA than in resurfacing patients (17.4% vs 5.9%, P < .001), and in 5 of the 7 THA brands, more than 20% of patients had elevated metal ion concentrations, whereas the proportion was less than 10% in all hip resurfacings. In resurfacings, small femoral head (odds ratio [OR] 1.30 per millimeter decrease [CI, 1.12-1.49]), high acetabular inclination (OR 1.15 per degree increase [CI 1.09-1.22]), and young age (OR 1.05 per year decrease [1.02-1.10]) were independent risk factors for elevated ions. In the THA group, female gender (OR 2.04 [CI 1.35-3.06]), longer time between surgery and ion measurement (OR 1.19 per year increase [CI 1.05-1.34]), and large headsize (OR 1.07 per millimeter increase [CI 1.01-1.13]) were risk factors for elevated ions. CONCLUSION: Given the high percentage of elevated levels, the systematic surveillance of especially large diameter MoM THAs seems justified.

Functional gain following knee replacement in patients aged 75 and older: a prospective follow-up study.

BACKGROUND AND AIMS: The aim of this prospective follow-up study was to analyze which patient characteristics predict better functional ability, as well as improvement in the ability, following knee replacement in the aged. The focus was on the impact of specific comorbidities and radiologic data. METHODS: Knee osteoarthritis patients aged ≥75 years (n = 167) scheduled for knee replacement answered to a questionnaire asking about performance in the activities of daily living (ADL) before the operation, and 1 year afterwards. Radiologic data were evaluated from the latest radiographs, and comorbidity data from patient records. The primary outcome was a sum score indicating how many ADLs (out of 10) the patient was able to perform without difficulty. The factors associated with ADL performance were analyzed with adjustment for age, gender, Charlson's comorbidity index and Kellgren-Lawrence score. RESULTS: Knee replacement resulted in improved performance in almost all the analyzed ADL activities. Except for cardiac diseases, the effect of the analyzed comorbidities on ADL performance was not significant. Older patients and women attained lower final functional ability than younger patients and men, but improved similarly. In more progressed osteoarthritis, the final ability was lower, but the improvement gained was greater. CONCLUSIONS: Comorbidity, age, or more progressed osteoarthritis should not be considered an impediment to knee replacement. Even though the final functional ability may be lower in some, the improvement gained by surgery is similar regardless of comorbidity, and was more pronounced in more progressed disease.

Diabetes is associated with persistent pain after hip and knee replacement.

BACKGROUND AND PURPOSE: In some patients, for unknown reasons pain persists after joint replacement, especially in the knee. We determined the prevalence of persistent pain following primary hip or knee replacement and its association with disorders of glucose metabolism, metabolic syndrome (MetS), and obesity. PATIENTS AND METHODS: The incidence of pain in the operated joint was surveyed 1-2 years after primary hip replacement (74 patients (4 bilateral)) or primary knee replacement (119 patients (19 bilateral)) in 193 osteoarthritis patients who had participated in a prospective study on perioperative hyperglycemia. Of the 155 patients who completed the survey, 21 had undergone further joint replacement surgery during the follow-up and were excluded, leaving 134 patients for analysis. Persistent pain was defined as daily pain in the operated joint that had lasted over 3 months. Factors associated with persistent pain were evaluated using binary logistic regression with adjustment for age, sex, and operated joint. RESULTS: 49 of the 134 patients (37%) had a painful joint and 18 of them (14%) had persistent pain. A greater proportion of knee patients than hip patients had a painful joint (46% vs. 24%; p = 0.01) and persistent pain (20% vs. 4%; p = 0.007). Previously diagnosed diabetes was strongly associated with persistent pain (5/19 vs. 13/115 in those without; adjusted OR = 8, 95% CI: 2-38) whereas MetS and obesity were not. However, severely obese patients (BMI ≥ 35) had a painful joint (but not persistent pain) more often than patients with BMI < 30 (14/21 vs. 18/71; adjusted OR = 5, 95% CI: 2-15). INTERPRETATION: Previously diagnosed diabetes is a risk factor for persistent pain in the operated joint 1-2 years after primary hip or knee replacement.

Risk factors for perioperative hyperglycemia in primary hip and knee replacements.

BACKGROUND AND PURPOSE: Perioperative hyperglycemia has been associated with adverse outcomes in several fields of surgery. In this observational study, we identified factors associated with an increased risk of hyperglycemia following hip and knee replacement. PATIENTS AND METHODS: We prospectively monitored changes in glucose following primary hip and knee replacements in 191 patients with osteoarthritis. Possible associations of patient characteristics and operation-related factors with hyperglycemia (defined as glucose > 7.8 mmol/L in 2 consecutive measurements) and severe hyperglycemia (glucose > 10 mmol/L) were analyzed using binary logistic regression with adjustment for age, sex, operated joint, and anesthesiological risk score. RESULTS: 76 patients (40%) developed hyperglycemia, and 48 of them (25% of the whole cohort) had severe hyperglycemia. Glycemic responses were similar following hip replacement and knee replacement. Previously diagnosed diabetes was associated with an increased risk of hyperglycemia and severe hyperglycemia, compared to patients with normal glucose metabolism, whereas newly diagnosed diabetes and milder glucose metabolism disorders had no effect. In patients without previously diagnosed diabetes, increased values of preoperative glycosylated hemoglobin (HbA1c) and fasting glucose on the day of operation were associated with hyperglycemia. Higher anesthesiological risk score-but none of the operation-related factors analyzed-was associated with an increased risk of hyperglycemia. INTERPRETATION: Perioperative hyperglycemia is common in primary hip and knee replacements. Previously diagnosed diabetes is the strongest risk factor for hyperglycemia. In patients with no history of diabetes, preoperative HbA1c and fasting glucose on the day of operation can be used to stratify the risk of hyperglycemia.

YKL-40 as a novel factor associated with inflammation and catabolic mechanisms in osteoarthritic joints.

YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients (r = 0.37, P = 0.010), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 (r = 0.36, P = 0.014), MMP-3 (r = 0.46, P = 0.001), IL-6 (r = 0.57, P < 0.001), and IL-17 (r = 0.52, P = 0.010) levels. Moreover, IL-6 and IL-17 enhanced YKL-40 production in human primary chondrocyte cultures. The present study introduces YKL-40 as a cartilage-derived factor associated with mediators of inflammation and cartilage destruction involved in the pathogenesis of OA.

Repeated metal ion measurements in patients with high risk metal-on-metal hip replacement.

PURPOSE: Conventional follow-up methods are not sufficient to identify adverse soft tissue reactions in patients with metal-on-metal hip replacements. The national guidelines regarding metal ion measurements are debatable. The aims of our study were to investigate (1) if there is a clinically significant change in whole blood (WB) cobalt (Co) or chrome (Cr) levels in repeated WB assessment in patients operated on with ASR hip replacements, and (2) what proportion of patients has WB Co or Cr level below the previously established safe upper limits (SUL) in the repeated WB metal ion assessment. METHODS: We identified all patients (n = 254) with unilateral ASR implants who had second blood sample taken eight to 16 months after the first. RESULTS: WB Co and Cr levels remained below SUL and within their initial values during a mean one-year measurement interval in the majority of patients with a high risk HR device. In contrast to this, 50 % of patients with THRs had metal ion levels exceeding the SUL in the first measurement. WB Co values significantly increased over the measurement interval in the THR group. CONCLUSION: In patients with a high risk HR, repeated metal ion measurement did not provide useful information for clinical decision-making. In patients with a LD MoM THR repeated measurements revealed a large number of patients with metal ion levels exceeding SUL and might thus be clinically beneficial.

Single periarticular local infiltration analgesia reduces opiate consumption until 48 hours after total knee arthroplasty. A randomized placebo-controlled trial involving 56 patients.

BACKGROUND: Randomized trials evaluating efficacy of local infiltration analgesia (LIA) have been published but many of these lack standardized analgesics. There is a paucity of reports on the effects of LIA on functional capability and quality of life. METHODS: 56 patients undergoing unilateral total knee arthroplasty (TKA) were randomized into 2 groups in this placebo-controlled study with 12-month follow-up. In the LIA group, a mixture of levobupivacaine (150 mg), ketorolac (30 mg), and adrenaline (0.5 mg) was infiltrated periarticularly. In the placebo group, infiltration contained saline. 4 different patient-reported outcome measures (PROMs) were used for evaluation of functional outcome and quality of life. RESULTS: During the first 48 hours postoperatively, patients in the LIA group used less oxycodone than patients in the placebo group in both cumulative and time-interval follow-up. The effect was most significant during the first 6 postoperative hours. The PROMs were similar between the groups during the 1-year follow-up. INTERPRETATION: Single periarticular infiltration reduced the amount of oxycodone used and enabled adequate pain management in conjunction with standardized peroral medication without adverse effects. No clinically marked effects on the functional outcome after TKA were detected.

Childhood serum fatty acid quality is associated with adult carotid artery intima media thickness in women but not in men.

Childhood nutrition may play a role in the development of cardiovascular disease risk in adulthood. We examined the links between childhood dietary fatty acid quality and adult subclinical atherosclerosis in a cohort of 374 males and 449 females, aged 3-18 y at baseline in 1980, followed for 27 y. Serum cholesterol ester fatty acid (CEFA) percentages were analyzed as markers of dietary fatty acid intake. Adulthood carotid artery intima media thickness (cIMT, µm), adjusted for childhood and adulthood lipid and nonlipid risk markers, was used as the outcome. In women, after adjustment for age and childhood nonlipid risk markers, the childhood saturated CEFA (B = 11.3; P = 0.011), monounsaturated CEFA (B = 2.5; P = 0.025), and n3 (ω3) polyunsaturated CEFA (B = 16.2; P = 0.035) percentages were directly associated with adult cIMT. In contrast, the n6 (ω6) polyunsaturated CEFA percentage was negatively associated with cIMT (B = -2.3; P = 0.008). Similar relationships were observed between childhood dietary intake data and adult cIMT. In men, these associations were generally weak and nonsignificant (P > 0.05) after controlling for confounders. These longitudinal data suggest that fat quality as reflected in the serum cholesterol ester fraction in childhood is associated with adult cIMT in women.

Increasing operating room productivity by duration categories and a newsvendor model.

PURPOSE: Previous studies approach surgery scheduling mainly from the mathematical modeling perspective which is often hard to apply in a practical environment. The aim of this study is to develop a practical scheduling system that considers the advantages of both surgery categorization and newsvendor model to surgery scheduling. DESIGN/METHODOLOGY/APPROACH: The research was carried out in a Finnish orthopaedic specialist centre that performs only joint replacement surgery. Four surgery categorization scenarios were defined and their productivity analyzed by simulation and newsvendor model. FINDINGS: Detailed analyses of surgery durations and the use of more accurate case categories and their combinations in scheduling improved OR productivity 11.3 percent when compared to the base case. Planning to have one OR team to work longer led to remarkable decrease in scheduling inefficiency. PRACTICAL IMPLICATIONS: In surgical services, productivity and cost-efficiency can be improved by utilizing historical data in case scheduling and by increasing flexibility in personnel management. ORIGINALITY/VALUE: The study increases the understanding of practical scheduling methods used to improve efficiency in surgical services.

Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients.

OBJECTIVES: In the present study, we investigated the role of adipocytokine leptin in the pathogenesis of osteoarthritis (OA) by measuring its effects on matrix metalloproteinase (MMP) production in human OA cartilage. In addition, the correlations between leptin and MMP concentrations in synovial fluid from OA patients were studied. METHODS: Cartilage tissue obtained from leftover pieces of total knee replacement surgery from patients with OA was used in the experiments. Production of collagenases MMP-1, MMP-8 and MMP-13, and stromelysin-1 (MMP-3) in the cartilage was measured by immunoassay and the signalling pathways were explored by pharmacological means. In addition, synovial fluid samples were collected from 84 OA patients undergoing knee replacement surgery. The concentrations of leptin and MMPs in synovial fluid were measured by immunoassay. RESULTS: Leptin alone and in combination with IL-1ß enhanced production of MMP-1, MMP-3, and MMP-13 in human OA cartilage, while MMP-8 concentrations remained undetectable. The effects of leptin on MMP-1, MMP-3 and MMP-13 production were mediated through transcription factor NF-κß, and through protein kinase C and MAP kinase pathways. Interestingly, leptin concentrations in synovial fluid from OA patients correlated positively with MMP-3 (r=0.51, p<0.001) and MMP-1 (r=0.41, p<0.001) levels. CONCLUSIONS: To our knowledge, this is the first study to show that leptin up-regulates MMP-1 and MMP-3 production in human OA cartilage and correlates positively to MMP-1 and MMP-3 in synovial fluid from OA patients. The findings suggest that leptin has catabolic effects in OA joints by increasing MMP production in cartilage.

Aurothiomalate inhibits cyclooxygenase 2, matrix metalloproteinase 3, and interleukin-6 expression in chondrocytes by increasing MAPK phosphatase 1 expression and decreasing p38 phosphorylation: MAPK phosphatase 1 as a novel target for antirheumatic drugs.

OBJECTIVE: Aurothiomalate is a disease-modifying antirheumatic drug that suppresses inflammation and retards cartilage degradation and bone erosion in arthritis. The molecular mechanisms of action of aurothiomalate are not known in detail. MAPK pathways are major signaling pathways in inflammation that regulate the production of many inflammatory and destructive factors in arthritis. The purpose of the present study was to investigate the effects of aurothiomalate on the activity of p38 MAPK and on the expression of MAPK phosphatase 1 (MKP-1), cyclooxygenase 2 (COX-2), matrix metalloproteinase 3 (MMP-3), and interleukin-6 (IL-6) in immortalized murine H4 chondrocytes and in intact human and murine cartilage. METHODS: Protein expression was examined by Western blotting or by enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was examined by real-time reverse transcription-polymerase chain reaction analysis. The mediator role of MKP-1 was investigated by using small interfering RNA (siRNA) methods to down-regulated MKP-1 expression in chondrocytes in culture and by comparing the responses in intact cartilage from MKP-1-deficient and wild-type mice. The effects of aurothiomalate were also confirmed in human rheumatoid cartilage by using tissue samples obtained at the time of total knee replacement surgery. RESULTS: Aurothiomalate inhibited IL-1beta-induced COX-2 expression and prostaglandin E(2) production by destabilizing COX-2 mRNA, as did the p38 MAPK inhibitor SB203580. Interestingly, aurothiomalate also increased the expression of MKP-1 and reduced the IL-1beta-induced phosphorylation of p38 MAPK. Knockdown of MKP-1 by siRNA significantly impaired the ability of aurothiomalate to inhibit the phosphorylation of p38 MAPK and the expression of COX-2, MMP-3, and IL-6. Likewise, aurothiomalate reduced COX-2, MMP-3, and IL-6 expression in articular cartilage from patients with rheumatoid arthritis, as well as in articular cartilage from wild-type mice but not from MKP-1(-/-) mice. CONCLUSION: Our findings indicate a novel mechanism for the antiinflammatory and antierosive actions of aurothiomalate, through increased expression of MKP-1, which leads to reduced activation of p38 MAPK and suppressed expression of COX-2, MMP-3, and IL-6. The results suggest that manipulation of MKP-1 levels is a promising new mechanism to be directed in the search and development of novel antiinflammatory and antierosive compounds that have the good efficacy of gold compounds but not their toxicity.