Effects of Etanercept on Experimental Osteoarthritis in Rats: Role of Histone Deacetylases.

OBJECTIVE: Mounting evidence suggests that histone deacetylases (HDAC) inhibitors reduce cartilage destruction in animal models of osteoarthritis (OA). Tumor necrosis factor (TNF)-α-blocking treatment for OA may provide effective joint protection by slowing joint damage. To investigate the effects of intraperitoneal administration of etanercept (a TNF-α inhibitor) on OA development in rats and changes in the nociceptive behavior of rats and expression of HDACs, RUNX2, and MMP13 in cartilage. METHODS: Induction of OA in Wistar rats was accomplished through anterior cruciate ligament transection (ACLT). One or five milligrams (mg) of etanercept was administered intraperitoneally for 5 consecutive weeks after ACLT to the ACLT + etanercept (1 and 5 mg/kg) groups. Nociceptive behavior and changes in knee joint width were analyzed. Cartilage was evaluated histologically and immunohistochemically. RESULTS: ACLT + etanercept significantly improved mechanical allodynia and weight-bearing distribution compared to ACLT alone. In OA rats treated with etanercept, cartilage degeneration and synovitis were significantly less pronounced than those in ACLT rats. OA-affected cartilage also showed reduced expression of HDAC 6, 7, RUNX-2, and MMP-13 in response to etanercept but increased expression of HDAC4. CONCLUSION: Our study demonstrated that etanercept therapy (1) attenuated the development of OA and synovitis in rats, (2) reduced nociception, and (3) regulated chondrocyte metabolism, possibly by inhibiting cell HDAC6 and HDAC7, RUNX2, and MMP13 and increasing HDAC4 expression. Based on new evidence, etanercept may have therapeutic potential in OA.

The COX-2 inhibitor etoricoxib reduces experimental osteoarthritis and nociception in rats: The roles of TGF-ß1 and NGF expressions in chondrocytes.

BACKGROUND: Osteoarthritis (OA) is the most common joint disease, especially affecting the knee joint. Etoricoxib, a highly selective cyclooxygenase (COX)-2 inhibitor which can reduce postoperative pain after orthopaedic surgery. The aim of this study was to investigate the effects of oral etoricoxib on the development of OA and to examine concomitant changes in the nociceptive behaviour of rats. METHOD: OA was induced in wistar rats by anterior cruciate ligament transection (ACLT) of the right knee. The ACLT + etoricoxib groups received 6.7 or 33.3 mg/kg of oral etoricoxib three times a week for 12 consecutive weeks, starting at week 8 after ACLT. Nociceptive behaviours and changes in knee joint width during OA development were analyzed. Histopathological studies were then performed on the cartilage. Immunohistochemical analysis was performed to examine the effect of etoricoxib on the expression of transforming growth factor-beta (TGF-ß) and nerve growth factor (NGF) in articular cartilage chondrocytes. RESULTS: OA rats receiving etoricoxib showed a significantly lower degree of cartilage degeneration than the rats receiving placebo. Nociceptive behaviour studies showed significant improvement in the ACLT + etoricoxib groups compared to that in the ACLT group. Moreover, etoricoxib attenuated NGF expression, but increased TGF-ß expression, in OA-affected cartilage. CONCLUSIONS: Oral etoricoxib in a rat OA model (a) attenuates the development of OA, (b) concomitantly reduces nociception, and (c) modulates chondrocyte metabolism, possibly by inhibiting NGF expression and increasing TGF-ß expression. SIGNIFICANCE: Oral administration of etoricoxib can attenuate the development of OA, with an associated attenuation of nociceptive behaviour in an experimental rat OA model. Moreover, etoricoxib attenuated NGF expression, but enhanced TGF-ß expression in OA-affected chondrocytes. These findings may pave the way for further investigations of etoricoxib as a potential therapeutic target for the treatment of the inflammatory component in OA.

Calcitonin attenuates cartilage degeneration and nociception in an experimental rat model of osteoarthritis: role of TGF-ß in chondrocytes.

We investigated the role of the calcitonin (Miacalcin) in the progression of osteoarthritis (OA) and in nociceptive behavior in an experimental rat model of OA and osteoporosis. OA was induced by anterior cruciate ligament transection (ACLT) of the right knee and by bilateral ovariectomy (OVX) in Wistar rats. Nociceptive behaviors (secondary mechanical allodynia and weight-bearing distribution of the hind paws) were analyzed prior to surgery and every week, beginning at 12 weeks after surgery, up to 20 weeks. At 20 weeks, histopathological studies were performed on the cartilage of the knee joints. Immunohistochemical analysis was performed to examine the effect of calcitonin on transforming growth factor (TGF)-ß1 expression in articular cartilage chondrocytes. Rats subjected to ACLT + OVX surgery showed obvious OA changes in the joints. Animals subjected to ACLT + OVX and treated with calcitonin showed significantly less cartilage degeneration and improved nociceptive tests compared with animals subjected to ACLT + OVX surgeries alone. Moreover, calcitonin increased TGF-ß1 expression in chondrocytes in ACLT + OVX-affected cartilage. Subcutaneous injection of calcitonin (1) attenuated the development of OA, (2) concomitantly reduced nociception, and (3) modulated chondrocyte metabolism, possibly by increasing cellular TGF-ß1 expression.

High-resolution CT for identify patients with smear-positive, active pulmonary tuberculosis.

PURPOSE: This study evaluates the use of high-resolution computed tomography (HRCT) to differentiate smear-positive, active pulmonary tuberculosis (PTB) from other pulmonary infections in the emergency room (ER) setting. METHODS: One hundred and eighty-three patients diagnosed with pulmonary infections in an ER were divided into an acid fast bacillus (AFB) smear-positive, active PTB group (G1=84) and a non-AFB smear-positive, pulmonary infection group (G2=99). HRCT images from a 64-Multidetector CT were analyzed, retrospectively, for the morphology, number, and segmental distribution of pulmonary lesions. RESULTS: Utilizing multivariate analysis, five variables were found to be independent risk factors predictive of G1: (1) consolidation involving the apex segment of right upper lobe, posterior segment of the right upper lobe, or apico-posterior segment of the left upper lobe; (2) consolidation involving the superior segment of the right or left lower lobe; (3) presence of a cavitary lesion; (4) presence of clusters of nodules; (5) absence of centrilobular nodules. A G1 prediction score was generated based on these 5 criteria to help differentiate G1 from G2. The area under the receiver operating characteristic (ROC) curve was 0.96 ± 0.012 in our prediction model. With an ideal cut-off point score of 3, the specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) are 90.9%, 96.4%, 90.0% and 96.8%, respectively. CONCLUSION: The use of this AFB smear-positive, active PTB prediction model based on 5 key HRCT findings may help ER physicians determine whether or not isolation is required while awaiting serial sputum smear results in high risk patients.

Identifying the most infectious lesions in pulmonary tuberculosis by high-resolution multi-detector computed tomography.

OBJECTIVE: This study aimed to determine whether characteristics detected by multi-detector computed tomography (MDCT) were predictive of highly infectious, smear-positive, active pulmonary tuberculosis (PTB). METHODS: Among 124 patients with active PTB, 84 had positive (group 1) and 40 had negative (group 2) smear results for acid-fast bacilli. Multiplanar MDCT, axial conventional CT and chest X-ray images were analysed retrospectively for morphology, number, and segmental (lobe) distribution of lesions. RESULTS: By multivariate analysis, consolidation over any segment of the upper, middle, or lingual lobes, cavitations, and clusters of nodules were associated with group 1, while centrilobular nodules were predictive of group 2. Using five independent variables associated with risk in group 1, a prediction model was created to distinguish between group 1 and group 2. ROC curve analysis showed an area under the curve of 0.951 +/- 0.021 for this prediction model. With the ideal cutoff point score of 1, the sensitivity, specificity, and positive predictive values were 84.5%, 97.5%, and 98.0%, respectively. CONCLUSIONS: A model to predict smear-positive active PTB on the basis of findings from MDCT may be a useful tool for clinical decisions about isolating patients pending sputum smear results.

Hyaluronic acid attenuates osteoarthritis development in the anterior cruciate ligament-transected knee: Association with excitatory amino acid release in the joint dialysate.

We previously reported increased release of the excitatory amino acid (EAA) neurotransmitters, glutamate and aspartate, during the early stage of experimental osteoarthritis (OA). Our present objective was to study the effect of intraarticular injection of hyaluronic acid (HA) on OA development, and to analyze concomitant changes in EAA levels in dialysates of anterior cruciate ligament-transected (ACLT) knee joints. OA was induced in Wistar rats by ACLT of one hindlimb; the knee of the other hindlimb was used as the sham-operated control. HA group (n = 12) were injected intraarticularly in the ACLT knee with 1 mg of HA once a week for 5 consecutive weeks, starting at 8 weeks after surgery. Saline group (n = 12) were injected as above with normal saline. The sham-operated group, underwent arthrotomy, but not ACLT, and received no treatment (n = 14). Twenty weeks after surgery, knee joint dialysates were collected by microdialysis and EAA levels assayed by high-performance liquid chromatography, and gross morphological examination and histopathological evaluation were performed on the medial femoral condyles and synovia. Rats receiving intraarticular HA injections showed a significantly lower degree of cartilage degeneration on the medial femoral condyle at both the macroscopic level and on the Mankin grading scale than rats receiving saline injections. Intraarticular HA treatment also suppressed synovitis. Moreover, glutamate and aspartate levels were significantly reduced in the HA group compared to the saline group. Intraarticular injection of HA limits articular cartilage and synovium damage and OA formation, and, in parallel, reduces EAA levels in ACLT joint dialysates. This study suggests that the underlying mechanism of the anti-inflammatory effect of HA is to inhibit glutamate and aspartate release in ACLT knee joints, which attenuates the early development of OA.

Increased concentrations of neuro-excitatory amino acids in rat anterior cruciate ligament-transected knee joint dialysates: a microdialysis study.

Changes in excitatory amino acid (EAA) levels were examined in the knee joint dialysates of rats with early osteoarthritis (OA). Early OA was induced by anterior cruciate ligament (ACL) transection in one knee and the contralateral knee was used as the sham-operated control, the side for ACL transection being assigned randomly. Twenty weeks after operation, knee joint dialysates were collected by microdialysis and assayed for EAAs by high performance liquid chromatography. The rats were then sacrificed for histopathological examination. Hematoxylin/eosin and Safranin-O staining showed cartilage fibrillation, clustering of chondrocytes, and a reduction in matrix proteoglycans at week 20 in the ACL-transected knee, but not in the sham-operated knee. Levels of glutamate and aspartate in dialysates from the ACL-transected knee were significantly increased by 92 +/- 20.3% or 57 +/- 17.5%, respectively, compared to those in the contralateral sham-operated knee. This increase may contribute to the pathogenesis of early OA.