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Cyclooxygenase-2 (COX-2) inhibitors suppress bone repair and bone formation by suppressing angiogenesis as well as potentially interfering with osteoblast and osteoclast functions. In spite of these reports, there is a controversy over the exact effects of COX-2 inhibitors on bone formation processes itself. This work was designed to investigate the effect of COX-2 inhibitor on osteogenesis of human bone marrow-derived mesenchymal stem cells (MSC). MSCs in osteogenesis were treated with COX-2 inhibitor (celecoxib and naproxen) in the absence or presence of interleukin-1β (IL-1β), which was used to induce inflammation. Following differentiation, alkaline phosphatase (ALP) and calcium contents of IL-1β-treated MSC were significantly reduced by high doses of COX-2 inhibitors compared with the low-dose group. However, in non-inflammatory-conditioned MSCs, ALP and calcium contents were not reduced by COX-2 inhibitors. The mRNA expression of Runx2/Cbfα1, Dlx5, and osteocalcinwas also decreased by COX-2 inhibitors in inflammatory-conditioned MSCs and showed a significant decrease for the high dose while they remained constant in the non-inflammatory-conditioned MSCs. These data indicate that the osteogenic potential of MSC is inhibited/delayed by the treatment of high-dose NSAIDs under inflammatory conditions. [ABSTRACT FROM AUTHOR]

Purpose: We report the unusual case of a 63-year-old man with gout and coexisting pseudogout (calcium pyrophosphate dihydrate crystal deposition disease) affecting the same joint. In this report, we describe the clinical features of the patient in addition to the characteristics of the crystals extracted from his affected joint, examined using compensated polarized microscopy. Methods: Synovial fluid and specimens of the lateral meniscus of the patient's knee joint taken during arthroscopy were analyzed using compensated polarized microscopy to evaluate the presence and type of crystals. Results: Compensated polarized microscopy revealed both monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals extracted from the knee joint. Conclusions: Our findings suggest that the coexistence of gout and pseudogout should be considered in the diagnosis of crystal-induced arthritis. Careful crystal evaluation using compensated polarized microscopy may reveal similar cases with MSU and CPPD crystals in the same joint. [ABSTRACT FROM AUTHOR]

ABCA1 is a major regulator of cellular cholesterol efflux and plasma HDL biogenesis. Even though the transcriptional activation of ABCA1 is well established, the posttranscriptional regulation of ABCA1 expression is poorly understood. Here, we investigate the potential contribution of the RNA binding protein (RBP) human antigen R (HuR) on the posttranscriptional regulation of ABCA1 expression. RNA immunoprecipitation assays demonstrate a direct interaction between HuR and ABCA1 mRNA. We found that HuR binds to the 3′ untranslated region of ABCA1 and increases ABCA1 translation, while HuR silencing reduces ABCA1 expression and cholesterol efflux to ApoA1 in human hepatic (Huh-7) and monocytic (THP-1) cells. Interestingly, cellular cholesterol levels regulate the expression, intracellular localization, and interaction between HuR and ABCA1 mRNA. Finally, we found that HuR expression was significantly increased in macrophages from human atherosclerotic plaques, suggesting an important role for this RBP in controlling macrophage cholesterol metabolism in vivo. In summary, we have identified HuR as a novel posttranscriptional regulator of ABCA1 expression and cellular cholesterol homeostasis, thereby opening new avenues for increasing cholesterol efflux from atherosclerotic foam macrophages and raising circulat­ing HDL cholesterol levels.

Fatty acid amide hydrolase (FAAH) is a well-characterized member of the amidase signature (AS) family of serine hydrolases. The membrane-bound FAAH protein is responsible for the catabolism of neuromodulatory fatty acid amides, including anandamide and oleamide, that regulate a wide range of mammalian behaviors, including pain perception, inflammation, sleep, and cognitive/emotional state. To date, limited crystal structures of FAAH and non-mammalian AS family proteins have been determined and used for structure-based inhibitor design. In order to provide broader structural information, the crystal structure of FAAH from the pathogenic fungus Candida albicans was determined at a resolution of 2.2 Å. A structural comparison with a brown rat Rattus norvegicus FAAH as well as with other bacterial AS family members, MAE2 and PAM, showed overall similarities but there were several discriminative regions found: the transmembrane domain and the hydrophobic cap of the brown rat FAAH were completely absent in the fungal FAAH structure. Along with these results, a phylogenetic analysis of 19 species within the AS family showed that fungal FAAHs diverged from a common ancestor before the separation of eukarya and prokarya. Taken together, this study provides insights into developing more potent inhibitors of FAAH as well as expanding our knowledge of the relationships between AS family members.

Abstract This study aimed to evaluate (1) the overall reasons for first revision in CoC THAs; (2) whether the reasons for revision differ between third-generation and fourth-generation CoC THAs; and (3) the specific factors associated with bearing-related problems as the reason for revision. We retrospectively reviewed 2045 patients (2194 hips) who underwent first revision THA between 2004 and 2013, among which 146 hips with CoC bearings underwent revision. There were 92 hips with third-generation ceramic bearings and 54 hips with fourth-generation ceramic bearings. The major reasons for CoC THA revisions were ceramic fracture and loosening of the cup or stem. When ceramic fracture, squeaking, incorrect ceramic insertion, and unexplained pain were defined as directly related or potentially related to ceramic use, 28.8% (42/146) of CoC revisions were associated with bearing-related problems. Among the third-generation ceramic bearings, revision was performed in 41.3% (38/92) of cases owing to bearing-related problems whereas revisions were performed for only 7.4% (4/54) of cases with fourth-generation ceramic bearings owing to bearing-related problems (p