Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE 2 at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage ϩ cytokines ϩ endotoxin. The superinduction of PGE 2 production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE 2 by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE 2 production, and not NO, in OA-affected cartilage. The NO synthase inhibitor H N G -monomethyl-L -arginine monoacetate inhibited OA cartilage NO production by Ͼ 90%, but augmented significantly (twofold) the spontaneous production of PGE 2 in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE 2 production. Cytokine ϩ endotoxin stimulation of OA explants increased PGE 2 production above the spontaneous release. Addition of L -NMMA further augmented cytokine-induced PGE 2 production by at least fourfold. Inhibition of PGE 2 by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE 2 did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows ( a ) superinduction of PGE 2 due to upregulation of COX-2, and ( b ) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE 2 . These studies, together with others, also suggest that PGE 2 may be differentially regulated in normal and OA-affected chondrocytes. ( J. Clin. Invest. 1997. 99:1231-1237.)

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SummaryClassically, osteoarthritis (OA) has been considered a noninflammatory disease . However, the detection of selected inflammatory mediators in osteoarthritic fluid, in the absence of significant inflammatory cell infiltrate, is increasingly appreciated. We sought to identify the inflammatory component in human OA-affected cartilage that may be involved in cartilage damage/destruction . Using Western blot analysis and an antibody to the conserved region ofnitric oxide synthase (NOS), we have observed up-regulation of NOS, one of the "key players" of inflammation, in chondrocytes of OA-affected patients. Remarkably, none of the cartilage samples examined from normal joints demonstrated detectable amounts of this NOS . Western blot analysis using the same ot-NOS antibody indicated that this NOS from OA-affected cartilage (OA-NOS) was larger in size than (and distinct from) transfected human hepatocyte or murine inducible NOS (iNOS) (150 versus 133 kD) and similar in size to neuronal constitutive NOS (ncNOS) . Antibodies specific for iNOS showed binding to murine and human iNOS but not to OA-NOS, endothelial constitutive NOS, or ncNOS . Antibodies specific for ncNOS bound to ncNOS and also to OA-NOS, but not to murine or human iNOS or endothelial constitutive NOS . Incubation of OA cartilage in serum-free medium resulted in spontaneous release, for up to 72 h, of substantial amounts of nitrite (up to^" 80 RM/100 mg wet tissue), which could be inhibited by at least 80% with various inhibitors of iNOS, including inhibitors ofprotein synthesis and transcription factor NF-KB, but which (unlike murine macrophage iNOS) was not sensitive to hydrocortisone or TGF-(3. Exposure of OA-affected cartilage to interleukin 1 R, tumor necrosis factor--(at, and lipopolysaccharide resulted in -20-50% augmentation of nitrite accumulation, which was also sensitive to cycloheximide and pyrrolidine dithiocarbamate. Hence, our data indicate that OA-NOS (based on immunoreactivity and molecular weight) is similar to ncNOS and that it releases nitric oxide, which may contribute to the inflammation and pathogenesis of cartilage destruction in OA.

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Approximately 100,000 total hip reconstructions are done annually in the United States. The nature of the surgical technique in a field close to the iliac and femoral vessels makes the occurrence of vascular injury an occasional but serious complications. We have reviewed retrospectively our experience of five cases of vascular injuries with total hip replacement and an additional 63 cases in the literature to identify those patients at risk and to define the management of these injuries. For the entire group of 68 patients, most injuries were sustained on the left side (66%), and 39% were seen in revisions. Complications were related to cement incorporation of the iliac vessels (44%), aggressive medial retraction (17%), excessive traction on atherosclerotic vessels (10%), and improper technique in preparation of the acetabulum. The most commonly injured vessels were the external iliac artery (36), common femoral artery (17), and external iliac vein (6). Twenty-seven of these injuries required emergent surgery, most for hemorrhage (66%). Injuries consisted of thromboembolic complications leading to distal ischemia (46%), vessel lacerations (26%), pseudoaneurysms (25%), and arteriovenous fistulas (3%). Vascular repair was individualized and included suture repair, thrombectomy and patch angioplasty, embolectomy, and arterial and venous bypass procedures. There was an overall 7% mortality and a 15% incidence of limb loss. Risk factors include (1) revision procedures, (2) left-sided procedures, and (3) intrapelvic migration of the acetabular component of the hip prosthesis. Elective vascular workup and preliminary retroperitoneal exposure of the iliac vessels at time of hip arthroplasty is recommended for patients at risk.

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