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Robert A Terkeltaub

Publications and source records attributed to Robert A Terkeltaub.

12 recordsLinked to original sources
PubMed2006

New developments in clinically relevant mechanisms and treatment of hyperuricemia.

The prevalence of gout has increased markedly in the United States in the past two decades, and new treatments for hyperuricemia are being developed. Recent molecular identification of urate transporter-1 (URAT1) as the central mediator of renal urate reabsorption has provided novel understanding of the pathogenesis of hyperuricemia, and the target site for current and possibly future primary uricosuric agents. Recent studies have also highlighted uricosuric effects of several drugs (losartan, atorvastatin, fenofibrate) that are prescribed for primary indications other than hyperuricemia. The niche of these agents in current management of hyperuricemia is discussed. We also review the ongoing development of recombinant uricase preparations and of novel xanthine oxidase inhibitors exemplified by febuxostat. These agents should provide novel options for patients with chronic, refractory gout and hyperuricemia, particularly in association with allopurinol hypersensitivity and renal insufficiency.

Febuxostat↗
PubMed2006

Recent developments in diet and gout.

PURPOSE OF REVIEW: Gout is the most common inflammatory arthritis in men, affecting approximately 1-2% of adult men in Western countries. United States gout prevalence has approximately doubled over the past two decades. In recent years, key prospective epidemiological and open-labeled dietary studies, coupled with recent advances in molecular biology elucidating proximal tubular urate transport, have provided novel insights into roles of diet and alcohol in hyperuricemia and gout. This review focuses on recent developments and their implications for clinical practice, including how we advise patients on appropriate diets and alcoholic beverage consumption. RECENT FINDINGS: Studies have observed an increased risk of gout among those who consumed the highest quintile of meat, seafood and alcohol. Although limited by confounding variables, low-fat dairy products, ascorbic acid and wine consumption appeared to be protective for the development of gout. SUMMARY: The most effective forms of dietary regimen for both hyperuricemia and gout flares remains to be unidentified. Until confirmed by a large, controlled study, it is prudent to advise patients to consume meat, seafood and alcoholic beverages in moderation, with special attention to food portion size and content of non-complex carbohydrates which are essential for weight loss and improved insulin sensitivity.

Beer↗
PubMed2006

Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression.

Macrophage-mediated inflammation is central to atherogenesis. We have determined previously that the CXC chemokine receptor CXCR2 is involved in advanced atherosclerosis. We sought to determine whether one of the ligands of CXCR2, KC/GRO-alpha, can also modulate atherogenesis. KC/GRO-alpha(-/-) mice were generated and mated with the atherosclerosis-prone LDLR(-/-) mice. There was a significant reduction in atherosclerosis in mice lacking KC/GRO-alpha; however, this reduction was only approximately half that seen previously in mice lacking CXCR2 in the leukocyte. To determine whether CXCR2 is involved in the early formation of atherosclerosis, leukocyte-specific CXCR2(-/-) chimeric mice on LDLR(-/-) background were generated. Early fatty streak lesion formation in these mice was not affected by leukocyte CXCR2 deficiency whereas lesions were less developed in mice lacking leukocyte CXCR2 when atherosclerosis was allowed to progress to the intermediate stage. Macrophages were relatively sparse in the lesions of leukocyte CXCR2(-/-) mice despite robust MCP-1 expression. These studies indicate that KC/GRO-alpha/CXCR2 does not play a critical role in recruitment of macrophages into early atherosclerotic lesions but both arterial KC/GRO-alpha and leukocyte-specific CXCR2 expression are central to macrophage accumulation in established fatty streak lesions.

Animals↗
PubMed2005

External GTP-bound transglutaminase 2 is a molecular switch for chondrocyte hypertrophic differentiation and calcification.

Chondrocyte maturation to hypertrophy, associated with up-regulated transglutaminase 2 (TG2) expression, mediates not only physiologic growth plate mineralization but also pathologic matrix calcification and dys-regulated matrix repair in osteoarthritic articular cartilage. TG2-/- mouse chondrocytes demonstrate markedly inhibited progression to hypertrophic differentiation in response to both retinoic acid and the chemokine CXCL1. Here, our objectives were to test if up-regulated TG2 alone is sufficient to promote chondrocyte hypertrophic differentiation and to identify TG2 molecular determinants and potential downstream signals involved. TG2 activities, regulated by nucleotides and calcium, include cross-linking of cartilage matrix proteins, binding of fibronectin, and hydrolysis of GTP and ATP. Following transfection of TG2 site-directed mutants into chondrocytic cells, we observed that wild type TG2, and TG catalytic site and fibronectin-binding mutants promoted type X collagen expression and matrix calcification consistent with chondrocyte hypertrophic differentiation. In contrast, transfected mutants of TG2 GTP binding (K173L) and externalization (Y274A) sites did not stimulate chondrocyte hypertrophy. Recombinant TG2 treatment of bovine cartilage explants demonstrated that extracellular TG2 induced hypertrophy more robustly in the GTP-bound state, confirming an essential role of TG2 GTP binding. Finally, TG2 treatment induced type X collagen in a beta1 integrin-mediated manner, associated with rapid phosphorylation of both Rac1 and p38 kinases that were inhibited by mutation of the TG2 GTP binding site. In conclusion, externalized GTP-bound TG2 serves as a molecular switch for differentiation of chondrocytes to a hypertrophic, calcifying phenotype in a manner that does not require either TG2 transamidation activity or fibronectin binding.

Adenosine Triphosphate↗
PubMed2005

Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate.

OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.

5' Untranslated Regions↗
PubMed2004

Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis.

OBJECTIVE: Monosodium urate monohydrate (MSU) crystals promote gouty inflammation that is critically mediated by neutrophil recruitment and activation. Interleukin-8 (IL-8) and closely related chemokines are major neutrophil chemotaxins in experimental gout. But MSU crystals also activate the classical and alternative pathways of complement, and MSU crystals directly cleave C5 on the crystal surface. Unlike IL-8, the roles in acute gout of individual complement-derived peptides and of the terminal C5b-9 complement components that comprise the membrane attack complex (MAC) are unclear. Hence, we studied rabbits deficient in the MAC component C6 to determine if MAC mediated urate crystal-induced arthritis. METHODS: We injected C6-deficient and C6-sufficient rabbit knee joints with 10 mg of pyrogen-free urate crystals and analyzed IL-8 levels, leukocyte influx, and joint inflammation 24 hours later. RESULTS: There was a significant decrease (>60%) in swelling in MSU crystal-injected knees of C6-deficient animals as compared with C6-sufficient animals (P < 0.05). An attenuated rise in MSU crystal-induced joint effusion levels of IL-8 also was observed, which was concordant with diminished numbers of neutrophils (P < 0.05) but not monocytes in MSU crystal-induced knee synovial fluid from C6-deficient animals. Synovial tissue analysis confirmed mononuclear leukocyte infiltration in response to MSU crystal injection in all animals, but substantial neutrophil infiltration only in C6-sufficient animals. CONCLUSION: MAC activation appears to play a major role in intraarticular IL-8 generation and in neutrophil recruitment in experimental acute gouty arthritis of the rabbit knee. C6 and MAC activation may represent novel therapeutic targets for suppression of neutrophil-mediated joint inflammation in gout.

Animals↗
PubMed2003

IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor.

Microvascular endothelial cells (HMECs) express both the CXCR1 and the CXCR2, but cell migration is almost entirely mediated by the CXCR2. Similarly, NIH 3T3 cells transfected with the CXCR2 migrated toward IL-8, whereas CXCR1-transfected cells failed to do so. This situation differs from that seen in leukocytes, where chemotaxis is primarily a function of the CXCR1. To define signal transduction pathways that explain this difference in behavior, various inhibitors were used to block cell migration. Apart from inhibitors of phosphatidylinositol 3-kinase, which blocked migration in all cases, inhibition of the epidermal growth factor (EGF) receptor blocked IL-8-mediated cell migration in HMECs and in CXCR2-transfected NIH 3T3 cells, but not in RBL2H3 cells, which do not express an EGFR. Blocking Abs against the EGFR or against heparin-binding EGF-like growth factor similarly blocked IL-8-mediated cell migration and in vitro tubulogenesis in HMECs. Furthermore, inhibition of the EGFR also attenuated focus formation in NIH 3T3 expressing the CXCR2. Immunoprecipitations of the EGFR in HMECs and in NIH 3T3 cells expressing the CXCR2 confirmed that the EGFR was phosphorylated following stimulation with IL-8. However, in contrast to previous reports, e.g., for the thrombin receptor, inhibition of matrix metalloproteases blocked IL-8-mediated cell migration only partially, whereas it was ablated by inhibition of cathepsin B. These results indicate that IL-8-induced transactivation of the EGFR is mediated by the CXCR2 and involves cathepsin B, and that this pathway is important for the migratory and tumorigenic effects of IL-8.

Animals↗
PubMed2003

Distinct transglutaminase 2-independent and transglutaminase 2-dependent pathways mediate articular chondrocyte hypertrophy.

Altered chondrocyte differentiation, including development of chondrocyte hypertrophy, mediates osteoarthritis and pathologic articular cartilage matrix calcification. Similar changes in endochondral chondrocyte differentiation are essential for physiologic growth plate mineralization. In both articular and growth plate cartilages, chondrocyte hypertrophy is associated with up-regulated expression of certain protein-crosslinking enzymes (transglutaminases (TGs)) including the unique dual-functioning TG and GTPase TG2. Here, we tested if TG2 directly mediates the development of chondrocyte hypertrophic differentiation. To do so, we employed normal bovine chondrocytes and mouse knee chondrocytes from recently described TG2 knockout mice, which are phenotypically normal. We treated chondrocytes with the osteoarthritis mediator IL-1 beta, with the all-trans form of retinoic acid (ATRA), which promotes endochondral chondrocyte hypertrophy and pathologic calcification, and with C-type natriuretic peptide, an essential factor in endochondral development. IL-1 beta and ATRA induced TG transamidation activity and calcification in wild-type but not in TG2 (-/-) mouse knee chondrocytes. In addition, ATRA induced multiple features of hypertrophic differentiation (including type X collagen, alkaline phosphatase, and MMP-13), and these effects required TG2. Significantly, TG2 (-/-) chondrocytes lost the capacity for ATRA-induced expression of Cbfa1, a transcription factor necessary for ATRA-induced chondrocyte hypertrophy. Finally, C-type natriuretic peptide, which did not modulate TG activity, comparably promoted Cbfa1 expression and hypertrophy (without associated calcification) in TG2 (+/+) and TG2 (-/-) chondrocytes. Thus, distinct TG2-independent and TG2-dependent mechanisms promote Cbfa1 expression, articular chondrocyte hypertrophy, and calcification. TG2 is a potential site for intervention in pathologic calcification promoted by IL-1 beta and ATRA.

Alkaline Phosphatase↗