UMLS:C0003864 - FACTA Search

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Query: UMLS:C0003864 (arthritis)
69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both type II collagen and the proteoglycan aggrecan are capable of inducing an erosive inflammatory polyarthritis in mice. In this study we provide the first demonstration that link protein (LP), purified from bovine cartilage, can produce a persistent, erosive, inflammatory polyarthritis when injected repeatedly intraperitoneally into BALB/c mice. We discovered a single T-cell epitope, located within residues 266 to 290 of bovine LP (NDGAQIAKVGQIFAAWKLLGYDRCD), which is recognized by bovine LP-specific T lymphocytes. We also identified three immunogenic regions in bovine LP that contain epitopes recognized by antibodies in hyperimmunized sera. One of these B-cell regions is found in the most species-variable domain of LP (residues 1 to 36), whereas the other epitopes are located in the most conserved regions (residues 186 to 230 and 286 to 310). The latter two regions contain an AGWLSDGSVQYP motif shared by the G1 globulin domain of aggrecan core protein, versican, neurocan, glial hyaluronan-binding protein, and the hyaluronan receptor CD44. Our data reveal that the induction of arthritis is associated with antibody reactivities to B-cell epitopes located at residues 1 to 19. Together, these observations show that another cartilage protein, LP, like type II collagen and the proteoglycan aggrecan, is capable of inducing an erosive inflammatory arthritis in mice and that the immunity to LP involves recognition of both T- and B-cell epitopes. This immunity may be of importance in the pathogenesis of inflammatory joint diseases, such as juvenile rheumatoid arthritis, in which cellular immunity to LP has been demonstrated.
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PMID:Induction of arthritis in BALB/c mice by cartilage link protein: involvement of distinct regions recognized by T and B lymphocytes. 977 60

Aggrecan, a major structural proteoglycan in cartilage, contains three globular domains, G1, G2, and G3, as well as sequences for glycosaminoglycan modification. A large number of proteases are implicated in aggrecan cleavage in normal metabolism, aging, and arthritis. These proteases are known to cleave at the IGD, KS, and CS domains. Here we report for the first time evidence of cleavage at a novel site, the carboxyl tail of aggrecan. Results from deletion mutants of the tail indicated that the likely cleavage sites were two consensus sequences, RRLXK and RSPR, present in the aggrecan analogs of many species. This was confirmed by site-directed mutagenesis. A construct containing two G3 domains (G3G3) was also found to cleave between the G3 duplicates. When G3 tail was linked to a glycosaminoglycan-modifying sequence, it was protected from cleavage. Furin inhibitor also reduced the levels of tail cleavage. The carboxyl tails of chicken and human versican were not cleaved, despite the presence of the consensus sequence. Our studies indicate that the basic amino acids present in the tail play an important role in cleavage, and this mechanism is specific to aggrecan.
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PMID:Cleavage of the carboxyl tail from the G3 domain of aggrecan but not versican and identification of the amino acids involved in the degradation. 1193 52

Increasing evidence is accumulating for the importance of the aggrecanases ADAMTS-4 and ADAMTS-5 in cartilage degradation in arthritis. Recent work from a number of laboratories has begun to provide insight into the regulation of the expression and activity of these proteins and the molecular basis of their role in aggrecan catabolism. Recombinant ADAMTS-4 and ADAMTS-5 cleave aggrecan at five distinct sites along the core protein and aggrecan fragments generated by cleavage at all of these sites have been identified in cartilage explants undergoing matrix degradation. This proteolytic activity of the aggrecanases can be modulated by several means, including altered expression, activation by proteolytic cleavage at a furin-sensitive site, binding to the aggrecan substrate through the C-terminal thrombospondin motif, activation through post-translational processing of a portion of the C-terminus and inhibition of activity by the endogenous inhibitor TIMP-3. ADAMTS-4 and ADAMTS-5 activity is detected in joint capsule and synovium in addition to cartilage, and may be upregulated in arthritic synovium at either the message level or through post-translational processing. Additional substrates have now been identified, including the chondroitin-sulfate proteoglycans brevican and versican. Finally, advances are occurring in the development of selective aggrecanase inhibitors designed to serve as therapeutics for the treatment of arthritis.
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PMID:Aggrecanase-mediated cartilage degradation. 1202 Apr 78

The rabbit suprapatella is a sesamoid fibrocartilage in the deep surface of the tendon of vastus intermedius and an integral part of the knee joint. We report the presence of a variety of proteoglycans (aggrecan and versican), glycosaminoglycans (chondroitin 4 and 6 sulfate, dermatan sulfate, keratan sulfate) and glycoproteins (tenascin) in its extracellular matrix and the intermediate filament vimentin in the fibrocartilage cells. The most significant finding is the presence of aggrecan in the extracellular matrix, along with its associated link protein and several of its integral glycosaminoglycans. Aggrecan probably enables the suprapatella to withstand compression. Although it can be assumed that aggrecan metabolites detected in synovial fluid from some human joints are predominantly associated with articular hyaline cartilage, the presence of aggrecan in the rabbit suprapatella means that this cannot be assumed for all animal knee joints. We conclude that it is important for orthopedic researchers who use animal models for arthritis research to check for the presence of a suprapatella when joint fluid analyses are interpreted.
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PMID:An immunohistochemical study of the rabbit suprapatella, a sesamoid fibrocartilage in the quadriceps tendon containing aggrecan. 1207 Feb 74

Many cartilage matrix proteins or domains such as collagen types II, IX, and XI, GP39, AG1, VG1, and LP are potential antigens that might induce polyarthritis in susceptible animals (Table 1). Ordinarily, spondylitis is not a feature of polyarthritis induced with collagen types II, IX, and XI, GP39, cartilage matrix protein (matrilin-1) and cartilage LP. It seems that only the proteoglycans aggrecan and versican are capable of inducing sacroiliitis and spondylitis. Both molecules are structural proteins in intervertebral discs. Moreover, the arthritogenic or spondylitogenic epitopes of both molecules have been localized to the homologous N-terminal G1 globular domains. This region of versican and aggrecan is highly conserved, with 52% identity of amino acids. The homology is seen exclusively in the G1 domain and is concentrated between residues 115 and 332 (AG1 numbering) near the natural cleavage DIPEN site of aggrecan [84, 85]. Extra-articular pathology is often seen in rheumatic diseases, especially in AS. Other tissues, such as the sclera of the eye [86] and the media of the arteries [86, 87], also contain type II collagen, AG1, VG1, and LP, and versican is present in the central and peripheral nervous systems. Thus, there is the potential for an immune response against cartilage G1 and LP to be directed against related structures in extra-articular tissues. The presence of versican in the tendon and trochlea of the human superior oblique muscle might account for the occurrence of transient attacks of acquired Brown syndrome in patients with juvenile and adult forms of chronic RA [88]. Thus, it will be interesting to determine whether or not extra-articular expression of these cartilage proteins is closely related to extra-articular pathogenic expression in rheumatic diseases. Uveitis develops in VG1-immunized BALB/c mice, which is not seen in AG1-, and LP-treated animals. There is evidence that aggrecan and LP are also localized at these sites in the eye, but only immunity to versican can induce uveitis. In sacroiliitis and enthesitis of AS patients, the inflammation is associated with chondrometaplasia. In versican-induced sacroiliitis, replacement of cartilage by bone is seen with relatively little inflammation, somewhat resembling the situation in AS (Fig. 2). Versican can also stimulate chondrocyte proliferation [43]. Three conserved domains of human cartilage matrix molecules, namely VG1, AG1, and LP, show considerable homology [77, 79, 80, 89], and each is capable of inducing a unique inflammatory arthritis in BALB/c mice, with VG1 inducing only spondylitis [65], LP inducing peripheral arthritis with no spondylitis [90], and AG1 inducing axial and peripheral arthritis [66, 91]. It remains a mystery why such similar molecules cause different pathology in different target tissues. The exact immunopathogenic mechanisms deserve further study.
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PMID:Animal models of inflammatory spinal and sacroiliac joint diseases. 1295 72

ADAMTS proteases are complex secreted enzymes containing a prometalloprotease domain of the reprolysin type attached to an ancillary domain with a highly conserved structure that includes at least one thrombospondin type 1 repeat. Known functions of ADAMTS proteases include processing of procollagens and von Willebrand factor as well as catabolism of aggrecan, versican and brevican. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. ADAMTS can be grouped into distinct clades within which there is conservation of modular organization, protein sequence, gene structure and possibly, of substrate preference. ADAMTS proteases are synthesized as zymogens, with constitutive proprotein convertase removal of the propeptide occurring prior to secretion. Their enzymatic specificity is heavily influenced by their ancillary domain, which plays a critical role in directing these enzymes to their substrates, the cell surface and the extracellular matrix.
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PMID:A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family. 1509 12

The ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are a group of proteases that are found both in mammals and invertebrates. Since the prototype ADAMTS-1 was first described in 1997, there has been a rapidly expanding body of literature describing this gene family and the proteins they encode. The complete human family has 19 ADAMTS genes, together with three members of a newly identified subgroup, the ADAMTSL (ADAMTS-like) proteins, which have several domains in common with the ADAMTSs. The ADAMTSs are extracellular, multidomain enzymes whose known functions include: (i) collagen processing as procollagen N-proteinase; (ii) cleavage of the matrix proteoglycans aggrecan, versican and brevican; (iii) inhibition of angiogenesis; and (iv) blood coagulation homoeostasis as the von Willebrand factor cleaving protease. Roles in organogenesis, inflammation and fertility are also apparent. Recently, some ADAMTS genes have been found to show altered expression in arthritis and various cancers. This review highlights progress in understanding the structural organization and functional roles of the ADAMTSs in normal and pathological conditions.
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PMID:The ADAMTS metalloproteinases. 1555 75

Matrix metalloproteinases (MMPs) are members of an enzyme family that require a zinc ion in their active site for catalytic activity. MMPs are critical for maintaining tissue allostasis. MMPs are active at neutral pH and can therefore catalyze the normal turnover of extracellular matrix (ECM) macromolecules such as the interstitial and basement membrane collagens, proteoglycans such as aggrecan, decorin, biglycan, fibromodulin and versican as well as accessory ECM proteins such as fibronectin. Members of the MMP family include the "classical" MMPs, the membrane-bound MMPs (MT-MMPs) the ADAMs (a disintegrin and metalloproteinase; adamlysins) and the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif). There are more than 20 members in the MMP and ADAMTS family including the collagenases, gelatinases, stromelysins, some elastases and aggrecanases. Adamlysins are membrane-bound MMPs that also degrade aggrecan, but more importantly, one ADAM family member (i.e.ADAM-17) is a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) that activates pro-TNF-alpha. Most of the MMPs are synthesized as inactive latent enzymes. Conversion to the active enzyme is generally mediated by activator systems that include plasminogen activator or the pro-hormone convertase, furin. MMP activity is regulated by a group of endogenous proteins, called, tissue inhibitor of metalloproteinases (TIMPs) that bind to active and alternative sites of the activated MMP. Significant advances have occurred in the understanding of the regulation of MMPs, ADAMs and ADAMTSs gene expression. In addition, development of MMP inhibitors to study MMP structure/function relationships spawned many studies to determine the effectiveness of MMP inhibitors in regulating abnormal connective tissue turnover. In addition, development of MMP null mice carrying specific MMP deletions has provided an opportunity to explore the role of MMPs in normal development as well as in such diverse conditions and diseases as skeletal dysplasias, coronary artery and heart disease, arthritis, cancer, and brain disorders.
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PMID:Matrix metalloproteinases (MMPs) in health and disease: an overview. 1636 48

The molecular basis to mammalian osteoarthritis (OA) is unknown. We hypothesised that the expression of selected proteases, matrix molecules, and collagens believed to have a role in the pathogenesis of OA would be changed in naturally occurring canine OA cartilage when compared to normal articular cartilage. Quantitative (real-time) reverse transcriptase-polymerase chain reaction assays were designed measuring the expression of selected matrix molecules (collagens and small leucine-rich proteoglycans), key mediators of the proteolytic degradation of articular cartilage (metalloproteinases, cathepsins), and their inhibitors (tissue inhibitors of matrix metalloproteinases). All data were normalised using a geometric mean of three housekeeping genes, and the results subjected to power calculations and corrections for multiple hypothesis testing. We detected increases in the expression of BGN, COL1A2, COL2A1, COL3A1, COL5A1, CSPG2, CTSB, CTSD, LUM, MMP13, TIMP1, and TNC in naturally occurring canine OA. The expression of TIMP2 and TIMP4 was significantly reduced in canine OA cartilage. The patterns of gene expression change observed in naturally occurring canine OA were similar to those reported in naturally occurring human OA and experimental canine OA. We conclude that the expression profiles of matrix-associated molecules in end-stage mammalian OA may be comparable but that the precise aetiologies of OA affecting specific joints in different species are presently unknown.
Arthritis Res Ther 2006
PMID:Analysis of normal and osteoarthritic canine cartilage mRNA expression by quantitative polymerase chain reaction. 1703 49

Stem cells derived from the infrapatellar fat pad (IPFP) are a potential source of stem cells for the repair of articular cartilage defects. Hypoxia has been shown to improve chondrogenesis in adult stem cells. In this study we investigated the effects of hypoxia on gene expression changes and chondrogenesis in stem cells from the IPFP removed from elderly patients with osteoarthritis at total knee replacement. Adherent colony-forming cells were isolated and cultured from the IPFP from total knee replacement. The cells at passage 2 were characterised for stem cell surface epitopes, and then cultured for 14 days as cell aggregates in chondrogenic medium under normoxic (20% oxygen) or hypoxic (5% oxygen) conditions. Gene expression analysis, DNA and glycosoaminoglycan assays and immunohistochemical staining were determined to assess chondrogenesis. IPFP-derived adherent colony-forming cells stained strongly for markers of adult mesenchymal stem cells, including CD44, CD90 and CD105, and they were negative for the haematopoietic cell marker CD34 and for the neural and myogenic cell marker CD56. Cell aggregates of IPFP cells showed a chondrogenic response. In hypoxic conditions there was increased matrix accumulation of proteoglycan but less cell proliferation, which resulted in 3.5-fold more glycosoaminoglycan per DNA after 14 days of culture. In hypoxia there was increased expression of hypoxia-inducible transcription factor (HIF)2alpha and not HIF1alpha, and the expression of key transcription factors SOX5, SOX6 and SOX9, and that of aggrecan, versican and collagens II, IX, X and XI, was also increased. These results show that cells with stem cell characteristics were isolated from the IPFP of elderly patients with osteoarthritis and that their response to chondrogenic culture was enhanced by lowered oxygen tension, which upregulated HIF2alpha and increased the synthesis and assembly of matrix during chondrogenesis. This has important implications for tissue engineering applications of cells derived from the IPFP.
Arthritis Res Ther 2007
PMID:Hypoxic conditions increase hypoxia-inducible transcription factor 2alpha and enhance chondrogenesis in stem cells from the infrapatellar fat pad of osteoarthritis patients. 1753 34

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