Hyaluronan Concentration in Non-Inflamed and Rheumatoid Synovium

Pitsillides, Andrew A.; Worrall, J. G.; Wilkinson, Leonora; Bayliss, Michael T.; Edwards, J. C. W.

doi:10.1093/rheumatology/33.1.5

Cited by 54 publications

(35 citation statements)

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“…HA Assay-An enzyme-linked immunosorbance-based assay was used to measure concentrations of HA released into the culture media 24 h after mechanical strain application (31). The assay is based upon the competition between HA absorbed on to the plate and HA free in solution for binding to biotinylated cartilage proteoglycan binding region (G1 domain) (32).…”

Section: Methodsmentioning

confidence: 99%

A Specific Mechanomodulatory Role for p38 MAPK in Embryonic Joint Articular Surface Cell MEK-ERK Pathway Regulation

Lewthwaite

Bastow

Lamb

et al. 2006

Journal of Biological Chemistry

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Mechanisms regulating cell behavior and extracellular matrix composition in response to mechanical stimuli remain unresolved. Our previous studies have established that the MEK-ERK cascade plays a specific role in the mechano-dependent joint formation process by promoting the assembly of pericellular matrices reliant upon hyaluronan (HA) for their integrity. Here we demonstrate: (i) novel cross-talk between p38 MAPK and MEK-ERK signaling pathways that is specific for mechanical stimuli and (ii) a role for p38 MAPK in facilitating HA production by cells derived from the articular surface of embryonic chick tibiotarsal joints. We find that p38 MAPK blockade restricts pericellular assembly of HA-rich matrices and reduces basal as well as mechanical strain-induced release of HA. p38 MAPK blockers potentiated early strain-induced increases but restricted sustained increases in MEK/ERK phosphorylation at later times; c-Fos hyperphosphorylation at threonine 325 was found to parallel this p38 MAPK-mediated modulation of ERK activation. In contrast, p38 MAPK inhibitors had no detectable effect on the ERK activation induced by fibroblast growth factor 2 or pervanadate, a phosphatase inhibitor, and MEK inhibitors did not influence p38 MAPK phosphorylation, confirming both the specificity and unidirectionality of p38 MAPK-ERK cross-talk. Immunochemical and immunoblotting studies revealed constitutive p38 MAPK activation in cells at, or derived from, developing articular joint surfaces. Unlike the MEK-ERK pathway, however, p38 MAPK was not further stimulated by mechanical stimulation in vitro. Thus, p38 MAPK specifically facilitates ERK activation and downstream signaling in response to mechanical stimuli. These results suggest that constitutively active p38 MAPK serves an essential, permissive role in mechanically induced changes in ERK activation and in the accumulation of HA-rich extracellular matrices that serve a key role in joint development.Mitogen-activated protein kinases (MAPKs) 3 are ubiquitous serine/ threonine kinases that are activated by diverse extracellular stimuli, including growth factors, cytokines, and physiological mechanical signals (1-3). MAPKs are essential for transducing signals from the cell surface that regulate diverse cellular behaviors, such as those coordinating development, proliferation, and differentiation. Much recent emphasis has been placed on members of three well characterized mammalian MAPK families, comprising extracellular signal-regulated kinases (ERKs), p38 MAPKs, and c-Jun N-terminal kinases (JNKs) (4 -6). Until relatively recently it was considered that these families were preferentially activated by certain types of signal: the ERK family by growth factors and the p38 MAPK and JNK families by cellular stress. It is now becoming increasingly clear, however, that the various MAPK pathways can also be co-activated by a single stimulus. The precise interaction between members of these distinct MAPK families and how they cooperate to control cell behavior are, however, ill-define...

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Section: Methodsmentioning

confidence: 99%

A Specific Mechanomodulatory Role for p38 MAPK in Embryonic Joint Articular Surface Cell MEK-ERK Pathway Regulation

Lewthwaite

Bastow

Lamb

et al. 2006

Journal of Biological Chemistry

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“…In the inflamed synovium HYA is distributed all through the synovial layers but especially around the vessels [24]. In one study [25] the amount of HYA was measured chemically and it was found that the normal synovium contains 1.07 Ϯ 0.16 mg HYA cm Ϫ3 whilst the rheumatoid synovium seen in RA-patients contains 0.71 Ϯ 0.10 mg HYA cm Ϫ3 . Thus the changes in HYA concentration in the synovial fluid are mirrored in the synovial membrane.…”

Section: Turnover Of Hyaluronan In Joint Diseasementioning

confidence: 99%

Hyaluronan in joint disease

Engström‐Laurent

1997

Journal of Internal Medicine

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Engström‐Laurent A (University of Umeå, Umeå, Sweden). Hyaluronan in joint disease (Minisymposium: Hyaluronan). J Intern Med 1997; 242: 57–60. Hyaluronan is a major component of synovial fluid. It is synthesized in the joint and partly degraded in joint capsule and partly carried by lymph to lymph nodes and the general circulation. During various joint disorders, especially inflammatory ones, the amount of hyaluronan in the joint and its turnover rate are increased leading to pathologically high serum levels of the polysaccharide. These levels are a complex function of synovitis mass and the physical activity of the patient. Intra‐articular injection of hyaluronan has been used in the treatment of osteoarthritis. Although it results in a relief of pain, controlled clinical trials have not yet convincingly shown any beneficiary effects of the treatment.

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“…CD44 has been shown to participate in the migration of leukocytes to inflammatory sites (9 -12), where there is often an increase in CD44ϩ cells due to both the immigration of CD44ϩ leukocytes and to a greater degree of CD44 expression on resident cells (1). CD44 expression is increased on many cell types in inflamed arthritic joints (11,13), in which the synthesis and degradation of HA are also enhanced (14,15).…”

mentioning

confidence: 99%

TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44

Lesley

Gál

Mahoney

et al. 2004

Journal of Biological Chemistry

161

203

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Interactions between CD44 and hyaluronan are implicated in the primary adhesion of lymphocytes to endothelium at inflammatory locations. Here we show that preincubation of hyaluronan with full-length recombinant TSG-6 or its Link module domain (Link_TSG6) enhances or induces the binding of hyaluronan to cell surface CD44 on constitutive and inducible cell backgrounds, respectively. These effects are blocked by CD44-specific antibodies and are absent in CD44-negative cells. Enhancement of CD44-mediated interactions of lymphoid cells with hyaluronan by TSG-6 proteins was seen under conditions of flow at shear forces that occur in post-capillary venules. Increases in the number of rolling cells were observed on substrates comprising TSG-6-hyaluronan complexes as compared with a substrate containing hyaluronan alone. In ligand competition experiments, cell surface-bound TSG-6-hyaluronan complexes were more potent than hyaluronan alone in inhibiting cell adhesion to immobilized hyaluronan. Link_TSG6 mutants with impaired hyaluronan binding function had a reduced ability to modulate ligand binding by cell surface CD44. However, some mutants that exhibited close to wild-type hyaluronan binding were found to have either reduced or increased activity, suggesting that some amino acid residues outside of the hyaluronan binding site might be involved in protein self-association, potentially leading to the formation of cross-linked hyaluronan fibers. In turn, cross-linked hyaluronan could increase the binding avidity of CD44 by inducing receptor clustering. The ability of TSG-6 to modulate the interaction of hyaluronan with CD44 has important implications for CD44-mediated cell activity at sites of inflammation, where TSG-6 is expressed.

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Hyaluronan Concentration in Non-Inflamed and Rheumatoid Synovium

Cited by 54 publications

References 0 publications

A Specific Mechanomodulatory Role for p38 MAPK in Embryonic Joint Articular Surface Cell MEK-ERK Pathway Regulation

A Specific Mechanomodulatory Role for p38 MAPK in Embryonic Joint Articular Surface Cell MEK-ERK Pathway Regulation

Hyaluronan in joint disease

TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44

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