Defining boundaries during joint cavity formation: going out on a limb

Lamb, Katherine J.; Lewthwaite, J; Bastow, Edward; Pitsillides, Andrew A.

doi:10.1046/j.1365-2613.2003.00338.x

Cited by 24 publications

(28 citation statements)

References 80 publications

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“…Hyaluronan attenuates synovial fluid loss from flexed joints (Lu et al, 2005) and provides low-load hydrodynamic lubrication (Mabuchi et al, 1994). Also, coupling between HA production and limb movement is crucial for joint cavitation during embryogenesis (Lamb et al, 2003). The present work concentrated exclusively on the coupling between static strain and qḢ A ; further studies are needed to assess the effects of dynamic, cyclical strain and whether it activates additional pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Also HAS trafficking between the plasmalemma and an intracellular pool (Rilla et al, 2005) could be subject to regulation. The Ca 2+ -dependent PKC isoforms (α, β1, β2) can activate c-Raf1, which activates ERK (Kanashiro and Khalil, 1998) leading to the activation of immediate early genes by transcription factors that include activator protein-1, Elk-1 and NF-κB (Hagemann and Blank, 2001), Smad (Lamb et al, 2003), c-fos and fra-1 (Wamel et al, 2000;Chiquet et al, 2003).…”

Section: Upstream: a Role For Ca 2+ Signallingmentioning

confidence: 99%

“…Additionally, HA is a vital structural component of the synovial lining since, if depleted, the synovial matrix becomes disorganised (Coleman, 2005) and its resistance to fluid escape collapses (Coleman et al, 1998). HA secretion also has a vital role in the induction of joint cavitation during embryogenesis, and its secretion depends critically on stimulation by embryo limb movement (Lamb et al, 2003). Since joint HA is chiefly concerned with protecting diarthrodial joints against the potentially damaging effects of joint use, we postulated that HA secretion into joints may be coupled to joint use through deformation of the synovial lining cells.…”

Section: Introductionmentioning

confidence: 99%

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Mechanosensitive synoviocytes: A Ca2+–PKCα–MAP kinase pathway contributes to stretch-induced hyaluronan synthesis in vitro

2006

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Section: Discussionmentioning

confidence: 99%

Section: Upstream: a Role For Ca 2+ Signallingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanosensitive synoviocytes: A Ca2+–PKCα–MAP kinase pathway contributes to stretch-induced hyaluronan synthesis in vitro

2006

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“…Our studies in AS cells have shown that mechanically induced ERK activation is both rapid and sustained and that these kinetic characteristics are allied to the formation and maintenance of pericellular matri-ces (8,22). A general mechanism through which ERK activation kinetics may be interpreted has recently been proposed; the immediate early gene product c-Fos has been shown to function as a downstream molecular sensor of ERK signal duration that allows cells to respond appropriately to extracellular signals (23,24).…”

mentioning

confidence: 84%

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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“…Indeed, disruption in UDPGD in zebrafish (Jekyll mutant) blocks atrioventricular differentiation by modifying the signaling boundaries involved in valve formation (39). The role of UD-PGD-derived HA in boundary formation is also supported by similar cardiac valve disruption in HAS2 (HA synthase 2) knockouts, which is correctable by exogenous HA (40,41).…”

Section: Mechanical Loading Regulates the Phenotype Of Cells At Thementioning

confidence: 99%

Selective Activation of the MEK-ERK Pathway Is Regulated by Mechanical Stimuli in Forming Joints and Promotes Pericellular Matrix Formation

Bastow

Lamb

Lewthwaite

et al. 2005

Journal of Biological Chemistry

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It is well established that local modification of extracellular matrix (ECM) hyaluronan composition is vital in the regulation of cell behavior. Indeed, the formation of articulating chick joint cavities, which requires mechanical stimuli derived from skeletal movement, is dependent upon the accumulation of an ECM rich in hyaluronan (HA). However, the mechanisms responsible for such precise mechano-dependent regulation of cell behavior and the formation of a HA-rich ECM remain undefined. Here we show that extracellular-regulated kinase 1/2 (ERK1/2) is selectively activated in cells at sites of cavity formation and activity diminished by in ovo immobilization that induces cartilaginous fusion across presumptive joint interzones. In vitro analyses offer mechanistic support for the role of mechanical stimuli in promoting a MEK-dependent activation of ERK1/2. In addition, our direct regulation of ERK1/2 phosphorylation status via modulation of its up-stream "classical cascade" activator either pharmacologically or by transfection with dominant negative or constitutively active Mek confirms the essential role for ERK1/2 activation in the elaboration of HA-rich pericellular matrices. Together, our findings demonstrate that the MEK-ERK pathway, regulated by mechanical stimuli, controls HA-rich matrix assembly. The precision of ERK1/2 activation selectively distinguishing cells at the joint line suggests that it directly contributes to the loss of tissue cohesion essential for generating HA-rich cavities between joint elements during their development.

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Defining boundaries during joint cavity formation: going out on a limb

Cited by 24 publications

References 80 publications

Mechanosensitive synoviocytes: A Ca2+–PKCα–MAP kinase pathway contributes to stretch-induced hyaluronan synthesis in vitro

Mechanosensitive synoviocytes: A Ca2+–PKCα–MAP kinase pathway contributes to stretch-induced hyaluronan synthesis in vitro

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

Selective Activation of the MEK-ERK Pathway Is Regulated by Mechanical Stimuli in Forming Joints and Promotes Pericellular Matrix Formation

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