Regulated Cleavage of a Contact-Mediated Axon Repellent

Hattori, Mitsuharu; Osterfield, Miriam; Flanagan, John G.

doi:10.1126/science.289.5483.1360

Cited by 490 publications

(392 citation statements)

References 32 publications

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“…However, Hattori et al (49) recently hypothesized that ephrin could be shed and that the protease ADAM10 may be involved in this cleavage. If such an ephrin B2 cleavage process occurs, then in addition to osteoclasts, osteoblasts could be implicated in providing soluble ephrin B2.…”

Section: Discussionmentioning

confidence: 99%

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Tat¹,

Pelletier²,

Amiable³

et al. 2008

Arthritis & Rheumatism

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Objective. Abnormal subchondral bone metabolism is involved in osteoarthritis (OA). It has been suggested that ephrin B2 and its specific receptor EphB4 participate in bone homeostasis. We previously reported that human OA subchondral bone osteoblasts could be classified into 2 subpopulations: low (L), having proresorption properties, and high (H), having proformation properties. The purpose of this study was to investigate the importance of the ephrin system in OA subchondral bone osteoblasts.Methods. The presence of the EphB4 receptor was determined by immunohistochemistry, and its expression level, modulation upon treatment, and consequences of activation by ephrin B2 were determined by quantitative polymerase chain reaction. The effects of ephrin B2 activation of the EphB4 receptor on bone resorption activity were also determined. EphB4 receptor activation signaling pathways were investigated by specific enzyme-linked immunosorbent assay.Results. EphB4 receptors were present in subchondral bone osteoblasts and osteocytes. Compared with normal and H-OA osteoblasts, EphB4 receptor expression levels were significantly increased in L-OA osteoblasts, with no difference between normal and H-OA osteoblasts. EphB4 receptor levels in L-OA osteoblasts were significantly up-regulated by prostaglandin E 2 (PGE 2 ) and interleukin-17 (IL-17). Ephrin B2, PGE 2 , and IL-17 significantly inhibited bone resorption activity in these cells. EphB4 activation by ephrin B2 significantly inhibited the expression of IL-1␤, IL-6, matrix metalloproteinase 1 (MMP-1), MMP-9, MMP-13, and RANKL, but not MMP-2 and osteoprotegerin. EphB4 receptor activation significantly inhibited the phosphatidylinositol 3-kinase/Akt pathway.Conclusion. This study is the first to provide evidence that EphB4 receptor activation by ephrin B2 in OA subchondral bone could affect abnormal metabolism in this tissue by inhibiting resorption factors and their activities. Ephrin B2 could be targeted as a specific therapeutic approach in the development of a diseasemodifying OA drug.Subchondral bone is made up of a specialized connective tissue formed by a mineralized matrix containing the specific type I collagen, proteoglycans, and several growth factors and cytokines, as well as bonespecific cell types (osteoblasts, osteocytes, and osteoclasts) (1,2). Osteoblast and osteoclast activities, either alone or in combination, contribute to the bone remodeling process, and any disturbance in the activities of these 2 cells is responsible for the development of altered bone metabolism.The ephrin B molecules (ephrin B1, ephrin B2, and ephrin B3) bind in a specific manner to their EphB

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Section: Discussionmentioning

confidence: 99%

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Tat¹,

Pelletier²,

Amiable³

et al. 2008

Arthritis & Rheumatism

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“…For Eph-ephrin heterophilic repulsion, two different mechanisms have been described. One involves the induction of a metalloprotease that cleaves the receptor complex from the cell surface, and the other involves internalization of the entire complex into one of the two opposing membranes [18,19]. Dscam1 homophilic repulsion likely proceeds through similar mechanisms.…”

Section: Box 1 Homophilic Repulsionmentioning

confidence: 99%

Dscam-mediated repulsion controls tiling and self-avoidance

Millard

Zipursky

2008

Current Opinion in Neurobiology

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SummaryRecent studies have uncovered the molecular basis of self-avoidance and tiling, two fundamental principles required for the formation of neural circuits. Both of these wiring strategies are established through homophilic repulsion between Dscam proteins expressed on opposing cell surfaces. In Drosophila, Dscam1 mediates self-avoidance whereas Dscam2 mediates tiling. In contrast, phenotypes in the retina of the DSCAM mutant mouse indicate that DSCAM functions in both selfavoidance and tiling. These findings suggest that homophilic recognition molecules that have classically been defined as adhesive, may also function as repulsive cues, and that Dscam proteins specialize in this function.

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“…Interestingly, recent genetic studies in C. elegans support a positive role for the basement membrane component Nidogen in establishing the placement of longitudinally-projecting nerves at various positions along the dorsoventral body axis (Kim and Wadsworth, 2000). With regard to the specific mechanism of Ephephrin mediated guidance events in the spinal cord, it is interesting to consider the recent observation that regulated, metalloprotease-dependent cleavage of Aclass ephrins rapidly converts the initial binding of A-class receptors and ligands into a repulsive interaction (Hattori et al, 2000). Given the presence of conserved metalloprotease recognition motifs in B-class ephrins, it is tempting to speculate that the initial attractive interaction between EphB1 and B-class ephrins accounts for growth along the contralateral margin of the floor plate, and that the subsequent cleavage and repulsive guidance events account for growth away from this structure into the dorsal spinal cord.…”

Section: Vertebrate Spinal Cordmentioning

confidence: 99%

Axon guidance at the midline choice point

Kaprielian

Runko

Imondi

2001

Developmental Dynamics

145

108

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The central nervous system (CNS) of higher organisms is bilaterally-symmetric. The transfer of information between the two sides of the nervous system occurs through commissures formed by neurons that project axons across the midline to the contralateral side of the CNS. Interestingly, these axons cross the midline only once. Other neurons extend axons that never cross the midline; they project exclusively on their own (ipsilateral) side of the CNS. Thus, the midline is an important choice point for several classes of pathfinding axons. Recent studies demonstrate that specialized midline cells play critical roles in regulating the guidance of both crossing and non-crossing axons at the ventral midline of the developing vertebrate spinal cord and the Drosophila ventral nerve cord. For example, these cells secrete attractive cues that guide commissural axons over long distances to the midline of the CNS. Furthermore, shortrange interactions between guidance cues present on the surfaces of midline cells, and their receptors expressed on the surfaces of pathfinding axons, allow commissural axons to cross the midline only once and prevent ipsilaterally-projecting axons from entering the midline. Remarkably, the molecular composition of commissural axon surfaces is dynamically-altered as they cross the midline. Consequently, commissural axons become responsive to repulsive midline guidance cues that they had previously ignored on the ipsilateral side of the midline. Concomitantly, commissural axons lose responsiveness to attractive guidance cues that had initially attracted them to the midline. Thus, these exquisitely regulated guidance systems prevent commissural axons from lingering within the confines of the midline and allow them to pioneer an appropriate pathway on the contralateral side of the CNS. Many aspects of midline guidance are controlled by mechanistically and evolutionarily-conserved ligand-receptor systems. Strikingly, recent studies demonstrate that these receptors are modular; the ectodomains determine ligand recognition and the cytoplasmic domains specify the response of an axon to a given guidance cue. Despite rapid and dramatic progress in elucidating the molecular mechanisms that control midline guidance, many questions remain.

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Regulated Cleavage of a Contact-Mediated Axon Repellent

Cited by 490 publications

References 32 publications

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Dscam-mediated repulsion controls tiling and self-avoidance

Axon guidance at the midline choice point

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