RHAMM Expression Influences Wound Repair and Tumor Progression

Cure Arthritis Naturally

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A. Alternative Use of CD44 and RHAMM in Tissue Response to Injury Processes

The importance of expression profiles of HABPs for cell response to HA was recently demonstrated by a study performed by Nedvetzky et al. (126). In this study, the role of CD44 in collagen II-induced arthritis was analyzed. Surprisingly, whereas CD44 — /— mice developed arthritis 25 days after a single injection of collagen II, a second injection was necessary to induce arthritis in wild-type (wt) mice. This difference was coupled to invading inflammatory cells because wt mice injected with spleenocytes from CD44 — /— mice respond like CD44 — /— mice and vice versa. The degree of arthritis in CD44 — /— and wt mice was reduced by injection of hyaluronidase, suggesting a HABP compensated for the function of CD44 in CD44 — /— mice. Collagen-induced arthritis induced the expression of a smaller, possibly activated, RHAMM isoform not seen in non-inflamed tissue, suggesting RHAMM might be the HABP compensating for the absence of CD44. Anti-RHAMM antibodies had a stronger blocking effect on in vitro migration of CD44 — /— spleenocytes through HA or fibronectin-coated boyden chamber filter than on migration of wt spleenocytes (126). Furthermore, injection of anti-RHAMM antibodies reduced the degree of arthritis in CD44 — /— mice, but not in wt mice, confirming that RHAMM was compensating for the absence of CD44. In the presence of CD44, RHAMM had only minor effects on the inflammation process, whereas in the absence of CD44, RHAMM not only compensated for the absence of CD44 but also enhanced the inflammation process resulting in a more complete joint destruction than that observed in wt joints. Although the precise mechanism is unknown, it can be speculated that in the absence of CD44, increased binding of HA to RHAMM and, therefore, a predominance of signaling via RHAMM occurred. These results

Cd168 Cell Surface

RHAMM

Figure 5 A model for proposed protein-protein and protein-HA interactions mediated by RHAMM. Cell surface RHAMM (CD168) binds to ECM constituents, HA, fibronectin and heparin. RHAMM is also proposed to associate directly or indirectly with other cell surface hyaladherins such as CD44, growth factor receptors such as the PDGFR and integrins such as the fibronectin receptor to create large signaling complexes that are at least in part also mediated by HA-protein interactions. Inside the cell, RHAMM is proposed to associate with kinases such as erk, linking them to the HA-mediated CD44/growth factor receptor/integrin complexes and to the cytoskeleton. Intracellular RHAMM forms are proposed to function primarily as adaptor proteins that regulate the activation, targeting and complexing of kinases with multiple signaling pathways.

RHAMM

Figure 5 A model for proposed protein-protein and protein-HA interactions mediated by RHAMM. Cell surface RHAMM (CD168) binds to ECM constituents, HA, fibronectin and heparin. RHAMM is also proposed to associate directly or indirectly with other cell surface hyaladherins such as CD44, growth factor receptors such as the PDGFR and integrins such as the fibronectin receptor to create large signaling complexes that are at least in part also mediated by HA-protein interactions. Inside the cell, RHAMM is proposed to associate with kinases such as erk, linking them to the HA-mediated CD44/growth factor receptor/integrin complexes and to the cytoskeleton. Intracellular RHAMM forms are proposed to function primarily as adaptor proteins that regulate the activation, targeting and complexing of kinases with multiple signaling pathways.

predict that the function of RHAMM might be suppressed by signaling via CD44 so that in the absence of CD44 uncontrolled inflammation occurs. From this and other studies, a paradigm is emerging whereupon CD44 and RHAMM are each required, but perform separate functions in a process, e.g., migration or tubule formation (85). In each other's absence, the functions associated with the one receptor are amplified. For example, antibody-blocking studies have established that during tubulogenesis associated with angiogenesis, RHAMM is required for migration of endothelial cells while CD44 is required for regulated proliferation.

We would predict, however, that interplay between RHAMM and CD44 regulates different aspects of processes. For example, CD44 is required for attachment to HA, and RHAMM is required for migration of these cells on HA, possibly mediating detachment (53,85,127,128). Our model would predict that if CD44 is required for attachment and RHAMM is required for detachment during the cycles of attachment/detachment associated with migration, RHAMM — /— cells would have predominantly CD44-mediated signaling resulting in flattened, well-attached cells that migrate poorly in response to HA. Whatever its specific role in processes such as migration or proliferation might be, RHAMM hyperexpression appears to be a hallmark of aggressive tumors, and we will now review in detail the association of RHAMM with wound repair and clinical tumor progression.

B. RHAMM and Wound Repair

During tissue homeostasis, expression and therefore signaling via RHAMM is suppressed whereas during tissue repair and remodeling following wounding RHAMM expression is upregulated (129). For example, using incisional and excisional wounds of fetal skin transplanted sub-cutaneously on immune-suppressed mice, Lovvorn et al. analyzed expression of the HABPs RHAMM and CD44 as well as HA content. Between 1 and 7 days after wounding, RHAMM and CD44 expression were upregulated at the edges of excisional, but not incisional wounds. This expression correlated with decreased HA concentration in excisional wounds compared to incisional wounds and is in agreement with a function of both CD44 and RHAMM in the uptake and subsequent degradation of HA. Because decreased concentration of high-molecular weight HA is thought to be required for fibroplasia and scar formation (39,130), Lovvorn et al. speculated that strategies limiting the expression of CD44 and RHAMM during wound repair might be useful for controlling scar formation. The upregulation of RHAMM during wound repair is not restricted to skin wounds. Capolicchio et al. (131) demonstrated an increase in RHAMM expression in a model of acute stretch injury of bladder where highest expression occurred 5-10 h after stretch injury. As in collagen-induced arthritis (126), the size of RHAMM isoforms changed, shifting from 55 to 120 kDa as a result of bladder stretch injury. The importance of RHAMM isoforms in wound repair was also demonstrated in vitro by analyzing the re-surfacing of scratch wounds in smooth muscle cell monolayers (92). Expression of a short (70 kDa) RHAMM isoform was upregulated only 1 h after injury and this correlated with the appearance of cell surface RHAMM at the wound edge. Cell migration was blocked by anti-RHAMM antibodies, demonstrating the importance of cell surface RHAMM (CD168) in directed cell migration (92). These results suggest RHAMM might play an important role in wound repair although the precise functions it regulates during this process have not yet been dissected.

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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