RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy.
We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined.
Nedvetzki
Shlomo
S
The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Gonen
Erez
E
Assayag
Nathalie
N
Reich
Reuven
R
Williams
Richard O
RO
Thurmond
Robin L
RL
Huang
Jing-Feng
JF
Neudecker
Birgit A
BA
Wang
Fu-Sheng
FS
Wang
Fu-Shang
FS
Turley
Eva A
EA
Naor
David
D
D000818:Animals; D001168:Arthritis / Q000235:genetics; D015153:Blotting, Western; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D003433:Crosses, Genetic; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D006820:Hyaluronic Acid / Q000378:metabolism*; D007249:Inflammation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D013997:Time Factors; D019076:Transgenes; D015854:Up-Regulation
D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid; D003094:Collagen