EGF upregulates, whereas TGF-beta downregulates, the hyaluronan synthases Has2 and Has3 in organotypic keratinocyte cultures: correlations with epidermal proliferation and differentiation.
Hyaluronan, a major extracellular matrix molecule in the vital cell layers of skin epidermis, has been suggested to support proliferation and migration of keratinocytes, during challenges like wounding and inflammation. An organotypic keratinocyte culture originated from continuous rat epidermal keratinocyte cell line was subjected to the proliferative and antiproliferative growth factors epidermal growth factor and transforming growth factor beta, respectively, to study their influence on hyaluronan synthesis and epidermal morphology. Epidermal growth factor induced a 4-fold increase of epidermal hyaluronan concentration. This was associated with upregulation of the hyaluronan synthases Has2 and Has3, and the hyaluronan receptor CD44. 5-Bromo-2'-deoxyuridine labeling, basal cell height, and the thickness of vital epidermis were increased, reflecting the hyperplastic effects of epidermal growth factor. The expression of keratin 10 and the maturation of filaggrin were inhibited, and epidermal permeability barrier became less efficient, indicating compromised terminal differentiation by epidermal growth factor. In contrast, transforming growth factor beta reduced the content of hyaluronan and the mRNA of Has2 and Has3. At the same time, transforming growth factor beta suppressed keratinocyte proliferation and epidermal thickness, but retained intact differentiation. The results suggest that epidermal hyaluronan synthesis, controlled by epidermal growth factor and transforming growth factor beta through changes in the expression of Has2 and Has3, correlates with epidermal proliferation, thickness, and differentiation.
Pasonen-Seppänen
Sanna
S
Department of Anatomy, University of Kuopio, Kuopio, Finland. Sanna.Pasonen@uku.fi
Karvinen
Susanna
S
Törrönen
Kari
K
Hyttinen
Juha M T
JM
Jokela
Tiina
T
Lammi
Mikko J
MJ
Tammi
Markku I
MI
Tammi
Raija
R
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D015536:Down-Regulation; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004817:Epidermis / Q000033:anatomy & histology / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D009924:Organ Culture Techniques; D010539:Permeability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation
D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491097:Has2 protein, rat; C491355:Has3 protein, rat; D000076002:Hyaluronan Synthases