Lactate-sensitive response elements in genes involved in hyaluronan catabolism

Abstract

Tissue anoxia occurs early in wound healing. This is accompanied by production of lactate followed by increased hyaluronan and CD44 expression, suggesting a cause and effect relationship. Fibroblasts increased hyaluronan and CD44 when lactate was added to cultures. Increased deposition of hyaluronan correlates with greater turnover. In current models of hyaluronan catabolism, it is tethered to cell surfaces by CD44 in caveolin-enriched invaginations. It is cleaved to 20-kDa fragments by Hyal-2 on the plasma membrane, endocytosed, and delivered ultimately to lysosomes, and further digested by Hyal-1. Sequence analyses of promoter regions of genes for CD44, caveolin-1, Hyal-1, and -2 revealed multiple AP-1 and ets-1 response elements. To test their relevance, RNA from lactate-treated fibroblasts was analyzed by reverse transcriptase-polymerase chain reaction. Increased transcripts of c-fos, c-jun, c-ets, Hyal-1, -2, CD44, and caveolin-1 mRNAs were observed. We have thus identified lactate-activated genes important in the wound healing responses. Similar responses facilitating tumor progression, the Warburg effect, may share such mechanisms.