Regulation of Hyaluronan (HA) Metabolism Mediated by HYBID (Hyaluronan-binding Protein Involved in HA Depolymerization, KIAA1199) and HA Synthases in Growth Factor-stimulated Fibroblasts

Abstract

Regulation of hyaluronan (HA) synthesis and degradation is essential to maintenance of extracellular matrix homeostasis. We recently reported that HYBID (HYaluronan-Binding protein Involved in hyaluronan Depolymerization), also called KIAA1199, plays a key role in HA depolymerization in skin and arthritic synovial fibroblasts. However, regulation of HA metabolism mediated by HYBID and HA synthases (HASs) under stimulation with growth factors remains obscure. Here we report that TGF-␤1, basic FGF, EGF, and PDGF-BB commonly enhance total amount of HA in skin fibroblasts through up-regulation of HAS expression, but molecular size of newly produced HA is dependent on HYBID expression levels. Stimulation of HAS1/2 expression and suppression of HYBID expression by TGF-␤1 were abrogated by blockade of the MAPK and/or Smad signaling and the PI3K-Akt signaling, respectively. In normal human skin, expression of the TGF-␤1 receptors correlated positively with HAS2 expression and inversely with HYBID expression. On the other hand, TGF-␤1 upregulated HAS1/2 expression but exerted only a slight suppressive effect on HYBID expression in synovial fibroblasts from the patients with osteoarthritis or rheumatoid arthritis, resulting in the production of lower molecular weight HA compared with normal skin and synovial fibroblasts. These data demonstrate that although TGF-␤1, basic FGF, EGF, and PDGF-BB enhance HA production in skin fibroblasts, TGF-␤1 most efficiently contributes to production of high molecular weight HA by HAS up-regulation and HYBID down-regulation and suggests that inefficient downregulation of HYBID by TGF-␤1 in arthritic synovial fibroblasts may be linked to accumulation of depolymerized HA in synovial fluids in arthritis patients. Hyaluronan (HA)3 is a nonsulfated linear glycosaminoglycan composed of repeating disaccharide units of ␤-(1,3)-linked-Dglucuronic acid and ␤-(1,4)-linked-N-acetyl-D-glucosamine. HA is ubiquitously present as a major component in vertebrate connective tissues such as skin and synovial membrane and contributes to space filling, lubrication, and cell proliferation and migration (1). The turnover of HA in most tissues is extraordinarily rapid; the half-life of HA in the skin, which contains about half of all HA in the body, is 1-1.5 days (2). Thus, the tight control of HA synthesis and degradation is necessary for this turnover and seems to finely balance the amounts of high molecular mass HA (1,000 -10,000 kDa) within tissues (1, 2). On the other hand, an imbalance of synthesis and degradation causes the accumulation of HA with different molecular weights, which is commonly observed in diseases such as arthritis and cancers (3-5). Synovial fluids from patients with osteoarthritis (OA) or rheumatoid arthritis (RA) contain lower molecular mass HA (as low as 200 kDa) than that from normal subjects, leading to decreased synovial viscosity and increased inflammatory responses (6). HA is synthesized by HA synthases (Has1, Has2, and Has3) at the cell membrane, and the expression of Has enzyme...

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

“…The signal transduction pathways of PDGFRb (43), LPA 1 (44), and EGFR (45) have all previously been shown to involve the b-arrestins, suggesting that non-cell autonomous fibroblast invasion driven by these mediators will depend on b-arrestin1 and/or -2 as well. Similarly, PDGF-BB, FGF-2, and EGF have all been shown to induce HAS2 expression in human fibroblasts (46), as has LPA (47), suggesting that the HAS2-HA-CD44 pathway described for cell-autonomous invasion may also contribute to the non-cellautonomous fibroblast invasion that we describe here. We believe that further elaboration of the common molecular mechanisms that drive non-cell-autonomous fibroblast invasion in pulmonary fibrosis has the potential to provide a rich set of drug targets for the treatment of IPF and other fibrotic lung diseases.…”

Relationship of hyaluronan and HYBID (KIAA1199) expression with roughness parameters of photoaged skin in Caucasian women

“…HA is synthesized by HA synthases (HAS1, HAS2, and HAS3), among which HAS1 and HAS2 play a key role in HA production in human normal skin fibroblasts . We have recently reported that HYBID (HYaluronan Binding protein Involved in hyaluronan Depolymerization, KIAA1199) plays an essential role in HA degradation in human normal skin fibroblasts . Our recent study also demonstrated that in the Japanese women, HYBID is overexpressed in the photoexposed skin compared with the photoprotected skin and up‐regulation of HYBID is correlated with HA reduction in the papillary dermis of the photoexposed skin, showing positive correlations with skin wrinkling and sagging .…”

Reduction of hyaluronan and increased expression of HYBID (alias CEMIP and KIAA1199) correlate with clinical symptoms in photoaged skin

“…RNA extraction, cDNA synthesis and a TaqMan real‐time polymerase chain reaction assay were performed as described previously . The relative quantification values of HYBID , HAS1 , HAS2 , HYAL1 , HYAL2 , CD44 and TGFBR2 were normalized to endogenous 18S rRNA.…”