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-β1, 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-β1 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-β1 receptors correlated positively with HAS2 expression and inversely with HYBID expression. On the other hand, TGF-β1 up-regulated 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-β1, basic FGF, EGF, and PDGF-BB enhance HA production in skin fibroblasts, TGF-β1 most efficiently contributes to production of high molecular weight HA by HAS up-regulation and HYBID down-regulation and suggests that inefficient down-regulation of HYBID by TGF-β1 in arthritic synovial fibroblasts may be linked to accumulation of depolymerized HA in synovial fluids in arthritis patients.
Highlights
Growth factors play key roles in extracellular matrix homeostasis and tissue remodeling under physiological and pathological conditions such as development and wound healing, which are commonly associated with increased HA production
Regulation of HA synthases (HASs)-mediated Synthesis and HYBID-mediated Depolymerization of HA by Growth Factors in Normal Human Skin Fibroblasts—When the effects of Transforming growth factor-1 (TGF-1), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and platelet-derived growth factor-BB (PDGF-BB) on HAS-mediated HA synthesis were examined in normal human embryonic skin fibroblast Detroit 551 cells, all these growth factors significantly enhanced the amounts of HA in the culture media (Fig. 1A) and HAS1 and HAS2 expression (Fig. 1, B and C), confirming the data of previous studies on skin fibroblasts from various origins [12,13,14,15]
Similar profiles of effects of TGF-1, bFGF, EGF, and PDGF-BB on the HA production and the mRNA expression of HAS and HYBID were observed with other human skin fibroblasts including NHDF-Ad (Fig. 3, A–D) and HS27 (Fig. 4, A–C), both cells produced a relatively lower amount of HA compared with Detroit 551 cells
Summary
Platelet-derived growth factor-BB (PDGF-BB) have been reported to up-regulate HAS genes expression, leading to HA overproduction in human skin fibroblasts [12,13,14,15]. TGF-1 and PDGF-BB have been well characterized to stimulate HA synthesis via distinctive mechanisms. In the present study we showed that TGF-1, bFGF, EGF, and PDGF-BB commonly up-regulate HA production by increasing HAS-mediated HA synthesis in skin fibroblasts. Polydisperse HA species containing intermediate-sized HA derived from growth factor-stimulated fibroblasts were dependent on the HYBID expression. To the best of our knowledge, the first evidence that sizes of newly produced HA under stimulation with growth factors are determined by the expression levels of HYBID, and down-regulation of the HYBID expression by TGF-1 is cell type-specific
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