Neutral Sphingomyelinase 2 Deficiency Increases Hyaluronan Synthesis by Up-regulation of Hyaluronan Synthase 2 through Decreased Ceramide Production and Activation of Akt

Abstract

Background:Fibroblasts from the fro/fro mouse contained reduced amounts of ceramides and elevated amounts of hyaluronan (HA). Results: Increased HA secretion was associated with increased activity of the Akt pathway and enhanced expression of the HAS2 gene. Conclusion: HA synthesis is regulated by NSMase2/ceramide through ceramide-activated phosphatase PP2A and Akt signaling pathway. Significance: There is a direct link between sphingolipid and glycosaminoglycan metabolism.

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

“…Ceramides have been shown to reduce the level of Akt phosphorylation by activating protein phosphatase 2A (PP2A) (58). The phosphorylation level of PP2A in fro/fro fibroblasts is reduced (50). Taken together, in the maturing phase of chondrogenesis, BMP-2-induced nSMase2 is thought to release ceramide, which in turn activates PP2A to inactivate Akt and the subsequent chondrogenic molecular cascades (Fig.…”

“…Recent studies have reported a significant level of Has2 expression and hyaluronan synthesis in fro/ fro fibroblasts and that nSMase2 suppressed production of Has2 via inactivation of Akt (50). Taken together, if Smpd3/ nSMase2 also regulates expression of Has2 in chondrocytes, Has2 might be another target for the inhibitory action of Smpd3/nSMase2 on chondrocyte hypertrophic maturation.…”

“…It is produced in the plasma membrane by three hyaluronan synthases (Has1-3); Has2 is the crucial hyaluronan synthase involved in the endochondral ossification process (53). The Akt-rpS6 pathway is important in the expression of Has2 in MCF-7 breast cancer cells (64), although nSMase2 suppresses production of Has2 via inactivation of Akt in mouse dermal fibroblasts (50). In chondrocytes, Has2 expression was decreased by BMP-2 stimulation and was then recovered by silencing of Smpd3, demonstrating the importance of BMP-induced Smpd3/nSMase2 in the suppression of Has2 (Fig.…”

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

“…Ionizing radiation activates acid sphingomyelinase to produce ceramide which promotes the induction of apoptosis (Haimovitz-Friedman et al 1994), implicating a crucial role for this enzyme in mediating stress-induced apoptosis (Santana et al 1996). Conversely, a cell permeable and non-competitive inhibitor of neutral sphingomyelinase (GW4869) blocks ceramide synthesis to rescue cell death in numerous cell types, such as cochlear hair cells (Chi et al 2014), retinal pigment epithelial cells (Kucuksayan et al 2014) and fibroblasts (Qin et al 2012). At least four isoforms of neutral sphingomyelinase are expressed in mammalian cells, each with distinct biochemical properties, localizations and physiological roles [for a review, see (Airola and Hannun 2013)].…”

Systems Chemo‐Biology and Transcriptomic Meta‐Analysis Reveal the Molecular Roles of Bioactive Lipids in Cardiomyocyte Differentiation

“…Furthermore, PI3K/Akt activation is associated with increased hyaluronan synthesis via a mechanism that involves S1P stimulation ( Fig. 5D) (Qin et al 2012). …”