Rapid hyaluronan uptake is associated with enhanced motility: implications for an intracellular mode of action

Collis, Lisa; Hall, Christine; Lange, L; Ziebell, Michael R.; Prestwich, R.; Turley, Eva A.

doi:10.1016/s0014-5793(98)01505-1

Cited by 105 publications

(80 citation statements)

References 46 publications

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“…It has also been suggested that both extracellular and intracellular HA have crucial roles in cell motility via interaction with cell surface receptors such as CD44, RHAMM and ICAM-1, and rapid uptake of exogenously added HA [31].…”

Section: Discussionmentioning

confidence: 99%

Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

Nishida

Knudson

et al. 2005

Experimental Cell Research

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Osteosarcoma is a common malignant bone tumor associated with childhood and adolescence. The results of numerous studies have suggested that hyaluronan plays an important role in regulating the aggressive behavior of various types of cancer cells. However, no studies have addressed hyaluronan with respect to osteosarcomas. In this investigation, the mRNA expression copy number of three mammalian hyaluronan synthases (HAS) was determined using competitive RT-PCR in the osteoblastic osteosarcoma cell line, MG-63. MG-63 are highly malignant osteosarcoma cells with an abundant hyaluronan-rich matrix. The results demonstrated that HAS-2 is the predominant HAS in MG-63. Accumulation of intracellular hyaluronan increased in association with the proliferative phase of these cells. The selective inhibition of HAS-2 mRNA in MG-63 cells by antisense phosphorothioate oligonucleotides resulted in reduced hyaluronan accumulation by these cells. As expected, the reduction in hyaluronan disrupted the assembly of cell-associated matrices. However, of most interest, coincident with the reduction in hyaluronan, there was a substantial decrease in cell proliferation, a decrease in cell motility and a decrease in cell invasiveness. These data suggest that hyaluronan synthesized by HAS-2 in MG-63 plays a crucial role in osteosarcoma cell proliferation, motility and invasion.

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Section: Discussionmentioning

confidence: 99%

Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

Nishida

Knudson

et al. 2005

Experimental Cell Research

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“…In this regard it is noteworthy that internalization into endothelial cells of a complex of heparan sulfate-proteoglycan and a heparin-binding protein targets the latter to mitochondria, consequently preventing apoptosis (40). Also, as mentioned above, exogenously added hyaluronan can be targeted to various intracellular compartments and results in increased cell motility (13). Interestingly, targeting of hyaluronan to the nucleus was blocked by (R/K)X 7 (R/K)-containing peptide in the latter study, suggesting the possible involvement of an IHABP.…”

Section: Discussionmentioning

confidence: 98%

“…Does intracellular hyaluronan, like extracellular hyaluronan, play an important role in regulating cellular behavior through interactions with IHABPs? Recently, it was reported that rapid uptake of Texas red-labeled hyaluronan and its subsequent accumulation in the cell processes, perinuclear area, and nucleus of transformed cells were associated with enhanced cell motility (13). Furthermore, careful examination confirmed the intracellular localization of endogenous hyaluronan as well as hyaluronan-binding sites and demonstrated dynamic changes in their pattern of distribution during proliferation of smooth muscle cells and fibroblasts (8).…”

Section: Hyaluronan Is a Ubiquitous Glycosaminoglycan (Gag)mentioning

confidence: 89%

“…Recent studies provide evidence that exogenous hyaluronan added to transformed 10T1/2 cells accumulates in multiple subcellular compartments and directly affects cell motility (13). Moreover, it has been shown that there is a dramatic increase in endogenous intracellular hyaluronan and redistribution from nucleolus to cytoplasm (mainly the perinuclear area) and interchromosomal regions during mitosis of mitogen-stimulated smooth muscle cells and fibroblasts (8).…”

Section: Discussionmentioning

confidence: 99%

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Molecular Characterization of a Novel Intracellular Hyaluronan-binding Protein

Huang

Grammatikakis

Yoneda

et al. 2000

Journal of Biological Chemistry

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Hyaluronan has well defined functions in extracellular matrices and at the surface of cells. However, several studies have now shown that significant pools of hyaluronan are also present intracellularly, but its function therein is unknown. One avenue of investigation that may assist in defining the function of intracellular hyaluronan is to identify intracellular hyaluronan-binding proteins. In previous studies we identified CDC37, a cell cycle regulatory protein, using a monoclonal antibody that recognizes a novel group of hyaluronan-binding proteins. In this study, we have identified a second hyaluronan-binding protein with this antibody and characterized its properties. This protein, which we have termed IHABP4, was also found to be an intracellular and a specific hyaluronan-binding protein, containing several hyaluronan-binding motifs: (R/K)X 7 (R/K) (where R/K denotes arginine or lysine and X denotes non-acidic amino acids). Furthermore, we have determined the gene organization of IHABP4 and cloned cDNAs for the chick, mouse, and human homologs. Comparison of the deduced chick, mouse, and human protein sequences showed that the hyaluronan-binding motifs, (R/K)X 7 (R/ K), in these sequences are conserved; both chick and mouse IHABP4 were shown directly to bind hyaluronan. Biochemical fractionation and immunofluorescent localization of epitope-tagged IHABP4 indicated that it is mainly present in the cytoplasm. These data support the possibility that intracellular hyaluronan and its binding proteins may play important roles in cell behavior.

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“…HA is involved in numerous important processes such as water homeostasis of tissues and joint lubrication [1], cartilage matrix stabilization [4,1], cell motility [5,6], morphogenesis and embryogenesis [7], and inflammation [8].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization and chondroprotective properties of a hyaluronan thioethyl ether derivative

2008

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Hyaluronan (HA), a non-sulfated glycosaminoglycan, is widely used in the clinic for viscosurgery, viscosupplementation, and treatment of osteoarthritis. Four decades of chemical modification of HA have generated derivatives in which the biophysical and biochemical properties, as well as the rates of enzymatic degradation in vivo have been manipulated and tailored for specific clinical needs. One earlier modification adds multiple thiol groups to HA through hydrazide linkages, leading to a readily crosslinkable material for adhesion prevention and wound healing. We now describe the synthesis and chemical characterization of a novel thioethyl ether derivative of HA, HA-sulfhydryl (HASH), with a minimal tether between the HA and the thiol group. Unlike earlier thiol-modified HA derivatives, HASH cannot be readily crosslinked to form a hydrogel using either oxidative or bivalent electrophilic conditions, thus offering a unique polymeric polythiol that remains soluble. Moreover, HASH showed no cytotoxicity towards primary human fibroblasts and reduced the apoptosis rates of primary chondrocytes exposed to hydrogen peroxide in vitro. These properties foreshadow the clinical potential of HASH to moderate inflammation and to act as a chondroprotective agent in vivo.

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Rapid hyaluronan uptake is associated with enhanced motility: implications for an intracellular mode of action

Cited by 105 publications

References 46 publications

Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

Molecular Characterization of a Novel Intracellular Hyaluronan-binding Protein

Synthesis, characterization and chondroprotective properties of a hyaluronan thioethyl ether derivative

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