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Reduced chondrogenic matrix accumulation by 4-methylumbelliferone reveals the potential for selective targeting of UDP-glucose dehydrogenase

Reduced chondrogenic matrix accumulation by 4-methylumbelliferone reveals the potential for selective targeting of UDP-glucose dehydrogenase
Reduced chondrogenic matrix accumulation by 4-methylumbelliferone reveals the potential for selective targeting of UDP-glucose dehydrogenase
4-Methylumbelliferone (4-MU) is described as a selective inhibitor of hyaluronan (HA) production. It is thought that 4-MU depletes UDP-glucuronic acid (UDP-GlcUA) substrate for HA synthesis and also suppresses HA-synthase expression. The possibility that 4-MU exerts at least some of its actions via regulation of UDP-glucose dehydrogenase (UGDH), a key enzyme required for both HA and sulphated-glycosaminoglycan (sGAG) production, remains unexplored. We therefore examined the effects of 4-MU on basal and retroviral UGDH-driven HA and sGAG release in cells derived from chick articular cartilage and its influence upon UGDH protein and mRNA expression and HA and sGAG production. We found that 4-MU: i) suppressed UGDH mRNA and protein expression and chondrogenic matrix accumulation in chick limb bud micromass culture, ii) significantly reduced both HA and sGAG production and iii) more selectively reversed the potentiating effects of UGDH overexpression on the production of HA than sGAG. Understanding how GAG synthesis is controlled and the mechanism of 4-MU action may inform its future clinical success.
ugdh, 4-methylumbelliferone, hyaluronan, glycosaminoglycan, chondrogenesis, articular cartilage
0945-053X
163-168
Clarkin, C.E.
05cd2a88-1127-41aa-a29b-7ac323b4f3c9
Allen, S.
48aec8ad-441b-4cec-8bd8-c90296ed54b2
Wheeler-Jones, C.P.
a1d68996-0878-4b26-8b3f-7587c17b2773
Bastow, E.R.
94a14733-7057-47d8-b64b-fc3777e59426
Pitsillides, A.A.
0181cd36-d160-4955-8b4b-06bc96bba25d
Clarkin, C.E.
05cd2a88-1127-41aa-a29b-7ac323b4f3c9
Allen, S.
48aec8ad-441b-4cec-8bd8-c90296ed54b2
Wheeler-Jones, C.P.
a1d68996-0878-4b26-8b3f-7587c17b2773
Bastow, E.R.
94a14733-7057-47d8-b64b-fc3777e59426
Pitsillides, A.A.
0181cd36-d160-4955-8b4b-06bc96bba25d

Clarkin, C.E., Allen, S., Wheeler-Jones, C.P., Bastow, E.R. and Pitsillides, A.A. (2011) Reduced chondrogenic matrix accumulation by 4-methylumbelliferone reveals the potential for selective targeting of UDP-glucose dehydrogenase. Matrix Biology, 30 (3), 163-168. (doi:10.1016/j.matbio.2011.01.002). (PMID:21292001)

Record type: Article

Abstract

4-Methylumbelliferone (4-MU) is described as a selective inhibitor of hyaluronan (HA) production. It is thought that 4-MU depletes UDP-glucuronic acid (UDP-GlcUA) substrate for HA synthesis and also suppresses HA-synthase expression. The possibility that 4-MU exerts at least some of its actions via regulation of UDP-glucose dehydrogenase (UGDH), a key enzyme required for both HA and sulphated-glycosaminoglycan (sGAG) production, remains unexplored. We therefore examined the effects of 4-MU on basal and retroviral UGDH-driven HA and sGAG release in cells derived from chick articular cartilage and its influence upon UGDH protein and mRNA expression and HA and sGAG production. We found that 4-MU: i) suppressed UGDH mRNA and protein expression and chondrogenic matrix accumulation in chick limb bud micromass culture, ii) significantly reduced both HA and sGAG production and iii) more selectively reversed the potentiating effects of UGDH overexpression on the production of HA than sGAG. Understanding how GAG synthesis is controlled and the mechanism of 4-MU action may inform its future clinical success.

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e-pub ahead of print date: 1 February 2011
Published date: April 2011
Keywords: ugdh, 4-methylumbelliferone, hyaluronan, glycosaminoglycan, chondrogenesis, articular cartilage
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 204371
URI: http://eprints.soton.ac.uk/id/eprint/204371
ISSN: 0945-053X
PURE UUID: f5391e26-1024-40cb-9cd2-507d4bc4662f

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Date deposited: 28 Nov 2011 10:26
Last modified: 19 Jul 2019 22:53

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