Hyaluronan promotes the chondrocyte response to BMP-7

Andhare, R.A.; Takahashi, N.; Knudson, W.; Knudson, C.B.

doi:10.1016/j.joca.2008.12.007

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Volume 17, Issue 7 , Pages 906-916, July 2009

Hyaluronan promotes the chondrocyte response to BMP-7

R.A. Andhare
- Department of Biochemistry, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Oral Biology, University of Illinois, Chicago, IL, USA
N. Takahashi
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
W. Knudson
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
C.B. Knudson
- Department of Biochemistry, Rush Medical College, Rush University Medical Center, Chicago, IL, USA
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
- Address correspondence and reprint requests to: C. B. Knudson, Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC, 27834, USA. Tel: 1-252-744-2851; Fax: 1-252-744-2850.

Received 22 February 2008; accepted 17 December 2008. published online 06 February 2009.

Summary

Objective

Chondrocytes exhibit specific responses to bone morphogenetic proteins (BMPs) and transforming growth factor-βs (TGF-βs). The bioactivity of these growth factors is regulated by numerous mediators. In our previous study, Smad1 was found to interact with the cytoplasmic domain of the hyaluronan receptor CD44. The purpose of this study was to determine the ability of hyaluronan in the pericellular matrix to modulate the chondrocyte responses to BMP-7 or TGF-β1.

Experimental design

Nuclear translocation of Smad1, Smad2 and Smad4 was studied in bovine articular chondrocytes in response to BMP-7 and TGF-β1. The effects of matrix disruption by hyaluronidase treatment and the initiation of matrix repair by the addition of hyaluronan on the nuclear translocation of Smad proteins, Smad1 phosphorylation and luciferase expression by a CD44 reporter construct in response to BMP-7 were also studied.

Results

The disruption of the hyaluronan-dependent pericellular matrix of chondrocytes resulted in diminished nuclear translocation of endogenous Smad1 and Smad4 in response to BMP-7; however, the nuclear translocation of Smad2 and Smad4 in these matrix-depleted chondrocytes in response to TGF-β1 was not diminished. Incubation of the matrix-depleted chondrocytes with exogenous hyaluronan restored Smad1 and Smad4 nuclear translocation and increased pCD44(499)-Luc luciferase expression in response to BMP-7. Both exogenous hyaluronan and matrix re-growth enhanced by hyaluronan synthase-2 (HAS2) transfection restored Smad1 phosphorylation.

Conclusions

Disruption of hyaluronan–CD44 interactions has little effect on the TGF-β responses; however, re-establishing CD44–hyaluronan ligation promotes a robust cellular response to BMP-7 by articular chondrocytes. Thus, changes in cell–hyaluronan interactions may serve as a mechanism to modulate cellular responsiveness to BMP-7.

Key words: Hyaluronan, Chondrocyte, CD44, BMP-7, TGF-β