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Mechanism of shortened bones in mucopolysaccharidosis VII.

Publication ,  Journal Article
Metcalf, JA; Zhang, Y; Hilton, MJ; Long, F; Ponder, KP
Published in: Mol Genet Metab
July 2009

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease in which deficiency in beta-glucuronidase results in glycosaminoglycan (GAG) accumulation in and around cells, causing shortened long bones through mechanisms that remain largely unclear. We demonstrate here that MPS VII mice accumulate massive amounts of the GAG chondroitin-4-sulfate (C4S) in their growth plates, the cartilaginous region near the ends of long bones responsible for growth. MPS VII mice also have only 60% of the normal number of chondrocytes in the growth plate and 55% of normal chondrocyte proliferation at 3weeks of age. We hypothesized that this reduction in proliferation was due to C4S-mediated overactivation of fibroblast growth factor receptor 3 (FGFR3). However, MPS VII mice that were FGFR3-deficient still had shortened bones, suggesting that FGFR3 is not required for the bone defect. Further study revealed that MPS VII growth plates had reduced tyrosine phosphorylation of STAT3, a pro-proliferative transcription factor. This was accompanied by a decrease in expression of leukemia inhibitory factor (LIF) and other interleukin 6 family cytokines, and a reduction in phosphorylated tyrosine kinase 2 (TYK2), Janus kinase 1 (JAK1), and JAK2, known activators of STAT3 phosphorylation. Intriguingly, loss of function mutations in LIF and its receptor leads to shortened bones. This suggests that accumulation of C4S in the growth plate leads to reduced expression of LIF and reduced STAT3 tyrosine phosphorylation, which results in reduced chondrocyte proliferation and ultimately shortened bones.

Duke Scholars

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Published In

Mol Genet Metab

DOI

EISSN

1096-7206

Publication Date

July 2009

Volume

97

Issue

3

Start / End Page

202 / 211

Location

United States

Related Subject Headings

  • Tibia
  • Signal Transduction
  • STAT3 Transcription Factor
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptor, Fibroblast Growth Factor, Type 3
  • Mucopolysaccharidosis VII
  • Mice, Inbred C57BL
  • Mice
  • In Situ Hybridization
  • Immunohistochemistry
 

Citation

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Metcalf, J. A., Zhang, Y., Hilton, M. J., Long, F., & Ponder, K. P. (2009). Mechanism of shortened bones in mucopolysaccharidosis VII. Mol Genet Metab, 97(3), 202–211. https://doi.org/10.1016/j.ymgme.2009.03.005
Metcalf, Jason A., Yanming Zhang, Matthew J. Hilton, Fanxin Long, and Katherine P. Ponder. “Mechanism of shortened bones in mucopolysaccharidosis VII.Mol Genet Metab 97, no. 3 (July 2009): 202–11. https://doi.org/10.1016/j.ymgme.2009.03.005.
Metcalf JA, Zhang Y, Hilton MJ, Long F, Ponder KP. Mechanism of shortened bones in mucopolysaccharidosis VII. Mol Genet Metab. 2009 Jul;97(3):202–11.
Metcalf, Jason A., et al. “Mechanism of shortened bones in mucopolysaccharidosis VII.Mol Genet Metab, vol. 97, no. 3, July 2009, pp. 202–11. Pubmed, doi:10.1016/j.ymgme.2009.03.005.
Metcalf JA, Zhang Y, Hilton MJ, Long F, Ponder KP. Mechanism of shortened bones in mucopolysaccharidosis VII. Mol Genet Metab. 2009 Jul;97(3):202–211.
Journal cover image

Published In

Mol Genet Metab

DOI

EISSN

1096-7206

Publication Date

July 2009

Volume

97

Issue

3

Start / End Page

202 / 211

Location

United States

Related Subject Headings

  • Tibia
  • Signal Transduction
  • STAT3 Transcription Factor
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptor, Fibroblast Growth Factor, Type 3
  • Mucopolysaccharidosis VII
  • Mice, Inbred C57BL
  • Mice
  • In Situ Hybridization
  • Immunohistochemistry