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Published on: December 18, 2019
Mechanism of shortened bones in mucopolysaccharidosis VII
Jason A Metcalf1, Yanming Zhang, Matthew J Hilton
1Department of Medicine, Washington University School of Medicine, Campus Box 8125, 660 South Euclid Avenue, Saint Louis, MO 63110, USA. jametcal@wustl.edu
Abstract:
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.
Insights
Mucopolysaccharidosis VII (MPS VII) causes shortened bones by accumulating chondroitin-4-sulfate (C4S) in growth plates. This GAG accumulation reduces chondrocyte proliferation via decreased leukemia inhibitory factor (LIF) signaling, impacting bone growth.
Area of Science:
- Biochemistry
- Genetics
- Skeletal Biology
Background:
- Mucopolysaccharidosis VII (MPS VII) is a genetic disorder characterized by beta-glucuronidase deficiency.
- This deficiency leads to the accumulation of glycosaminoglycans (GAGs) in tissues, impacting cellular function and skeletal development.
- The precise mechanisms by which GAG accumulation causes shortened long bones in MPS VII remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying bone shortening in MPS VII.
- To identify the specific GAGs involved and their impact on chondrocyte proliferation and signaling pathways in the growth plate.
- To determine the role of fibroblast growth factor receptor 3 (FGFR3) and STAT3 signaling in MPS VII-related skeletal defects.
Main Methods:
- Analysis of GAG accumulation in growth plates of MPS VII mice.
- Assessment of chondrocyte number and proliferation rates in MPS VII growth plates.
- Evaluation of FGFR3 signaling, STAT3 phosphorylation, and expression of leukemia inhibitory factor (LIF) and related cytokines.
- Genetic manipulation of FGFR3 and LIF pathways in MPS VII mouse models.
Main Results:
- MPS VII mice exhibit massive accumulation of chondroitin-4-sulfate (C4S) in their growth plates, with reduced chondrocyte numbers and proliferation.
- FGFR3 deficiency did not prevent bone shortening in MPS VII mice, indicating FGFR3 is not essential for this defect.
- Reduced tyrosine phosphorylation of STAT3, decreased expression of LIF and related cytokines, and impaired JAK/TYK kinase activity were observed in MPS VII growth plates.
- Loss-of-function mutations in LIF or its receptor also resulted in shortened bones.
Conclusions:
- Accumulation of C4S in MPS VII growth plates disrupts chondrocyte proliferation.
- This disruption is mediated by reduced LIF expression and subsequent decreased STAT3 tyrosine phosphorylation, not FGFR3 overactivation.
- The LIF-STAT3 signaling pathway is critical for normal chondrocyte proliferation and longitudinal bone growth, and its impairment contributes to the skeletal phenotype in MPS VII.
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