Excessive phosphorylation of STATs leads to reduced chondrocyte proliferation and shortened bones in mucopolysaccharidosis VII mice

Abstract

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease in which a deficiency in β‐glucuronidase activity results in glycosaminoglycan (GAG) accumulation in the growth plate, causing shortened long bones in various species through unclear mechanisms. Immunohistochemistry and RNA in‐situ hybridization showed that MPS VII mouse growth plates accumulate massive amounts of the GAG chondroitin‐4‐sulfate (C4S), have 53% of normal chondrocyte proliferation, express reduced levels of hypertrophic chondrocyte genes, and exhibit excessive phosphorylation of STAT proteins. In contrast, MPS I mice have less GAG storage and their bones and growth plates are nearly normal. Phosphorylated STATs are thought to mediate bone shortening in achondroplasia, a disease in which STATs are excessively phosphorylated by overactivation of fibroblast growth factor receptor 3 (FGFR3). Therefore, it was postulated that accumulation of C4S overstimulates FGFR3 in MPS VII. However, MPS VII mice that are FGFR3 deficient had shortened bones, suggesting that FGFR3 is not required for the bone defect. We propose that MPS VII bone disease is caused by a chondrocyte proliferation defect that may be mediated by STATs phosphorylated by an alternative pathway. Funding provided by Howard Hughes Medical Institute, Ryan Foundation, Mucopolysaccharidosis Society, and NIH (DK066448 and DK54481).