Heparan sulfate (HS) binds and functionally modulates a number of growth factors and morphogens. Genetic studies have revealed that HS is an integral component of many developmental signaling pathways in model animals. However, our understanding of the role of HS in the mammalian skeletal development and remodeling is still quite limited, and this is in spite of the fact that the tissue most affected by aberrant expression of HS is bone. For example, mutations of the gene encoding an enzyme essential for HS synthesis cause Hereditary Multiple Exostosis (HME), which is one of the most common genetic bone disorders in clinical orthopedics. In the adults, long-term heparin treatment for patients with thromboembolism and other vascular diseases often leads to a low bone mass condition resembling osteoporosis. The improved understanding of the mechanisms by which HS regulates growth factor signaling in the developing and adult skeletal system is critical for devising therapies for these diseases. Toward this long- term goal, we have employed conditional mouse genetics approaches to dissect the function of HS in skeletal development and physiology. Our evidence suggests that HS is essential for normal skeletal patterning and skeletal cell differentiation, being involved in key growth factor signaling pathways. Based on these and other preliminary data, we propose the following specific aims: 1. To dissect time-dependence and structural specificity of HS function in chondrogenesis. 2. To determine the mechanisms by which HS regulates BMP function during chondrogenesis. 3. To determine the role of HS in developmental bone formation and the regulation of bone mass. The proposed studies will generate new insights into the pathogenesis of HME, and may help define new drug targets for osteoporosis.
Heparan sulfate is essential for normal bone development and physiology, as illustrated by the existence of the genetic (hereditary multiple exostosis) and metabolic (heparin- induced osteoporosis) bone diseases that are directly linked to aberrant expression of heparan sulfate. This project will employ advanced mouse genetics to elucidate the molecular mechanisms by which heparan sulfate regulates bone cell function. The proposed studies will generate new insights into the pathogenesis of hereditary multiple exostosis, and may help define new drug targets for osteoporosis.
|Nozawa, Satoshi; Inubushi, Toshihiro; Irie, Fumitoshi et al. (2018) Osteoblastic heparan sulfate regulates osteoprotegerin function and bone mass. JCI Insight 3:|
|Inubushi, Toshihiro; Lemire, Isabelle; Irie, Fumitoshi et al. (2018) Palovarotene Inhibits Osteochondroma Formation in a Mouse Model of Multiple Hereditary Exostoses. J Bone Miner Res 33:658-666|
|Inubushi, Toshihiro; Nozawa, Satoshi; Matsumoto, Kazu et al. (2017) Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice. JCI Insight 2:|
|Saez, Borja; Ferraro, Francesca; Yusuf, Rushdia Z et al. (2014) Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood 124:2937-47|
|Huegel, Julianne; Mundy, Christina; Sgariglia, Federica et al. (2013) Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses. Dev Biol 377:100-12|
|Zak, Beverly M; Schuksz, Manuela; Koyama, Eiki et al. (2011) Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones. Bone 48:979-87|
|Mundy, Christina; Yasuda, Tadashi; Kinumatsu, Takashi et al. (2011) Synovial joint formation requires local Ext1 expression and heparan sulfate production in developing mouse embryo limbs and spine. Dev Biol 351:70-81|
|Ogata-Iwao, Minako; Inatani, Masaru; Iwao, Keiichiro et al. (2011) Heparan sulfate regulates intraretinal axon pathfinding by retinal ganglion cells. Invest Ophthalmol Vis Sci 52:6671-9|
|Matsumoto, Yoshihiro; Matsumoto, Kazu; Irie, Fumitoshi et al. (2010) Conditional ablation of the heparan sulfate-synthesizing enzyme Ext1 leads to dysregulation of bone morphogenic protein signaling and severe skeletal defects. J Biol Chem 285:19227-34|
|Matsumoto, Kazu; Irie, Fumitoshi; Mackem, Susan et al. (2010) A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Proc Natl Acad Sci U S A 107:10932-7|
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