TY - JOUR
T1 - Altered hematopoiesis in glypican-3-deficient mice results in decreased osteoclast differentiation and a delay in endochondral ossification
AU - Viviano, Beth L.
AU - Silverstein, Laura
AU - Pflederer, Camila
AU - Paine-Saunders, Stephenie
AU - Mills, Kathy
AU - Saunders, Scott
N1 - Funding Information:
This study was supported by NIH Grants DK56063 and HD39952 (S.S.) and March of Dimes Birth Defects Foundation Grant 1-FY-02196 (S.S.).
PY - 2005/6/1
Y1 - 2005/6/1
N2 - Loss of function mutations in the gene encoding the heparan sulfate proteoglycan Glypican-3 (GPC3) causes an X-linked disorder in humans known as Simpson-Golabi-Behmel Syndrome (SGBS). This disorder includes both pre- and postnatal overgrowth, a predisposition to certain childhood cancers, and a complex assortment of congenital defects including skeletal abnormalities. In this study, we have identified a previously unrecognized delay in endochondral ossification associated with the loss of Gpc3 function. Gpc3 knockout animals show a marked reduction in calcified trabecular bone, and an abnormal persistence of hypertrophic chondrocytes at embryonic day 16.5 (E16.5). These hypertrophic chondrocytes down-regulate Type X collagen mRNA expression and undergo apoptosis, suggesting a normal progression of hypertrophic chondrocyte cell fate. However, replacement of these cells by mineralized bone is delayed in association with a marked delay in the appearance of osteoclasts in the bone in vivo. This delay in vivo correlates with a significant reduction in the capacity to form osteoclasts from bone marrow macrophage precursors in vitro in response to M-CSF and RANKL, and with a reduction in the numbers of bone-marrow-derived cells expressing the markers CD11b and Gr-1. Together, these results indicate selective impairment in the development of the common hematopoietic lineage from which monocyte/macrophages and PMNs are derived. This is the first report of a requirement for heparan sulfate, and specifically Gpc3, in the lineage-specific differentiation of these cell types in vivo.
AB - Loss of function mutations in the gene encoding the heparan sulfate proteoglycan Glypican-3 (GPC3) causes an X-linked disorder in humans known as Simpson-Golabi-Behmel Syndrome (SGBS). This disorder includes both pre- and postnatal overgrowth, a predisposition to certain childhood cancers, and a complex assortment of congenital defects including skeletal abnormalities. In this study, we have identified a previously unrecognized delay in endochondral ossification associated with the loss of Gpc3 function. Gpc3 knockout animals show a marked reduction in calcified trabecular bone, and an abnormal persistence of hypertrophic chondrocytes at embryonic day 16.5 (E16.5). These hypertrophic chondrocytes down-regulate Type X collagen mRNA expression and undergo apoptosis, suggesting a normal progression of hypertrophic chondrocyte cell fate. However, replacement of these cells by mineralized bone is delayed in association with a marked delay in the appearance of osteoclasts in the bone in vivo. This delay in vivo correlates with a significant reduction in the capacity to form osteoclasts from bone marrow macrophage precursors in vitro in response to M-CSF and RANKL, and with a reduction in the numbers of bone-marrow-derived cells expressing the markers CD11b and Gr-1. Together, these results indicate selective impairment in the development of the common hematopoietic lineage from which monocyte/macrophages and PMNs are derived. This is the first report of a requirement for heparan sulfate, and specifically Gpc3, in the lineage-specific differentiation of these cell types in vivo.
KW - Endochondral ossification
KW - Glypican-3
KW - Hematopoiesis
KW - Heparan sulfate
KW - Osteoclasts
KW - Proteoglycans
UR - http://www.scopus.com/inward/record.url?scp=20344398904&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2005.03.003
DO - 10.1016/j.ydbio.2005.03.003
M3 - Article
C2 - 15936336
AN - SCOPUS:20344398904
SN - 0012-1606
VL - 282
SP - 152
EP - 162
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -