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Osteoblastic heparan sulfate regulates osteoprotegerin function and bone mass
Satoshi Nozawa, … , Haruhiko Akiyama, Yu Yamaguchi
Satoshi Nozawa, … , Haruhiko Akiyama, Yu Yamaguchi
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e89624. https://doi.org/10.1172/jci.insight.89624.
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Research Article Bone biology

Osteoblastic heparan sulfate regulates osteoprotegerin function and bone mass

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Abstract

Bone remodeling is a highly coordinated process involving bone formation and resorption, and imbalance of this process results in osteoporosis. It has long been recognized that long-term heparin therapy often causes osteoporosis, suggesting that heparan sulfate (HS), the physiological counterpart of heparin, is somehow involved in bone mass regulation. The role of endogenous HS in adult bone, however, remains unclear. To determine the role of HS in bone homeostasis, we conditionally ablated Ext1, which encodes an essential glycosyltransferase for HS biosynthesis, in osteoblasts. Resultant conditional mutant mice developed severe osteopenia. Surprisingly, this phenotype is not due to impairment in bone formation but to enhancement of bone resorption. We show that osteoprotegerin (OPG), which is known as a soluble decoy receptor for RANKL, needs to be associated with the osteoblast surface in order to efficiently inhibit RANKL/RANK signaling and that HS serves as a cell surface binding partner for OPG in this context. We also show that bone mineral density is reduced in patients with multiple hereditary exostoses, a genetic bone disorder caused by heterozygous mutations of Ext1, suggesting that the mechanism revealed in this study may be relevant to low bone mass conditions in humans.

Authors

Satoshi Nozawa, Toshihiro Inubushi, Fumitoshi Irie, Iori Takigami, Kazu Matsumoto, Katsuji Shimizu, Haruhiko Akiyama, Yu Yamaguchi

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Figure 1

Osteoblast-targeted Ext1 ablation induces osteopenia.

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Osteoblast-targeted Ext1 ablation induces osteopenia.
(A) X-ray images o...
(A) X-ray images of the whole body, femur, and lumbar spine of a 12-week-old Oc-Cre;Ext1flox/flox mouse and a WT littermate. Whole-body images show that there are no gross skeletal abnormalities in Oc-Cre;Ext1flox/flox mice. Images of the femur and lumbar spine show that bones of Oc-Cre;Ext1flox/flox mice are more translucent that those of WT mice. (B) Von Kossa staining of lumbar vertebrae at 5 weeks, 3 months, and 6 months of age. (C) Histomorphometric analysis of bone mass in lumbar vertebrae at 5 weeks, 3 months, and 6 months of age. Data represent the mean ± SD of 5 mice per genotype. CKO, Oc-Cre;Ext1flox/flox; BV/TV, bone volume over tissue volume; Tb.N, trabecular number; Tb.Sp, trabecular separation. ***P < 0.001 by Student’s t test. Scale bar: 5 mm (A, whole body images); 1 mm (A, femur and lumber spine images); 1 mm (B).

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