Abstract
The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.
Highlights
Hedgehog (Hh) signaling, well-known as a mitogen and morphogen during animal development, regulates adult tissue homeostasis and tumorigenesis [1,2,3,4]
We show that treatment with cyclopamine, GANT-58, or GANT-61 exerts a potent inhibitory effect on osteoclast formation in primary cultured bone marrow-derived macrophages (BMMs) stimulated by RANKL and suggest that Hh signaling is a requisite for osteoclastic differentiation
This study demonstrates that Hh inhibitors directly function as suppressors of osteoclast formation in in vitro cultures, indicating that Hh signaling in the macrophage/osteoclast lineage is
Summary
Hedgehog (Hh) signaling, well-known as a mitogen and morphogen during animal development, regulates adult tissue homeostasis and tumorigenesis [1,2,3,4]. Hh ligands in mammals are three proteins, Indian hedgehog (Ihh), Sonic hedgehog, and Desert hedgehog; they are expressed in different cells and tissues, their functions are not considered different [5,6]. Among GLI transcription factors GLI1, GLI2, and GLI3 that collectively mediate all Hh pathways, GLI2 and GLI3 are the initial mediators of Hh signal transduction, and GLI1, being a direct target gene, functions as a positive feedback to enhance GLI activity [8]. In the activated Hh-signaling pathway, GLI proteins are released from the inhibitory complex with the Suppressor of Fused (SuFu) [9,10]. Activated GLI forms are translocated to the nucleus, where they act as transcription factors and promote Hh target gene expression
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call