Hedgehog Signaling in Mature Osteoblasts Regulates Bone Formation and Resorption by Controlling PTHrP and RANKL Expression

Mak, Kinglun Kingston; Bi, Yanming; Wan, Chao; Chuang, Pao-Tien; Clemens, Thomas; Young, Marian; Yang, Yingzi

doi:10.1016/j.devcel.2008.02.003

Cited by 202Bone Metabolism and DiseasesHedgehog Signaling Pathway StudiesBone health and osteoporosis research

Hedgehog Signaling in Mature Osteoblasts Regulates Bone Formation and Resorption by Controlling PTHrP and RANKL Expression

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Mak, Kinglun Kingston, Bi, Yanming, Wan, Chao, Chuang, Pao-Tien, Clemens, Thomas, Young, Marian, Yang, Yingzi·2008·Developmental Cell

DOI 10.1016/j.devcel.2008.02.003

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Abstract

Hedgehog (Hh) signaling is required for osteoblast differentiation from mesenchymal progenitors during endochondral bone formation. However, the role of Hh signaling in differentiated osteoblasts during adult bone homeostasis remains to be elucidated. We found that in the postnatal bone, Hh signaling activity was progressively reduced as osteoblasts mature. Upregulating Hh signaling selectively in mature osteoblasts led to increased bone formation and excessive bone resorption. As a consequence, these mutant mice showed severe osteopenia. Conversely, inhibition of Hh signaling in mature osteoblasts resulted in increased bone mass and protection from bone loss in older mice. Cellular and molecular studies showed that Hh signaling indirectly induced osteoclast differentiation by upregulating osteoblast expression of PTHrP, which promoted RANKL expression via PKA and its target transcription factor CREB. Our results demonstrate that Hh signaling in mature osteoblasts regulates both bone formation and resorption and that inhibition of Hh signaling reduces bone loss in aged mice.

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Hedgehog signaling is important for maintaining bone homeostasis in adult mice, with down-regulation of hedgehog signaling being protective against bone loss.
“In addition to the roles that IHH and SHH play in regulating bone development, hedgehog signaling is also important for maintaining bone homeostasis in adult mice, with down-regulation of hedgehog signaling being protective against bone loss (41, 42).”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [41]

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TNF‑α and RANKL promote osteoclastogenesis by upregulating RANK via the NF‑κB pathway
Luo, G., Li, F., Li, X., Wang, Z., & Zhang, B. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.8698 · Cited by 174 · see citing works

Authors: Mak, K. K., Bi, Y., Wan, C., Chuang, P.-T., Clemens, T., Young, M., & Yang, Y.
Affiliations: National Human Genome Research Institute (US)
National Institute of Dental and Craniofacial Research (US)
University of Alabama at Birmingham (US)
University of California, San Francisco (US)
Corresponding author: Yang, Yingzi
ORCID: Mak, Kinglun Kingston
Wan, Chao
Chuang, Pao-Tien
Young, Marian
Yang, Yingzi
Venue: Developmental Cell
Publisher: Elsevier BV
Published: 2008-05
Volume: 14
Issue: 5
Pages: 674-688
ISSN: 1534-5807 (ISSN-L)
DOI: 10.1016/j.devcel.2008.02.003
OpenAlex: W2092827845
Cited by: 202
References: 69
Citations by year: 2026: 6 · 2025: 8 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 11 · 2020: 18 · 2019: 8 · 2018: 13 · 2017: 10 · 2016: 14 · 2015: 14 · 2014: 11 · 2013: 14 · 2012: 10
FWCI: 5.49
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1939 d)
Locations: Developmental Cell (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Dental and Craniofacial Research (HL66600, HL67822, R01 AR049410)
National Institutes of Health
National Human Genome Research Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords: Hedgehog signaling, bone formation, bone resorption, parathyroid hormone-related protein, RANKL, osteoclastogenesis, pKa, CREB, bone homeostasis, osteopenia, aging, bone loss
MeSH terms: Animals, Bone Diseases, Metabolic, Bone Resorption, Cell Differentiation, Cell Survival, Gene Expression Regulation, Organ Size, Osteoblasts, Osteoclasts, Osteogenesis, Signal Transduction, Up-Regulation, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Parathyroid Hormone-Related Protein, Cell Proliferation, Mice, RANK Ligand, Hedgehog Proteins

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Hedgehog Signaling in Mature Osteoblasts Regulates Bone Formation and Resorption by Controlling PTHrP and RANKL Expression

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