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The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool.

Publication ,  Journal Article
Lawal, RA; Zhou, X; Batey, K; Hoffman, CM; Georger, MA; Radtke, F; Hilton, MJ; Xing, L; Frisch, BJ; Calvi, LM
Published in: J Bone Miner Res
June 2017

Notch signaling is critical for osteoblastic differentiation; however, the specific contribution of individual Notch ligands is unknown. Parathyroid hormone (PTH) regulates the Notch ligand Jagged1 in osteoblastic cells. To determine if osteolineage Jagged1 contributes to bone homeostasis, selective deletion of Jagged1 in osteolineage cells was achieved through the presence of Prx1 promoter-driven Cre recombinase expression, targeting mesenchymal stem cells (MSCs) and their progeny (PJag1 mice). PJag1 mice were viable and fertile and did not exhibit any skeletal abnormalities at 2 weeks of age. At 2 months of age, however, PJag1 mice had increased trabecular bone mass compared to wild-type (WT) littermates. Dynamic histomorphometric analysis showed increased osteoblastic activity and increased mineral apposition rate. Immunohistochemical analysis showed increased numbers of osteocalcin-positive mature osteoblasts in PJag1 mice. Also increased phenotypically defined Lin- /CD45- /CD31- /Sca1- /CD51+ osteoblastic cells were measured by flow cytometric analysis. Surprisingly, phenotypically defined Lin- /CD45- /CD31- /Sca1+ /CD51+ MSCs were unchanged in PJag1 mice as measured by flow cytometric analysis. However, functional osteoprogenitor (OP) cell frequency, measured by Von Kossa+ colony formation, was decreased, suggesting that osteolineage Jagged1 contributes to maintenance of the OP pool. The trabecular bone increases were not due to osteoclastic defects, because PJag1 mice had increased bone resorption. Because PTH increases osteoblastic Jagged1, we sought to understand if osteolineage Jagged1 modulates PTH-mediated bone anabolism. Intermittent PTH treatment resulted in a significantly greater increase in BV/TV in PJag1 hind limbs compared to WT. These findings demonstrate a critical role of osteolineage Jagged1 in bone homeostasis, where Jagged1 maintains the transition of OP to maturing osteoblasts. This novel role of Jagged1 not only identifies a regulatory loop maintaining appropriate populations of osteolineage cells, but also provides a novel approach to increase trabecular bone mass, particularly in combination with PTH, through modulation of Jagged1. © 2017 American Society for Bone and Mineral Research.

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Published In

J Bone Miner Res

DOI

EISSN

1523-4681

Publication Date

June 2017

Volume

32

Issue

6

Start / End Page

1320 / 1331

Location

United States

Related Subject Headings

  • X-Ray Microtomography
  • Stem Cells
  • Parathyroid Hormone
  • Osteogenesis
  • Osteoclasts
  • Osteoblasts
  • Models, Biological
  • Mice
  • Ligands
  • Jagged-1 Protein
 

Citation

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Lawal, R. A., Zhou, X., Batey, K., Hoffman, C. M., Georger, M. A., Radtke, F., … Calvi, L. M. (2017). The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool. J Bone Miner Res, 32(6), 1320–1331. https://doi.org/10.1002/jbmr.3106
Lawal, Rialnat A., Xichao Zhou, Kaylind Batey, Corey M. Hoffman, Mary A. Georger, Freddy Radtke, Matthew J. Hilton, Lianping Xing, Benjamin J. Frisch, and Laura M. Calvi. “The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool.J Bone Miner Res 32, no. 6 (June 2017): 1320–31. https://doi.org/10.1002/jbmr.3106.
Lawal RA, Zhou X, Batey K, Hoffman CM, Georger MA, Radtke F, et al. The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool. J Bone Miner Res. 2017 Jun;32(6):1320–31.
Lawal, Rialnat A., et al. “The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool.J Bone Miner Res, vol. 32, no. 6, June 2017, pp. 1320–31. Pubmed, doi:10.1002/jbmr.3106.
Lawal RA, Zhou X, Batey K, Hoffman CM, Georger MA, Radtke F, Hilton MJ, Xing L, Frisch BJ, Calvi LM. The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool. J Bone Miner Res. 2017 Jun;32(6):1320–1331.
Journal cover image

Published In

J Bone Miner Res

DOI

EISSN

1523-4681

Publication Date

June 2017

Volume

32

Issue

6

Start / End Page

1320 / 1331

Location

United States

Related Subject Headings

  • X-Ray Microtomography
  • Stem Cells
  • Parathyroid Hormone
  • Osteogenesis
  • Osteoclasts
  • Osteoblasts
  • Models, Biological
  • Mice
  • Ligands
  • Jagged-1 Protein