Please use this identifier to cite or link to this item: https://doi.org/10.1073/pnas.2006093117
Title: Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model
Authors: Quang, Tien Phan
Tan, Wen Hui 
Liu, Ranran
Sundaram, Sudha 
Buettner, Anita 
Kneitz, Susanne
Cheong, Benedict
Vyas, Himanshu
Mathavan, Sinnakaruppan
Schartl, Manfred
Winkler, Christoph
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
osteoporosis
bone homeostasis
osteoblast
osteoclast
chemokine
HEMATOPOIETIC STEM
RECEPTOR
LIGANDS
OSTEOBLASTS
CELLS
RANK
MINERALIZATION
MOBILIZATION
ACTIVATION
EXPRESSION
Issue Date: 11-Aug-2020
Publisher: NATL ACAD SCIENCES
Citation: Quang, Tien Phan, Tan, Wen Hui, Liu, Ranran, Sundaram, Sudha, Buettner, Anita, Kneitz, Susanne, Cheong, Benedict, Vyas, Himanshu, Mathavan, Sinnakaruppan, Schartl, Manfred, Winkler, Christoph (2020-08-11). Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 117 (32) : 19276-19286. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.2006093117
Abstract: Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka (Oryzias latipes) osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits mpeg1-positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in cxcr3.2 prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.
Source Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
URI: https://scholarbank.nus.edu.sg/handle/10635/217958
ISSN: 0027-8424
1091-6490
DOI: 10.1073/pnas.2006093117
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