Phospholipase Cγ2 Mediates RANKL-stimulated Lymph Node Organogenesis and Osteoclastogenesis*
- Yabing Chen‡,
- Xiaohong Wang§,
- Lie Di¶,
- Guoping Fu¶,
- Yuhong Chen¶,
- Li Bai¶,
- Jianzhong Liu‡,
- Xu Feng‡,
- Jay M. McDonald‡∥,
- Sue Michalek**,
- Yinghong He¶,
- Mei Yu¶,
- Yang-Xin Fu‡‡,
- Renren Wen¶,
- Hui Wu§1 and
- Demin Wang¶2
- Departments of ‡Pathology, §Pediatric Dentistry, and **Microbiology, University of Alabama at Birmingham and ∥Veterans Affairs Medical Center, Birmingham, Alabama 35294, ‡‡Department of Pathology, the University of Chicago, Chicago, Illinois 60637, and ¶Blood Research Institute, the BloodCenter of Wisconsin, Milwaukee, Wisconsin 53226
- 1 To whom correspondence may be addressed. Fax: 205-975-6251; E-mail: hwu{at}uab.edu.
- 2 To whom correspondence may be addressed: Blood Research Institute, 8727 Watertown Plank Rd., Milwaukee, WI 53226. Fax: 414-937-3838; E-mail: demin.wang{at}bcw.edu.
Abstract
Phospholipase Cγ2 (PLCγ2) is an important signaling effector of multiple receptors in the immune system. Here we show that PLCγ2-deficient mice displayed impaired lymph node organogenesis but normal splenic structure and Peyer's patches. Receptor activator of NF-κB ligand (RANKL) is a tumor necrosis factor family cytokine and is essential for lymph node organogenesis. Importantly, PLCγ2 deficiency severely impaired RANKL signaling, resulting in marked reduction of RANKL-induced activation of MAPKs, p38 and JNK, but not ERK. The lack of PLCγ2 markedly diminished RANKL-induced activation of NF-κB, AP-1, and NFATc1. Moreover, PLCγ2 deficiency impaired RANKL-mediated biological function, leading to failure of the PLCγ2-deficient bone marrow macrophage precursors to differentiate into osteoclasts after RANKL stimulation. Re-introduction of PLCγ2 but not PLCγ1 restores RANKL-mediated osteoclast differentiation of PLCγ2-deficient bone marrow-derived monocyte/macrophage. Taken together, PLCγ2 is essential for RANK signaling, and its deficiency leads to defective lymph node organogenesis and osteoclast differentiation.
Footnotes
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↵3 The abbreviations used are: PKC, protein kinase C; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; PLC, phospholipase C; BMM, RANKL, receptor activator of NF-κB ligand; IRES, internal ribosome entry site; BMM, bone marrow (BM)-derived monocyte/macrophage; M-CSF, macrophage-colony stimulating factor; α-MEM, α-minimal essential medium; RT, reverse transcription; GFP, green fluorescent protein; LT, lymphotoxin; TRAP, tartrate resistant acid phosphatase; CTR, calcitonin receptor; CATH K, cathepsin K.
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↵* This work was supported, in whole or in part, by National Institutes of Health Grants AR055339 (to Yabing Chen), AR046031-080003 (to H. W.), AI52327 (to R. W.), and HL073284 and AI079087 (to D. W.). This work was also supported by a University of Alabama at Birmingham Center for Metabolic Bone Disease pilot project award (to Yabing Chen), a Scholar Award from the Leukemia and Lymphoma Society, and a grant from Advancing a Healthier Wisconsin endowment fund (to D. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received March 31, 2008.
- Revision received August 25, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
