The authors have no conflict of interest.
RANK Signaling Is Not Required for TNFα-Mediated Increase in CD11bhi Osteoclast Precursors but Is Essential for Mature Osteoclast Formation in TNFα-Mediated Inflammatory Arthritis†
Article first published online: 16 DEC 2003
Copyright © 2004 ASBMR
Journal of Bone and Mineral Research
Volume 19, Issue 2, pages 207–213, February 2004
How to Cite
Li, P., Schwarz, E. M., O'Keefe, R. J., Ma, L., Boyce, B. F. and Xing, L. (2004), RANK Signaling Is Not Required for TNFα-Mediated Increase in CD11bhi Osteoclast Precursors but Is Essential for Mature Osteoclast Formation in TNFα-Mediated Inflammatory Arthritis. J Bone Miner Res, 19: 207–213. doi: 10.1359/JBMR.0301233
- Issue published online: 2 DEC 2009
- Article first published online: 16 DEC 2003
- Manuscript Accepted: 24 SEP 2003
- Manuscript Revised: 10 SEP 2003
- Manuscript Received: 2 JUL 2003
- erosive arthritis
To address the controversy of whether TNFα can compensate for RANKL in osteoclastogenesis in vivo, we used a TNFα-induced animal model of inflammatory arthritis and blocked RANKL/RANK signaling. TNFα increased osteoclast precursors available for RANK-dependent osteoclastogenesis. RANK signaling is not required for the TNFα-stimulated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation.
Introduction: Although critical roles of TNFα in inflammatory arthritis and RANKL in bone resorption have been firmly established, a central controversy remains about the extent to which TNFα can compensate for RANKL during osteoclastogenesis and the stage at which RANK signaling is required for osteoclastogenesis. Here, we used the human TNFα transgenic mouse model (TNF-Tg) of erosive arthritis to determine if there are both RANK-dependent and -independent stages of osteoclastogenesis in TNFα-induced erosive arthritis.
Materials and Methods: Osteoclastogenesis and osteoclast precursor (OCP) frequency were analyzed using histology, fluorescence-activated cell sorting (FACS), and cell culture from (1) TNF-Tg mice treated with the RANKL antagonist, RANK:Fc, or (2) TNF-Tg × RANK−/− mice generated by crossing TNF-Tg mice with RANK−/− mice.
Results: Treatment of TNF-Tg mice, which have increased OCPs in their spleens, with RANK:Fc dramatically reduced osteoclast numbers on the surface of their arthritic joints and within their bones, but did not decrease CD11bhi OCP numbers in their spleens. Long-term RANK:Fc administration alleviated joint erosion. Furthermore, TNF-Tg × RANK−/− mice had severe osteopetrosis, no osteoclasts, and no joint erosion, but increased CD11bhi precursor numbers that failed to form mature osteoclasts in vitro.
Conclusion: RANK signaling is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis but not for the TNFα-induced increase in CD11bhi OCP that subsequently can differentiate into osteoclasts in inflamed joints.