NF- sub( Kappa )B p50 and p52 Expression Is Not Required for RANK-Expressing Osteoclast Progenitor Formation but Is Essential for RANK- and Cytokine-Mediated Osteoclastogenesis

• Published in: Journal of bone and mineral research 2002-07, Vol.17 (7), p.1200-1210
• Main Authors: Xing, L, Bushnell, T P, Carlson, L, Tai, Z, Tondravi, M, Siebenlist, U, Young, F, Boyce, B F
• Format: Article
• Language: English
• ISSN: 0884-0431

Expression of RANKL by stromal cells and of RANK and both NF- sub( Kappa )B p50 and p52 by osteoclast precursors is essential for osteoclast formation. To examine further the role of RANKL, RANK, and NF- sub( Kappa )B signaling in this process, we used NF- sub( Kappa )B p50 super(-/-); p52 super(-/-) double knockout (dKO) and wild-type (WT) mice. Osteoclasts formed in cocultures of WT osteoblasts with splenocytes from WT mice but not from dKO mice, a finding unchanged by addition of RANKL and macrophage colony-stimulating factor (M-CSF). NF- sub( Kappa )B dKO splenocytes formed more colony-forming unit granulocyte macrophage (CFU-GM) colonies than WT cells, but no osteoclasts were formed from dKO CFU-GM colonies. RANKL increased the number of CFU-GM colonies twofold in WT cultures but not in dKO cultures. Fluorescence-activated cell sorting (FACS) analysis of splenocytes from NF- sub( Kappa )B dKO mice revealed a two-to threefold increase in the percentage of CD11b (Mac-1) and RANK double-positive cells compared with WT controls. Treatment of NF- sub( Kappa )B dKO splenocytes with interleukin (IL)-1, TNF- sub( alpha ), M-CSF, GM-CSF, and IL-6 plus soluble IL-6 receptor did not rescue the osteoclast defect. No increase in apoptosis was observed in cells of the osteoclast lineage in NF- sub( Kappa )B dKO or p50 super(-/-); p52 super(+/-) (3/4KO) mice. Thus, NF- sub( Kappa )B p50 and p52 expression is not required for formation of RANK-expressing osteoclast progenitors but is essential for RANK-expressing osteoclast precursors to differentiate into TRAP super(+) osteoclasts in response to RANKL and other osteoclastogenic cytokines.