Defective Osteoclastogenesis by IKKβ-null Precursors Is a Result of Receptor Activator of NF-κB Ligand (RANKL)-induced JNK-dependent Apoptosis and Impaired Differentiation

• Published in: The Journal of biological chemistry Vol. 283; no. 36; pp. 24546 - 24553
• Main Authors: Otero, Jesse E., Dai, Simon, Foglia, Domenica, Alhawagri, Muhammad, Vacher, Jean, Pasparakis, Manolis, Abu-Amer, Yousef
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.09.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Mechanisms of Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M800434200

It has been reported previously that inhibitory κB kinase (IKK) supports osteoclastogenesis through NF-κB-mediated prevention of apoptosis. This finding suggests that the ligand for receptor activator of NF-κB (RANKL), the master osteoclastogenic cytokine, induces apoptosis of osteoclast precursors (OCPs) in the absence of IKKβ/NF-κB competency. To validate this hypothesis, we sought to determine the pro-apoptotic signaling factors induced by RANKL in IKKβ-null osteoclast OCPs and to rescue osteoclast differentiation in the absence of IKKβ through their inhibition. To accomplish this, we generated mice that lack IKKβ in multiple hematopoietic lineages, including OCPs. We found that these mice possess both in vitro and in vivo defects in osteoclast generation, in concurrence with previous reports, and that this defect is a result of susceptibility to RANKL-mediated apoptosis as a result of gain-of-function of JNK activation. We demonstrate that differentiation of OCPs depends on IKKβ because reduced IKKβ mRNA expression correlates with impaired induction of osteoclast differentiation markers in response to RANKL stimulation. We further show that fine-tuned inhibition of JNK activation in these cells inhibits RANKL-induced apoptosis and restores the ability of IKKβ-null OCPs to become mature osteoclasts. Our data highlight the pro-osteoclastogenic and anti-apoptotic roles of IKKβ in OCPs and identify a pro-apoptotic mechanism activated within the RANK signalosome.