期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：154-159
DOI：10.1073/pnas.1415213112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSkeletal anomalies are major health disparities resulting from dysregulation of bone homeostasis. Osteoclasts (OCs) are the principal bone resorbing and remodeling cells. The function of the OC relies on intricate signaling network dominated by NF-{kappa}B and MAP kinases. TGF-{beta} activated kinase-1 (TAK1) is the proximal activator of these pathways and ultimately is a key target for regulating cellular functions. The role of TAK1 in physiologic and pathologic cellular functions has been widely described. However, the precise mechanism by which TAK1 regulates these functions remains enigmatic. We discovered a novel mechanism by which TAK1 regulates expression of the sensory proteins NUMB/NUMB-like and subsequent activation of Notch-recombinant recognition sequence binding protein at J{kappa} site (RBPJ) pathway in myeloid cells. We provide genetic evidence that dysregulation of this pathway leads to osteopetrosis. The MAP kinase TGF{beta}-activated kinase (TAK1) plays a crucial role in physiologic and pathologic cellular functions including cell survival, differentiation, apoptosis, inflammation, and oncogenesis. However, the entire repertoire of its mechanism of action has not been elucidated. Here, we found that ablation of Tak1 in myeloid cells causes osteopetrosis in mice as a result of defective osteoclastogenesis. Mechanistically, Tak1 deficiency correlated with increased NUMB-like (NUMBL) levels. Accordingly, forced expression of Numbl abrogated osteoclastogenesis whereas its deletion partially restored osteoclastogenesis and reversed the phenotype of Tak1 deficiency. Tak1 deletion also down-regulated Notch intracellular domain (NICD), but increased the levels of the transcription factor recombinant recognition sequence binding protein at J{kappa} site (RBPJ), consistent with NUMBL regulating notch signaling through degradation of NICD, a modulator of RBPJ. Accordingly, deletion of Rbpj partially corrected osteopetrosis in Tak1-deficient mice. Furthermore, expression of active IKK2 in RBPJ/TAK1-deficient cells significantly restored osteoclastogenesis, indicating that activation of NF-{kappa}B is essential for complete rescue of the pathway. Thus, we propose that TAK1 regulates osteoclastogenesis by integrating activation of NF-{kappa}B and derepression of NOTCH/RBPJ in myeloid cells through inhibition of NUMBL.
