ECTS Abstracts (2015) 1 P188

Unfolded Protein Response Mediator, the IRE1[alpha]-XBP1 Pathway Promotes Osteoclast Differentiation

Takahide Tohmonda1,2, Masaki Yoda1,2, Morio Matsumoto1, Yoshiaki Toyama1 & Keisuke Horiuchi1,2

1Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan, 2Department of Anti-aging Orthopedic Research, School of Medicine, Keio University, Tokyo, Japan.

Background: Unfolded protein response (UPR) is a cellular stress response that is involved in the quality control of protein folding in the ER. We and others have recently shown that UPR is induced during bone formation and plays essential roles in promoting the differentiation and maturation of osteoblasts. In the present study, we aimed to clarify the potential roles of the IRE1α-XBP1 pathway, one of the major branch of UPR pathways, in the regulation of osteoclast differentiation.

Method and Results: We first performed in-vitro osteoclastogenesis experiments and found that the IRE1α-XBP1 pathway is temporarily activated during osteoclast differentiation. To explore the potential roles of the IRE1α-XBP1 pathway in osteoclastogenesis, we generated Ire1αMx1cre mice, in which the Ire1α locus can be excised in hematopoietic cells by injecting Polyinosinic-Polycytidylic acid. Excision was induced on day 10 after birth. The mice were sacrificed at 9-wk-old and subjected to uCT analysis and bone histomorphometry. The analyses showed a significant increase in bone volume in Ire1αMx1cre mice compared with wild type controls due to a decrease in osteoclast number and activity, indicating that IRE1α functions as a positive regulator of osteoclastogenesis. Consistently, bone marrow transplantation experiments showed that wild type recipient mice transplanted with IRE1α-deficient bone marrow cells exhibited higher bone volume than those transplanted with wild type bone marrow cells. Transcriptional analysis revealed that IRE1α-deficient osteoclast precursors are defective in inducing Nfatc1, the master regulator of osteoclast differentiation. Most importantly, we found that XBP1, a transcription factor that is activated by IRE1α, binds to the promoter of Nfatc1 gene and promotes its transcription. These observations indicate that the IRE1α-XBP1 pathway is a novel regulator of Nfatc1 transcription.

Conclusion: The present study shows that the UPR mediator, the IRE1α-XBP1 pathway regulates osteoclast differentiation by promoting the transcription of Nfatc1.

Disclosure: The authors declared no competing interests.

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