Constitutive activation of the alternative NF-κB pathway disturbs endochondral ossification

Chihiro Nakatomi, Mitsushiro Nakatomi, Takuma Matsubara, Toshihisa Komori, Takahiro Doi-Inoue, Naozumi Ishimaru, Falk Weih, Tsutomu Iwamoto, Miho Matsuda, Shoichiro Kokabu, Eijiro Jimi

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5 Citations (Scopus)

Abstract

Endochondral ossification is important for skeletal development. Recent findings indicate that the p65 (RelA) subunit, a main subunit of the classical nuclear factor-κB (NF-κB) pathway, plays essential roles in chondrocyte differentiation. Although several groups have reported that the alternative NF-κB pathway also regulates bone homeostasis, the role of the alternative NF-κB pathway in chondrocyte development is still unclear. Here, we analyzed the in vivo function of the alternative pathway on endochondral ossification using p100-deficient (p100 −/− ) mice, which carry a homozygous deletion of the COOH-terminal ankyrin repeats of p100 but still express functional p52 protein. The alternative pathway was activated during the periarticular stage in wild-type mice. p100 −/− mice exhibited dwarfism, and histological analysis of the growth plate revealed abnormal arrangement of chondrocyte columns and a narrowed hypertrophic zone. Consistent with these observations, the expression of hypertrophic chondrocyte markers, type X collagen (ColX) or matrix metalloproteinase 13, but not early chondrogenic markers, such as Col II or aggrecan, was suppressed in p100 −/− mice. An in vivo BrdU tracing assay clearly demonstrated less proliferative activity in chondrocytes in p100 −/− mice. These defects were partly rescued when the RelB gene was deleted in p100 −/− mice. Taken together, the alternative NF-κB pathway may regulate chondrocyte proliferation and differentiation to maintain endochondral ossification.

Original languageEnglish
Pages (from-to)29-41
Number of pages13
JournalBone
Volume121
DOIs
Publication statusPublished - Apr 2019

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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    Nakatomi, C., Nakatomi, M., Matsubara, T., Komori, T., Doi-Inoue, T., Ishimaru, N., Weih, F., Iwamoto, T., Matsuda, M., Kokabu, S., & Jimi, E. (2019). Constitutive activation of the alternative NF-κB pathway disturbs endochondral ossification. Bone, 121, 29-41. https://doi.org/10.1016/j.bone.2019.01.002