BoneKEy Reports | BoneKEy Watch

Mice with old bones suggest targeting NF-κB pathway to treat osteoporosis

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DOI:10.1038/bonekey.2013.37

In this study, Chen et al. investigated bone loss in mice lacking the gene encoding an important endonuclease that is involved in many DNA repair pathways, Excision Repair Cross Complementary group (ERCC) 1-XPF (Xeroderma Pigmentosum Group F). Ercc1-null mice (Ercc1−/−) developed progressive and severe osteoporosis and usually died within 4 weeks after birth. Hypomorphic mice (Ercc1−/Δ), which express ERCC1 and XPF at 5% of the level of wild-type mice, were therefore used to study the impact of ERCC1 in adult mice.

Bone formation in Ercc1−/Δ mice at 8 weeks was significantly reduced, and tibial bones showed an increase in staining for tartrate-resistant acid phosphatase, indicating that mice lacking normal ERCC1 expression showed enhanced bone resorption, which had become uncoupled from bone formation. These mice also showed abnormal cell differentiation in the bone marrow, resulting in significantly fewer osteoblastic progenitor cells. Osteoblasts and bone marrow stem cells both showed higher levels of DNA damage and senesced prematurely.

Ercc1−/Δ mice developed senescence-associated secretory phenotype, as proposed by Coppé et al. Their osteoblasts and osteoclasts also expressed activated NF-κB, but p65 haploinsufficiency in Ercc1−/Δ mice was able to rescue the osteoporotic phenotype.

Editor’s comment: The DNA damage that arises in mice lacking Ercc1 acts through an NF-κB-dependent mechanism to promote the development of severe osteoporosis; the pathway warrants exploration for drug targets relevant to human disease.

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