| First Author | Yu J | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 39 | Pages | 14203-14214 |
| PubMed ID | 31371452 | Mgi Jnum | J:282778 |
| Mgi Id | MGI:6383256 | Doi | 10.1074/jbc.RA119.009824 |
| Citation | Yu J, et al. (2019) The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor alpha. J Biol Chem 294(39):14203-14214 |
| abstractText | Hajdu Cheney syndrome (HCS) is characterized by craniofacial developmental abnormalities, acro-osteolysis, and osteoporosis and is associated with gain-of-NOTCH2 function mutations. A mouse model of HCS termed Notch2(tm1.1Ecan) harboring a mutation in exon 34 of Notch2 replicating the one found in HCS was used to determine whether the HCS mutation sensitizes the skeleton to the osteolytic effects of tumor necrosis factor alpha (TNFalpha). TNFalpha injected over the calvarial vault caused a greater increase in osteoclast number, osteoclast surface, and eroded surface in Notch2(tm1.1Ecan) mice compared with littermate WT controls. Accordingly, the effect of TNFalpha on osteoclastogenesis was greatly enhanced in cultures of bone marrow-derived macrophages (BMMs) from Notch2(tm1.1Ecan) mice when compared with the activity of TNFalpha in control cultures. TNFalpha induced the expression of Notch2 and Notch2 mutant mRNA by approximately 2-fold, possibly amplifying the NOTCH2-dependent induction of osteoclastogenesis. The effect of TNFalpha on osteoclastogenesis in Notch2(tm1.1Ecan) mutants depended on NOTCH2 activation because it was reversed by anti-NOTCH2 negative regulatory region and anti-jagged 1 antibodies. The inactivation of Hes1 prevented the TNFalpha effect on osteoclastogenesis in the context of the Notch2(tm1.1Ecan) mutation. In addition, the induction of Il1b, but not of Tnfa and Il6, mRNA by TNFalpha was greater in Notch2(tm1.1Ecan) BMMs than in control cells, possibly contributing to the actions of TNFalpha and NOTCH2 on osteoclastogenesis. In conclusion, the HCS mutation enhances TNFalpha-induced osteoclastogenesis and the inflammatory bone-resorptive response possibly explaining the acro-osteolysis observed in affected individuals. |
