| Autor: |
Miyagawa K; Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Tenshin H; Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Mulcrone PL; Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Delgado-Calle J; Department of Physiology & Cell Biology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA., Subler MA; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA., Windle JJ; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA., Chirgwin JM; Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA.; Research Service, Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA., Roodman GD; Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Kurihara N; Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA. |
| Abstrakt: |
We previously reported that measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) of patients with Paget disease (PD) or targeted to the OCL lineage in MVNP-transgenic mice (MVNP mice) increases IGF1 production in osteoclasts (OCL-IGF1) and leads to development of PD OCLs and pagetic bone lesions (PDLs). Conditional deletion of Igf1 in OCLs of MVNP mice fully blocked development of PDLs. In this study, we examined whether osteocytes (OCys), key regulators of normal bone remodeling, contribute to PD. OCys in PDLs of patients and of MVNP mice expressed less sclerostin, and had increased RANKL expression compared with OCys in bones from WT mice or normal patients. To test whether increased OCL-IGF1 is sufficient to induce PDLs and PD phenotypes, we generated TRAP-Igf1 (T-Igf1) transgenic mice to determine whether increased IGF1 expression in the absence of MVNP in OCLs is sufficient to induce PDLs and pagetic OCLs. We found that T-Igf1 mice at 16 months of age developed PD OCLs, PDLs, and OCys, with decreased sclerostin and increased RANKL, similar to MVNP mice. Thus, pagetic phenotypes could be induced by OCLs expressing increased IGF1. OCL-IGF1 in turn increased RANKL production in OCys to induce PD OCLs and PDLs. |
