Osteoclast-derived IGF1 induces RANKL production in osteocytes and contributes to pagetic lesion formation

We previously reported that measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) of Paget's disease (PD) patients or targeted to the OCL lineage in transgenic (T-MVNP) mice increases IGF1 production in osteoclasts (OCL-IGF1) and develop PD-OCLs and pagetic bone lesions (PDLs). Conditional deletion of Igf1 in OCLs of T-MVNP mice fully blocked development of pagetic bone lesions (PDLs). In this manuscript we examined if osteocytes (OCys), key regulators of normal bone remodeling, contribute to PD. OCys in PDLs of patients and of T-MVNP mice expressed less sclerostin, and had increased RANKL expression compared to OCys in bones from WT mice or normal patients. To test if increased OCL-IGF1 is sufficient to induce PDLs and PD-phenotypes, we generated TRAP-Igf1 (T-Igf1) transgenic mice to characterize if increased IGF1 expression in the absence of MVNP in OCLs is sufficient to induce pagetic lesions 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 T-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-OCL and PDLs.