Osteoclast-derived IGF1 induces RANKL production in osteocytes and contributes to pagetic lesion formation
Kazuaki Miyagawa, Hirofumi Tenshin, Patrick L. Mulcrone, Jesus Delgado-Calle, Mark A. Subler, Jolene J. Windle, John M. Chirgwin, G. David Roodman, Noriyoshi Kurihara
Kazuaki Miyagawa, Hirofumi Tenshin, Patrick L. Mulcrone, Jesus Delgado-Calle, Mark A. Subler, Jolene J. Windle, John M. Chirgwin, G. David Roodman, Noriyoshi Kurihara
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Research Article Bone biology Endocrinology

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

Abstract

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.

Authors

Kazuaki Miyagawa, Hirofumi Tenshin, Patrick L. Mulcrone, Jesus Delgado-Calle, Mark A. Subler, Jolene J. Windle, John M. Chirgwin, G. David Roodman, Noriyoshi Kurihara

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Figure 1

Osteocyte morphology and sclerostin expression in WT, Igf1-cKO, MVNP, and MVNP/Igf1-cKO mice at 20 months of age and a PD and normal patient.

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Osteocyte morphology and sclerostin expression in WT, Igf1-cKO, MVNP, an...
(A) Sclerostin expression was determined by immunostaining as described in Methods. Arrows indicate canalicular tubes. Scale bars: 10 μm. (B) Ratio of sclerostin-positive OCys/total OCys per area (0.5 mm2). Results are expressed as the mean ± SEM from 3 male (blue) and female (red) mice of the 4 genotypes, analyzed using a 1-way ANOVA with Tukey’s test. (C) Serum sclerostin from mice in B measured by ELISA, expressed as mean ± SEM. (D) Canalicular length per 0.5 mm2 was measured using ImageJ software from the same sections shown in A and used for B. Results are expressed as the mean ± SEM from 1 average value per mouse (randomly selected 30 measurements from each mouse) of 3 male (blue) and female (red) mice of the 4 genotypes, analyzed using a 1-way ANOVA with Tukey’s test. The same mice were used in A–D. No statistical differences were found for results between males and females. (E) OCy phenotype and sclerostin expression in bone specimens from a patient with Paget disease (PD) and a normal donor. Transiliac crest bone biopsies were taken from a 58-year-old female with PD (center panel) and a 30-year-old healthy female control (left) and immunostained for sclerostin. The PD patient sample was also stained with control IgG (right). Scale bars: 10 μm.