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Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo
Kazuaki Miyagawa, … , G. David Roodman, Noriyoshi Kurihara
Kazuaki Miyagawa, … , G. David Roodman, Noriyoshi Kurihara
Published February 20, 2020
Citation Information: JCI Insight. 2020;5(6):e133113. https://doi.org/10.1172/jci.insight.133113.
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Research Article Bone biology Hematology

Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo

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Abstract

We report that transgenic mice expressing measles virus nucleocapsid protein (MVNP) in osteoclasts (OCLs) (MVNP mice) are Paget’s disease (PD) models and that OCLs from patients with PD and MVNP mice express high levels of OCL-derived IGF1 (OCL-IGF1). To determine OCL-IGF1’s role in PD and normal bone remodeling, we generated WT and MVNP mice with targeted deletion of Igf1 in OCLs (Igf1-cKO) and MVNP/Igf1-cKO mice, and we assessed OCL-IGF1’s effects on bone mass, bone formation rate, EphB2/EphB4 expression on OCLs and osteoblasts (OBs), and pagetic bone lesions (PDLs). A total of 40% of MVNP mice, but no MVNP/Igf1-cKO mice, had PDLs. Bone volume/tissue volume (BV/TV) was decreased by 60% in lumbar vertebrae and femurs of MVNP/Igf1-cKO versus MVNP mice with PDLs and by 45% versus all MVNP mice tested. Bone formation rates were decreased 50% in Igf1-cKO and MVNP/Igf1-cKO mice versus WT and MVNP mice. MVNP mice had increased EphB2 and EphB4 levels in OCLs/OBs versus WT and MVNP/Igf1-cKO, with none detectable in OCLs/OBs of Igf1-cKO mice. Mechanistically, IL-6 induced the increased OCL-IGF1 in MVNP mice. These results suggest that high OCL-IGF1 levels increase bone formation and PDLs in PD by enhancing EphB2/EphB4 expression in vivo and suggest OCL-IGF1 may contribute to normal bone remodeling.

Authors

Kazuaki Miyagawa, Yasuhisa Ohata, Jesus Delgado-Calle, Jumpei Teramachi, Hua Zhou, David D. Dempster, Mark A. Subler, Jolene J. Windle, John M. Chirgwin, G. David Roodman, Noriyoshi Kurihara

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Figure 6

Effects of loss of OCL-Igr1 on IL-6 and EphB2 expression in OCLs from WT, Igf1-cKO, MVNP, and MVNP/Igf1-cKO mice BM cultures.

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Effects of loss of OCL-Igr1 on IL-6 and EphB2 expression in OCLs from WT...
All experiments used BM mononuclear cells from 12-month-old mice. (A) IL-6 expression in OCLs formed in mouse BM cultures. IL-6 expression was assayed by Western blotting using anti–IL-6 antibody as describe in Methods. GAPDH was used as the loading control. Results are representative of 3 different experiments using 3 biological replicates for 4 genotype mice. (B) IL-6 levels in culture media. Purified OCLs (5 × 104 cells/mL) from BM cultures derived from the 4 genotypes were cultured with 50 ng/mL of RANKL in αMEM-10% FCS for 72 hours, and CM were used fro ELISA assays of IL-6 and IGF1. The data are shown as mean ± SEM (4 technical replicates from the 4 genotypes). The data were analyzed using a 1-way ANOVA with Tukey test. *P < 0.01 as compared with WT mice. This assay was performed on 2 biological replicates and were similarly. (C) IGF1 levels in conditioned media. IGF1 was measured by ELISA as described in Methods. The data are shown as mean ± SEM (3 biological replicates the from the 4 genotypes). The data were analyzed using 1-way ANOVA with Tukey test. *P < 0.01 as compared with WT mice. This assay was performed in 2 individual experiments. (D) EphB2 expression in OCLs formed in mouse BM cultures. EphB2 expression was assayed by Western blotting using an EphB2 antibody as described in Methods. The expression levels of EphB2 were quantitated by ImageJ software (NIH). The basal ratio for every protein/loading control from OCLs of WT mice was set at 1.0. Results shown are from 2 biological replicates from the 4 genotypes.

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