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

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 2

Bone structure and remodeling in WT, Igf1-cKO, MVNP, and MVNP/Igf1-cKO mice.

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Bone structure and remodeling in WT, Igf1-cKO, MVNP, and MVNP/Igf1-cKO m...
(A) Representative μCT images of fifth lumber vertebra. Scale bar: 1 mm. (B) Bone volume and structural parameters of trabecular bone in vertebrae. Results are expressed as the mean ± SEM for WT (3 male, 4 female, 19 ± 2 months), Igf1-cKO (2 male, 4 female, 16 ± 2 months), MVNP with PDLs (1 male, 2 female, 21 ± 2 months), MVNP without PDL (3 male, 3 female, 20 ± 1 months), and MVNP/Igf1-cKO (3 male, 3 female, 22 ± 2 months old). The data were analyzed using a 1-way ANOVA with Tukey test. *P < 0.05. **P < 0.01 as compared with each indicated group. The blue circles represent results from male mice; red circles represent results from female mice. (C) Representative μCT images of tibia (vertical section). Scale bar: 1 mm. (D) Cortical bone parameters. Results are shown the mean ± SEM for WT (3 male, 4 female, 19 ± 2 months), Igf1-cKO (2 male, 4 female, 16 ± 2 months), MVNP (4 male, 5 female, 21 ± 2 months), and MVNP/Igf1-cKO (3 male, 3 female, 22 ± 2 months) mice. The blue circles represent results from male mice; red circles represent results from female mice. Results in D were not significantly different. Results in B and D are representative of 6–9 biological replicates. Mice of similar age were used in each experiment. The μCT results of male versus female in WT, MVNP without PDLs, and MVNP/Igf1-cKO were not statistically different. Results of male versus female MVNP mice with PDLs and MVNP/Igf1-cKO could not be analyzed because the 1 male MVNP mouse with PDL and 2 male Igf1-cKO mice were insufficient for comparison.