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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 3

Histomorphometric analysis and bone formation rates in WT, Igf1-cKO, MVNP, and MVNP/Igf1-cKO mice.

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Histomorphometric analysis and bone formation rates in WT, Igf1-cKO, MVN...
(A) OCL morphology. OCLs in vertebra sections were stained with TRACP. Scale bars: 100 μm. (B) Bone morphometric analysis. Results are expressed as the mean ± SEM for WT (2 male, 4 female, 19 ± 2 months), Igf1-cKO (1 male, 4 female, 16 ± 3 months), MVNP with PDLs (1 male, 2 female, 21 ± 2 months), MVNP without PDL (3 male, 1 female, 21 ± 2 months), and MVNP/Igf1-cKO (3 male, 1 female, 25 ± 2 months). The data were analyzed using 1-way ANOVA with Tukey test. *P < 0.05 as compared with each indicated group. (C) Photomicrograph of new bone formation in vertebra (L5). Scale bars: 50 μM. (D) Mineralized perimeter, mineral apposition, and new bone formation rates. Data are expressed as the mean ± SEM WT (2 male, 4 female, 19 ± 2 months), Igf1-cKO (1 male, 4 female, 16 ± 3 months), MVNP with PDLs (1 male, 2 female, 21±2 months), MVNP without PDLs (3 male, 1 female, 21 ± 2 months old), and MVNP/Igf1-cKO (3 male, 1 female, 25 ± 2 months). The data were analyzed using 1-way ANOVA with Tukey test. *P < 0.05, **P < 0.01 as compared with each indicated group. Results in B and D are representative of 4–6 biological replicates. Mice of similar age were used in each experiment.

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