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 4

Detection of IGF1, EphB2, and EphB4 in bone sections of WT, Igf1-cKO, MVNP, and MVNP/Igf1-cKO mice.

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Detection of IGF1, EphB2, and EphB4 in bone sections of WT, Igf1-cKO, MV...
Femur sections from the 4 genotype mice were stained with anti-IGF1, anti-EphB2, and anti-EphB4 antibodies as described in Methods. OCLs from MVNP mice were clearly stained for IGF1 and EphB2 compared with OCLs from the other genotype mice, which showed minimal or negative staining. OBs from MVNP mice strongly stained positively for EphB4 compared with OBs from the other genotype mice. Determination of staining intensity (positive or negative) was performed by blinded observers. Arrows point to OCLs, and arrowheads point to OBs. Bones of MVNP mice stained with control IgG. Scale bars: 50 μm. Results are representative of WT (17 months), Igf1-cKO (21 months), MVNP-PDL (24 months), MVNP-No PDL (21 months), and MVNP/Igf1-cKO (23 months old mice). Results are representative of 3 biological replicates. Mice of similar age were used in each experiment.