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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 7

Characteristics of OBs derived from long bones in WT, Igf1-cKO, MVNP, and MVNP/Igf1-cKO mice.

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Characteristics of OBs derived from long bones in WT, Igf1-cKO, MVNP, an...
All experiments used 12-month-old mice. (A) Image of ALP staining of OB outgrowing cells from bone cultured for 14 days. Cells were stained ALP and staining was quantitated by ImageJ software (NIH). Results are representative of 3 biological replicates. (B) Expression of OB differentiation maker proteins. The expression of EphB4, osterix, and Col-1A were assessed by Western blotting using anti-EphB4 antibody, anti-osterix antibody, and anti–Col-1A antibody as described in Methods. β-Actin was used as the loading control. The expression levels of EphB4, osterix, and Col-1A were quantitated by ImageJ software (NIH). The basal ratio for every protein/loading control for OBs from WT mice was set at 1.0. Results are representative of 3 biological replicates. (C) OB differentiation in cocultures with MVNP-OCLs. OCLs (5 × 104/well) derived from MVNP mice were scraped with a rubber policeman as described in Methods and were then replated and cultured with 50 ng/mL RANKL overnight. The OBs (1 × 105/well) described above were plated on top of the OCLs the next day, and the cells were cocultured for 72 hours. The expression levels of EphB4, osterix, and Col-1A was determined by Western blotting using these antibodies as above. β-Actin was used as the loading control. The expression levels of EphB4, osterix, and Col-1A were quantitated by ImageJ software. The basal ratio of every protein/loading control for OBs from WT mice was set at 1.0. Results are expressed as the mean ± SEM (representative of 3 biological replicated for 4 genotype mice). The data were analyzed using 1-way ANOVA with Tukey test. *P < 0.01 as compared with each indicated group. These results of experiment were similarly in 2 different biological replicates.

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