TY - JOUR
T1 - Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo
AU - Miyagawa, Kazuaki
AU - Ohata, Yasuhisa
AU - Delgado-Calle, Jesus
AU - Teramachi, Jumpei
AU - Zhou, Hua
AU - Dempster, David D.
AU - Subler, Mark A.
AU - Windle, Jolene J.
AU - Chirgwin, John M.
AU - David Roodman, G.
AU - Kurihara, Noriyoshi
N1 - Funding Information:
This work was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH (R01-AR057308, to GDR); the National Cancer Institute (NCI), NIH (5P30CA016059, to JJW); and the US Department of Defense (W81XWH-12-1-0533, to NK). The mice for this research were provided by the VCU Transgenic/Knock-out Mouse Shared Resource. We thank Mohammad S. Khalid for his technical assistance of immunostaining.
Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/3/26
Y1 - 2020/3/26
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.133113
DO - 10.1172/jci.insight.133113
M3 - Article
C2 - 32078587
AN - SCOPUS:85082755399
SN - 2379-3708
VL - 5
JO - JCI insight
JF - JCI insight
IS - 6
M1 - e133113
ER -
