Measles virus nucleocapsid protein increases osteoblast differentiation in Paget’s disease
Jumpei Teramachi, … , Noriyoshi Kurihara, G. David Roodman
Jumpei Teramachi, … , Noriyoshi Kurihara, G. David Roodman
Published February 15, 2016
Citation Information: J Clin Invest. 2016;126(3):1012-1022. https://doi.org/10.1172/JCI82012.
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Measles virus nucleocapsid protein increases osteoblast differentiation in Paget’s disease

Abstract

Paget’s disease (PD) is characterized by focal and dramatic bone resorption and formation. Treatments that target osteoclasts (OCLs) block both pagetic bone resorption and formation; therefore, PD offers key insights into mechanisms that couple bone resorption and formation. Here, we evaluated OCLs from 3 patients with PD and determined that measles virus nucleocapsid protein (MVNP) was expressed in 70% of these OCLs. Moreover, transgenic mice with OCL-specific expression of MVNP (MVNP mice) developed PD-like bone lesions that required MVNP-dependent induction of high IL-6 expression levels in OCLs. In contrast, mice harboring a knockin of p62P394L (p62-KI mice), which is the most frequent PD-associated mutation, exhibited increased bone resorption, but not formation. Evaluation of OCLs from MVNP, p62-KI, and WT mice revealed increased IGF1 expression in MVNP-expressing OCLs that resulted from the high IL-6 expression levels in these cells. IL-6, in turn, increased the expression of coupling factors, specifically ephrinB2 on OCLs and EphB4 on osteoblasts (OBs). IGF1 enhanced ephrinB2 expression on OCLs and OB differentiation. Importantly, ephrinB2 and IGF1 levels were increased in MVNP-expressing OCLs from patients with PD and MVNP-transduced human OCLs compared with levels detected in controls. Further, anti-IGF1 or anti-IGF1R blocked Runx2 and osteocalcin upregulation in OBs cocultured with MVNP-expressing OCLs. These results suggest that in PD, MVNP upregulates IL-6 and IGF1 in OCLs to increase ephrinB2-EphB4 coupling and bone formation.

Authors

Jumpei Teramachi, Yuki Nagata, Khalid Mohammad, Yuji Inagaki, Yasuhisa Ohata, Theresa Guise, Laëtitia Michou, Jacques P. Brown, Jolene J. Windle, Noriyoshi Kurihara, G. David Roodman

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Figure 7

EphB4 and OCN expression in OBs cocultured with OCLs from WT or MVNP mice.

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EphB4 and OCN expression in OBs cocultured with OCLs from WT or MVNP mic...
(A) OCLs (2.5 × 104/well) derived from MVNP or WT OCL precursors were cultured overnight with 50 ng/ml RANKL. OBs (1 × 105/well), then plated on top of the OCLs and the cells cocultured for 72 hours. Lysates were tested for EphB4 and OCN expression. Data represent the mean ± SD for 3 biological replicates. *P < 0.01 compared with cocultures with WT OCLs using a 2-tailed, unpaired Student’s t test. (B) OCLs formed by WT or MVNP OCL precursors were prepared and cocultured with OBs for 72 hours as described in Figure 5A in the presence of anti-IGF1 (10 ng/ml), anti-IGF1R (0.5 μg/ml), or rabbit IgG (20 ng/ml), then assayed for OCN expression. The relative ratios of OCN/GAPDH were measured by ImageJ software. Data represent the mean ± SD for 3 biological replicates. *P < 0.01 compared with cultures with control IgG using a 2-tailed, unpaired Student’s t test. (C) OCLs formed by MVNP OCL precursors were cocultured with OBs for 72 hours (as described in Figure 5A) with anti–IL-6 (0.5 μg/ml), anti–IL-6R (0.5 μg/ml), or EphB4-Fc (5 μg/ml), then assayed for OCN expression. The relative ratios of OCN/GAPDH were measured by ImageJ software. Data are from a representative experiment of 2 biological replicates. (D) Model of OCL-OB coupling in PD: MVNP induces high IL-6 expression in OCLs, which increases expression of IGF1 and ephrinB2 in OCLs and EphB4 on OBs to enhance coupling. IGF1 enhances ephrinB2 expression on OCLs and increases Runx2 and OCN levels in OBs to increase bone formation.