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 1

Expression of ephrins and Ephs in WT, MVNP, p62-KI, and MVNP p62-KI mice.

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Expression of ephrins and Ephs in WT, MVNP, p62-KI, and MVNP p62-KI mice...
(A) Bone lysates from 8-month-old WT, MVNP, and p62-KI mice were assayed for ephrin and Eph protein expression. Results are representative of 3 biological replicates. (B) Bone lysates were obtained from 2- to 12-month-old mice and tested for ephrinB2 and EphB4 expression. Results are representative of 3 biological replicates. (C) Vertebral sections from 12-month-old mice were stained with anti-ephrinB2 and -EphB4 Abs as described in Methods. Results are representative of 3 to 7 biological replicates. OCLs from MVNP mice clearly stained for ephrinB2 compared with OCLs from p62-KI and WT mice, which showed minimal or negative staining. OBs from MVNP mice stained positively for EphB4 compared with OBs from WT and p62-KI mice. Scoring was based on staining intensity (positive or negative) and was performed by a blinded observer. Solid arrows point to OCLs, and arrowheads point to OBs. As previously reported, marrow cells (indicated by asterisks) also stained positively for EphB4 (33). Original magnification, ×400. (D) OCLs derived from cultures of CD11b+ cells from 8-month-old mice were assayed for ephrinB2 as described in Methods. Results are representative of 3 biological replicates. The basal ratio of every molecule/loading control is shown as 1.0 for WT samples in A, B, and D.