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.
View: Text | PDF
Research Article Bone biology Article has an altmetric score of 2

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

×

Figure 4

Effect of IL-6 on ephrinB2 and EphB4 expression by OCLs and OBs.

Options: View larger image (or click on image) Download as PowerPoint
Effect of IL-6 on ephrinB2 and EphB4 expression by OCLs and OBs. (A) Bon...
(A) Bone extracts were analyzed for ephrinB2 and EphB4 proteins. (B) OCLs from CD11b+ marrow cells from 8-month-old WT, MVNP, MVNP Il6–/–, and Il6–/– mice were analyzed for ephrinB2 expression. (C) Cell lysates from OBs derived from WT, MVNP, MVNP Il6–/–, and Il6–/– mice were prepared as previously described (26) and analyzed for EphB4 expression. (D) CD11b+ cells from WT mice were cultured with M-CSF for 3 days, treated with IL-6 for 4 days, and analyzed for ephrinB2 expression. (E) Human OCL precursors transduced with EV or MVNP, as previously described (34), were cultured with RANKL, then treated with IL-6 (10 ng/ml) for 3 days and tested for ephrinB2 expression. (F) OBs prepared as described previously (26) were treated with IL-6 for 3 days and then analyzed for EphB4 expression. (G) OCLs from CD11b+ cells of WT and TRACP–IL-6 mice were analyzed for ephrinB2 expression. The basal ratio of every molecule/loading control for vehicle treatment of WT cells was set at 1 in A–G. All results are representative of 3 biological replicates.