Osteoclast-derived IGF1 induces RANKL production in osteocytes and contributes to pagetic lesion formation

Date
2023-07-24
Language
American English
Embargo Lift Date
Committee Members
Degree
Degree Year
Department
Grantor
Journal Title
Journal ISSN
Volume Title
Found At
The American Society for Clinical Investigation
Abstract

We previously reported that measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) of patients with Paget disease (PD) or targeted to the OCL lineage in MVNP-transgenic mice (MVNP mice) increases IGF1 production in osteoclasts (OCL-IGF1) and leads to development of PD OCLs and pagetic bone lesions (PDLs). Conditional deletion of Igf1 in OCLs of MVNP mice fully blocked development of PDLs. In this study, we examined whether osteocytes (OCys), key regulators of normal bone remodeling, contribute to PD. OCys in PDLs of patients and of MVNP mice expressed less sclerostin, and had increased RANKL expression compared with OCys in bones from WT mice or normal patients. To test whether increased OCL-IGF1 is sufficient to induce PDLs and PD phenotypes, we generated TRAP-Igf1 (T-Igf1) transgenic mice to determine whether increased IGF1 expression in the absence of MVNP in OCLs is sufficient to induce PDLs and pagetic OCLs. We found that T-Igf1 mice at 16 months of age developed PD OCLs, PDLs, and OCys, with decreased sclerostin and increased RANKL, similar to MVNP mice. Thus, pagetic phenotypes could be induced by OCLs expressing increased IGF1. OCL-IGF1 in turn increased RANKL production in OCys to induce PD OCLs and PDLs.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Miyagawa K, Tenshin H, Mulcrone PL, et al. Osteoclast-derived IGF1 induces RANKL production in osteocytes and contributes to pagetic lesion formation. JCI Insight. 2023;8(14):e159838. Published 2023 Jul 24. doi:10.1172/jci.insight.159838
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
JCI Insight
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Final published version
Full Text Available at
This item is under embargo {{howLong}}