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

Kazuaki Miyagawa1, Hirofumi Tenshin1, Patrick L Mulcrone1

  • 1Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA.

JCI Insight
|June 20, 2023
PubMed

Insights

Increased insulin-like growth factor 1 (IGF1) in osteoclasts (OCLs) drives Paget

Area of Science:

  • Bone Biology
  • Endocrinology
  • Pathology

Background:

  • Paget's disease (PD) is a chronic bone disorder characterized by abnormal bone remodeling.
  • Previous work linked measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) to increased IGF1 production and PD development.
  • The role of osteocytes (OCys) in PD pathogenesis remained unclear.

Purpose of the Study:

  • To investigate the contribution of osteocytes (OCys) to Paget's disease (PD).
  • To determine if increased osteoclast-derived IGF1 (OCL-IGF1) is sufficient to induce PD phenotypes.

Main Methods:

  • Generated TRAP-Igf1 (T-Igf1) transgenic mice with increased IGF1 specifically in OCLs.
  • Analyzed osteocyte (OCy) sclerostin and RANKL expression in PD patients and mouse models.
  • Compared bone phenotypes in T-Igf1 mice with MVNP-transgenic mice and wild-type controls.

Main Results:

  • Osteocytes (OCys) in Paget's disease (PD) lesions showed decreased sclerostin and increased RANKL.
  • TRAP-Igf1 (T-Igf1) mice developed PD-like OCLs, bone lesions (PDLs), and osteocyte (OCy) changes.
  • These findings were similar to MVNP-transgenic mice, indicating OCL-IGF1 sufficiency.

Conclusions:

  • Increased osteoclast-derived IGF1 (OCL-IGF1) is sufficient to induce Paget's disease (PD) phenotypes.
  • OCL-IGF1 stimulates osteocyte (OCy) RANKL production, further promoting PD OCLs and PDLs.
  • This highlights a critical pathway in Paget's disease pathogenesis involving OCL-IGF1 and OCy-RANKL interactions.
Keywords:
Bone BiologyEndocrinologyOsteoclast/osteoblast biology

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