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Cited by 47Growth Hormone and Insulin-like Growth FactorsBone Metabolism and DiseasesBone health and osteoporosis research

IGFBP-4 regulates adult skeletal growth in a sex-specific manner

Open access
Maridas, David E, DeMambro, Victoria E, Le, Phuong T, Nagano, Kenichi, Baron, Roland, Mohan, Subburaman, Rosen, Clifford J·2017·Journal of Endocrinology
DOI 10.1530/joe-16-0673PMC PMC5425953
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Abstract

Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro . Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4 −/− mice. Both male and female adult Igfbp4 −/− mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4 −/− females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4 −/− females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4 −/− females. In contrast, Igfbp4 −/− males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4 −/− males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4 −/− females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor.

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  • In igfbp-4-null female mice, cortical area fraction and cortical thickness at the femur midshaft are significantly reduced.

    “Significant reductions were also observed in cortical area fraction and cortical thickness at the femur midshaft.”

    From Pituitary Diseases and Bone (2018) · cites this paper as [155]

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Cited by

Sorted by citations

Authors
Maridas, D. E., DeMambro, V. E., Le, P. T., Nagano, K., Baron, R., Mohan, S., & Rosen, C. J.
Affiliations
  • Maine Medical Center (US)
  • Harvard University (US)
  • VA Loma Linda Healthcare System (US)
Corresponding author
Maridas, David E
ORCID
Venue
Journal of Endocrinology
Publisher
Bioscientifica
Published
2017-04
Volume
233
Issue
1
Pages
131-144
ISSN
  • 0022-0795 (ISSN-L)
  • 1479-6805
DOI
10.1530/joe-16-0673
PMC
PMC5425953
OpenAlex
W2586828410
Cited by
47
References
2
Citations by year
2026: 5 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 9 · 2017: 3
FWCI
5.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (P30GM103392, P30GM106391, P20GM103465)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR061164)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
IGFBP-4, insulin-like growth factor I, skeletal development, sex differences, bone mineral density, trabecular bone microarchitecture, sclerostin, osteoclastogenesis, bone formation, bone resorption, mesenchymal stem cells, osteoblasts, growth retardation
MeSH terms
Animals, Body Weight, Bone and Bones, Bone Development, Female, Male, Osteoclasts, Osteogenesis, Sex Characteristics, Mice, Knockout, Insulin-Like Growth Factor Binding Protein 4, Mice

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