Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity
Abstract
This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by cross-breeding Igf1 floxed mice with Dmp1- Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes ( Igf1, Cox-2, c-fos) or osteogenic genes ( Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes ( Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40%) Sost expression in WT mice, but the loading not only did not reduce but upregulated (∼1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone β-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocyte-derived IGF-I plays a key determining role in bone mechanosensitivity.
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IGF-1 is produced under loading and might contribute to the mechanotransduction process.
“Since IGF-1 is produced under loading, it might contribute to the mechanotransduction process.214”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [214]
Increased insulin in MAFLD patients mimics the action of IGF1 through binding with IGF-1 receptors on osteocytes, further suppressing sclerostin production.
“This might be explained by “insulin-based”: increased insulin in MAFLD patients mimics the action of IGF1 through binding with IGF-1 receptors on osteocytes, further suppressing sclerostin production [140].”
From Emerging role of liver-bone axis in osteoporosis (2024) · cites this paper as [140]
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- Authors
- William Lau, K.-H., Baylink, D. J., Zhou, X.-D., Rodriguez, D., Bonewald, L. F., Li, Z., Ruffoni, D., Müller, R., Kesavan, C., & Sheng, M. H.-C.
- Affiliations
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University School of Medicine, Loma Linda, California;
- Loma Linda University Medical Center (US)
- University of Missouri–Kansas City (US)
- ETH Zurich (CH)
- Jerry L. Pettis Memorial VA Medical Center (US)
- Corresponding author
- Sheng, Matilda H.-C.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2013-07-15
- Volume
- 305
- Issue
- 2
- Pages
- E271-E281
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2150256970
- Cited by
- 94
- References
- 71
- Citations by year
- 2026: 3 · 2024: 7 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 12 · 2019: 5 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 16 · 2014: 8 · 2013: 3
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- ORBi (University of Liège) (submittedVersion)
- Funders
- Telemedicine and Advanced Technology Research Center
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- bone mechanosensitivity, Wnt signaling, canonical Wnt/β-catenin pathway, sclerostin, conditional knockout mice, four-point bending, cyclooxygenase-2, c-fos, osteocalcin, bone remodeling
- MeSH terms
- Animals, Biomechanical Phenomena, Bone and Bones, Bone Development, DNA, Genotype, Insulin-Like Growth Factor I, Mice, Transgenic, Osteocytes, Phosphatidylinositols, Tibia, Tomography, X-Ray Computed, Blotting, Western, Mice, Knockout, Mechanotransduction, Cellular, Extracellular Signal-Regulated MAP Kinases, beta Catenin, Mice, Wnt Signaling Pathway, Real-Time Polymerase Chain Reaction
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