Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism
Open accessAbstract
The broad expression of the insulin receptor suggests that the spectrum of insulin function has not been fully described. A cell type expressing this receptor is the osteoblast, a bone-specific cell favoring glucose metabolism through a hormone, osteocalcin, that becomes active once uncarboxylated. We show here that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis because it increases osteocalcin activity. To achieve this function insulin signaling in osteoblasts takes advantage of the regulation of osteoclastic bone resorption exerted by osteoblasts. Indeed, since bone resorption occurs at a pH acidic enough to decarboxylate proteins, osteoclasts determine the carboxylation status and function of osteocalcin. Accordingly, increasing or decreasing insulin signaling in osteoblasts promotes or hampers glucose metabolism in a bone resorption-dependent manner in mice and humans. Hence, in a feed-forward loop, insulin signals in osteoblasts activate a hormone, osteocalcin, that promotes glucose metabolism.
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OCN promoted the survival and function of pancreatic β-cells and increased insulin secretion, while insulin itself induced the release of OCN.
“OCN promoted the survival and function of pancreatic β-cells and increased insulin secretion [209], while insulin itself induced the release of OCN [210].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [210]
For citation [210], the Results section on osteocalcin carboxylation reports that insulin signaling in osteoblasts increases circulating active (undercarboxylated) osteocalcin, while total serum osteocalcin is unaffected. The Discussion explains that insulin signaling promotes bone resorption, which activates osteocalcin stored in the bone matrix. This supports increased availability of active OCN, but not the broader claim that insulin induces OCN release or increases total OCN secretion; the β-cell clause is attributed to [209], not this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIL-6 increases production of OCN by osteoblasts, which itself stimulates transient pancreatic secretion of the anorexic hormone insulin and triggers a positive feed-forward mechanism that results in increased OCN and thus more insulin.
“Moreover, IL-6 increases production of OCN by osteoblasts [71] (2c), which itself stimulates transient pancreatic secretion of the anorexic hormone insulin and triggers a positive feed-forward mechanism that results in increased OCN and thus more insulin [28,209,210] (2d).”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [210]
The Introduction (page unavailable) says undercarboxylated osteocalcin enhances insulin secretion by β-cells, and the Discussion (page unavailable) describes a positive feedback loop in which insulin signaling in osteoblasts increases osteocalcin activity. The copy does not establish that the insulin secretion is transient or describe insulin as an anorexic hormone. The IL-6 clause is attached to a different citation and is not judged here. (LLM, conf=0.84)
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IGF-1 regulation of key signaling pathways in bone
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Mediation of the Acute Stress Response by the Skeleton
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Glucocorticoids and bone: Local effects and systemic implications
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Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast
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Altered Bone Development and an Increase in FGF-23 Expression in Enpp1−/− Mice
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An overview of osteocalcin progress
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Endocrine role of bone in the regulation of energy metabolism
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Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism
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Endocrine Actions of Osteocalcin
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Bone Development: Overview of Bone Cells and Signaling
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- Authors
- Ferron, M., Wei, J., Yoshizawa, T., Del Fattore, A., DePinho, R. A., Teti, A., Ducy, P., & Karsenty, G.
- Affiliations
- Columbia University (US)
- Harvard University (US)
- University of L'Aquila (IT)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 142
- Issue
- 2
- Pages
- 296-308
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2910411
- OpenAlex
- W1971400919
- Cited by
- 1,123
- References
- 49
- Citations by year
- 2026: 30 · 2025: 47 · 2024: 50 · 2023: 41 · 2022: 43 · 2021: 62 · 2020: 84 · 2019: 65 · 2018: 73 · 2017: 89 · 2016: 75 · 2015: 100 · 2014: 76 · 2013: 84 · 2012: 87
- FWCI
- 37.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078042)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR045548)
- 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
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Keywords
- insulin signaling, osteoblasts, osteocalcin, bone remodeling, bone resorption, glucose homeostasis, energy metabolism, uncarboxylated osteocalcin, decarboxylation, osteoclasts, feed-forward loop
- MeSH terms
- Animals, Cells, Cultured, Energy Metabolism, Extracellular Matrix, Glucose, Humans, Insulin, Mice, Inbred C57BL, Osteoblasts, Signal Transduction, Osteocalcin, Bone Remodeling, Mice
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