Hepatic Selenoprotein P Impairs Bone Formation via Osteoblastic IGF-1 Resistance

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ID: 329770
2026
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Abstract
Abstract Bone fragility is increasingly recognized as a complication of metabolic dysfunction, but endocrine mechanisms linking hepatic stress to impaired bone formation remain incompletely defined. We tested whether selenoprotein P, a hepatokine elevated in metabolic disease, suppresses osteoblast function and skeletal integrity. In mice fed a high-fat, high-sucrose diet, whole-body Selenop deficiency preserved trabecular bone mass, bone formation, bone stiffness, and cortical bone defect repair. Hepatocyte-specific Selenop deficiency also preserved trabecular bone mass. Histomorphometry showed that selenoprotein P primarily suppressed osteoblast activation without materially altering osteoclast indices. In calvaria-derived osteoblast cultures, purified human plasma-derived selenoprotein P inhibited IGF-1-induced phosphorylation of IGF-1 receptor, IRS-1, PI3K, PDK1, and Akt, reduced alkaline phosphatase activity, matrix mineralization, and osteogenic gene expression, and blunted receptor-proximal ROS generation. LRP1 was the predominant candidate receptor during osteogenic differentiation. Osteoblast cultures derived from Osx-Cre/+ Lrp1fl/fl mice showed reduced cell-associated human selenoprotein P, and the inhibitory effects of selenoprotein P on IGF-1 signaling and osteoblast maturation were absent in these cultures. In vivo, pharmacologic blockade of IGF-1 receptor signaling eliminated the skeletal protection conferred by Selenop deficiency, supporting a requirement for intact IGF-1 receptor signaling in this pathway. In a cross-sectional analysis of a general population cohort, serum selenoprotein P was not significantly associated with OSI across the full cohort, whereas exploratory analyses in the highest quintile suggested an inverse association between high circulating selenoprotein P and bone mass. Together, these findings identify hepatic selenoprotein P as a negative regulator of bone formation and define a hepato-osteogenic reductive stress axis that links metabolic stress to impaired skeletal integrity.
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Authors Kiyo‐aki Ishii, Hiroaki Takayama, Cynthia M. Galicia‐Medina, Hein Ko Oo, Guzel Gafiyatullina, Yoshiro Saito, Hiroyuki Tsuchiya, Hiroyuki Nakamura, Toshinari Takamura
Journal journal of bone and mineral research : the official journal of the american society for bone and mineral research
Year 2026
DOI
10.1093/jbmr/zjag139
URL
https://doi.org/10.1093/jbmr/zjag139
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