Abstract
This study investigated the role of leptin receptor (Lepr) signaling in determining the bone mechanosensitivity and also evaluated whether differences in the Lepr signaling may contribute to the differential osteogenic response of the C57BL/6J (B6) and C3H/HeJ (C3H) pair of mouse strains to mechanical stimuli. This study shows that a loading strain of ∼2,500 με, which was insufficient to produce a bone formation response in B6 mice, significantly increased bone formation parameters in leptin-deficient ob(-)/ob(-) mice and that a loading strain of ∼3,000 με also yielded greater osteogenic responses in Lepr-deficient db(-)/db(-) mice than in wild-type littermates. In vitro, a 30-min steady shear stress increased [(3)H]thymidine incorporation and Erk1/2 phosphorylation in ob(-)/ob(-) osteoblasts and db(-)/db(-) osteoblasts much greater than those in corresponding wild-type osteoblasts. The siRNA-mediated suppression of Lepr expression in B6 osteoblasts enhanced (but in osteoblasts of C3H (the mouse strain with poor bone mechanosensitivity) restored) their anabolic responses to shear stress. The Lepr signaling (leptin-induced Jak2/Stat3 phosphorylation) in C3H osteoblasts was higher than that in B6 osteoblasts. One of the three single nucleotide polymorphisms in the C3H Lepr coding region yielded an I359V substitution near the leptin binding region, suggesting that genetic variation of Lepr may contribute to a dysfunctional Lepr signaling in C3H osteoblasts. In conclusion, Lepr signaling is a negative modulator of bone mechanosensitivity. Genetic variations in Lepr, which result in a dysfunctional Lepr signaling in C3H mice, may contribute to the poor osteogenic response to loading in C3H mice.
Highlights
This study investigated the role of leptin receptor (Lepr) signaling in determining the bone mechanosensitivity and evaluated whether differences in the Lepr signaling may contribute to the differential osteogenic response of the C57BL/6J (B6) and C3H/HeJ (C3H) pair of mouse strains to mechanical stimuli
We provide several lines of strong in vivo and in vitro evidence that Lepr or its signaling may function as a negative modulator of bone mechanosensitivity in mice
We showed that young adult female leptin-deficient obϪ/obϪ mice exhibited an enhanced bone formation response to loading compared with young adult female B6 control mice in vivo and that the in vitro anabolic response of osteoblasts of obϪ/obϪ mice to a steady fluid shear stress was consistently and significantly greater than that in osteoblasts derived from WT littermates or B6 control mice
Summary
This study investigated the role of leptin receptor (Lepr) signaling in determining the bone mechanosensitivity and evaluated whether differences in the Lepr signaling may contribute to the differential osteogenic response of the C57BL/6J (B6) and C3H/HeJ (C3H) pair of mouse strains to mechanical stimuli. Our previous studies, using primary osteoblasts of the C3H/B6 pair of mouse strains as an in vitro model system and fluid shear stress as an in vitro surrogate of mechanical strain [7], have disclosed two pieces of relevant information: 1) some of the genetic components determining bone mechanosensitivity in the C3H/B6 pair of mouse strains are intrinsic to osteoblasts, and 2) some of the “mechanosensitivity” genes contributing to the good and poor bone formation response in B6 and C3H mice, respectively, are upstream from four anabolic pathways (the Wnt (wingless- and Int-related protein), IGF-I, estrogen receptor (ER), and bone morphogenetic protein (BMP)/ transforming growth factor  (TGF) pathways). Because the chromosome 4 congenic locus is currently the only clearly defined chromosomal region that has demonstrated functional ability to modulate mechanosensitivity [8], we focused on candidate genes in this region
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