Leptin Receptor (Lepr) Is a Negative Modulator of Bone Mechanosensitivity and Genetic Variations in Lepr May Contribute to the Differential Osteogenic Response to Mechanical Stimulation in the C57BL/6J and C3H/HeJ Pair of Mouse Strains

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 ϳ2,500 ⑀, 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 ϳ3,000 ⑀ also yielded greater osteogenic responses in Genetics play a key role in determining the bone response to mechanical loading. Accordingly, C57BL/6J (B6) 2 inbred strain mice respond to in vivo loading with an increase in bone formation, but C3H/HeJ (C3H) inbred strain mice show no such response (1-4). Quantitative trait locus mapping studies of the C3H/B6 pair of mouse strains revealed that the bone mechanosensitivity is regulated by genes located in multiple quantitative trait loci on a number of chromosomes (5, 6) and that significant interactions exist among these quantitative trait loci (6). Thus, the genetic component contributing to the differential bone response to loading in the B6/C3H pair of mouse strains is complex and involves multiple genes. Studies of the identity of and interactions among these mechanosensitivity-modulating genes would yield not only information about mechanical stimulation of bone formation but also insights into the pathophysiology of various bone-wasting diseases (e.g. osteoporosis).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).Our search for candidate mechanosensitivity genes focused initially on mouse chromosome 4, because functional genetic studies indicated that at least one region in mouse chromosome 4 harbors mechanosensitivity-modulating genes. Specifically, the B6.C3H-4T congenic mouse strain, which is genetically identical to B6 except that it carried a segment of C3H chromosome 4 (between 40 and 80 centimorgans), was more respon-

Cross-sectional and longitudinal associations between circulating leptin and knee cartilage thickness in older adults

“…40 It is possible that obesity loads can be perceived by mechanoreceptors on chondrocyte surfaces triggering leptin signalling cascades, and thus induces more cartilage loss in the medial compartment. A study in mice illustrated that leptin receptor signalling is a negative modulator of bone mechanosensitivity, 41 which supports this assumption.…”

Uterine artery leptin receptors during the ovarian cycle and pregnancy regulate angiogenesis in ovine uterine artery endothelial cells†

“…However, supplementation with 17β-estradiol returned leptin gene expression and plasma leptin levels in the ovarietomized group [48]. It is also possible that elevations in local shear forces transduced by the UAendo [26,51] may help regulate the follicular rises in LEPR [52]. In addition, others have elucidated the role of leptin on the regulation of the LEPR, showing that 7 days of twice daily leptin administration reduced the LEPR mRNA expression at the level of the arcuate nucleus in obese (ob/ob) mice, which may be indicative of leptin regulation of its LEPR [53].…”

Role of Osteoglycin in the Linkage between Muscle and Bone

“…Leptin, a circulating hormone produced by adipose tissue, is a multifunctional hormone that plays important roles in body weight homeostasis, neuroendocrine function, fertility, immune function, and angiogenesis (31). A recent study showed that the role of leptin receptor signaling is as a negative modulator of bone mechanosensitivity (32). Moreover, leptin affects bone in a catabolic fashion through the central nervous system (33).…”