Gender specific differences in the skeletal response to continuous PTH in mice lacking the IGF1 receptor in mature osteoblasts


Muriel Babey (MD), Yongmei Wang (MD, PhD), Takuo Kubota (MD, PhD), Chak Fong (BS), Alicia Menendez (BS), Hashem Z. ElAlieh (BS) and Daniel D. Bikle (MD, PhD)


The primary goal of this study was to determine whether the IGF1R in mature osteoblasts and osteocytes was required for the catabolic actions of continuous PTH (cPTH). Igf1r was deleted from male and female FVN/B mice by breeding with mice expressing cre recombinase under control of the osteocalcin promoter (OCNIgfr1-/-). Littermates lacking the cre recombinase served as controls. PTH, 60μg/kg/day, was administered continuously by Alzet minipumps for 4 weeks. Blood was obtained for indices of calcium metabolism. The femurs were examined by microcomputed tomography for structure, immunohistochemistry for IGF1R expression, histomorphometry for bone formation rates (BFR), mRNA levels by qPCR, and bone marrow stromal cell cultures (BMSC) for alkaline phosphatase activity (AP+), mineralization, and osteoblast induced osteoclastogenesis. Whereas cPTH led to a reduction in trabecular BV/TV and cortical thickness in the control females, no change was found in the control males. Although trabecular BV/TV and cortical thickness were reduced in the OCNIgfr1-/- mice of both genders, no further reduction after cPTH was seen in the females, unlike the reduction in males. BFR was stimulated by cPTH in the controls, but blocked by Igf1r deletion in the females. The OCNIgfr1-/- male mice showed a partial response. AP+ and mineralized colony formation were higher in BMSC from control males than from control females. These markers were increased by cPTH in both genders, but BMSC from male OCNIgfr1-/- also were increased by cPTH, unlike those from female OCNIgfr1-/-. cPTH stimulated RANKL and decreased osteoprotegerin and alkaline phosphatase expression more in control female bone than control male bone. Deletion of Igf1r blocked these effects of cPTH in the female but not in the male. However, PTH stimulation of osteoblast driven osteoclastogenesis was blocked by deleting Igfr1 in both genders. We conclude that cPTH is catabolic in female but not male mice. Moreover, IGF1 signaling plays a greater role in the skeletal actions of cPTH in the female mouse than the male mouse, which may underlie the gender differences in the response to cPTH.

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