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Gender-Specific Differences in the Skeletal Response to Continuous PTH in Mice Lacking the IGF1 Receptor in Mature
Muriel Babey1, Yongmei Wang1, Takuo Kubota1
1Endocrine Research Unit, University of California, San Francisco, CA, USA.
Abstract:
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 parathyroid hormone (cPTH). Igf1r was deleted from male and female FVN/B mice by breeding with mice expressing cre recombinase under control of the osteocalcin promoter ((0CN) Igfr1(-/-) ). Littermates lacking the cre recombinase served as controls. PTH, 60 μg/kg/d, was administered continuously by Alzet minipumps for 4 weeks. Blood was obtained for indices of calcium metabolism. The femurs were examined by micro-computed 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 (ALP(+) ), mineralization, and osteoblast-induced osteoclastogenesis. Whereas cPTH led to a reduction in trabecular bone volume/tissue volume (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 (0CN) Igfr1(-/-) mice of both sexes, no further reduction after cPTH was found 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 (0CN) Igfr1(-/-) male mice showed a partial response. ALP(+) and mineralized colony formation were higher in BMSC from control males than from control females. These markers were increased by cPTH in both sexes, but BMSC from male (0CN) Igfr1(-/-) also were increased by cPTH, unlike those from female (0CN) Igfr1(-/-) . cPTH stimulated receptor activator of NF-κB ligand (RANKL) and decreased osteoprotegerin and alkaline phosphatase expression more in control female bone than in 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 sexes. 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 in the male mouse, which may underlie the sex differences in the response to cPTH.
Insights
Continuous parathyroid hormone (cPTH) is catabolic in female mice, but not males. Insulin-like growth factor 1 receptor (IGF1R) signaling is crucial for cPTH
Area of Science:
- Endocrinology
- Bone Biology
- Skeletal Physiology
Background:
- Continuous parathyroid hormone (cPTH) administration affects bone metabolism.
- Sex differences in skeletal responses to hormones are well-documented.
- The role of Insulin-like Growth Factor 1 Receptor (IGF1R) in mediating these effects is not fully understood.
Purpose of the Study:
- To investigate whether IGF1R in mature osteoblasts and osteocytes is essential for the catabolic actions of cPTH.
- To determine the role of IGF1R in sex-specific responses to cPTH treatment.
Main Methods:
- Conditional deletion of Igf1r in osteoblasts/osteocytes using the osteocalcin promoter (OCN)-cre mice.
- Administration of cPTH (60 μg/kg/d) via minipumps for 4 weeks in male and female mice.
- Analysis of bone structure (micro-CT), bone formation rate (histomorphometry), gene expression (qPCR), and bone marrow stromal cell (BMSC) function.
Main Results:
- cPTH reduced bone mass in control females but not males.
- Igf1r deletion abolished cPTH-induced bone loss in females and partially in males.
- cPTH-stimulated bone formation markers and osteoclastogenesis were blocked by Igf1r deletion in females, with partial effects in males.
- Sex differences in cPTH-induced changes in RANKL/osteoprotegerin ratios were observed and modulated by Igf1r deletion.
Conclusions:
- Continuous PTH exhibits catabolic effects predominantly in female mice.
- IGF1R signaling is critical for mediating the catabolic actions of cPTH, particularly in females.
- These findings highlight sex-specific roles of IGF1R in skeletal responses to PTH therapy.
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