β-Arrestin 2 knockout prevents bone loss in response to continuous parathyroid hormone stimulation in male and female mice

ABSTRACT

Background

β-Arrestin 2 (β-arr2) binds activated parathyroid hormone (PTH) receptors stimulating internalization. PTH stimulates both anabolic and catabolic effect on bone depending on the way it is administered. Intermittent PTH stimulation increases trabecular bone formation in mice, but this is decreased in mice lacking β-arr 2, suggesting a role for β-arr 2 in the anabolic effects of PTH. The role of β-arr 2 in the catabolic effects of continuous PTH (cPTH) treatment is not known.

Objective

To assess the effects of cPTH administration on bone in mice lacking β-arr 2 compared to wild-type (WT).

Methods

Groups of male and female WT or β-arr2 knockout (KO) mice were administered either PTH or phosphate-buffered saline by osmotic pumps for 2 weeks. Following treatment, serum calcium and phosphate levels were measured, bone structure and mineral density were measured by microcomputed tomography, and bone cells measured by static and dynamic histomorphometry.

Results

β-arr2 KO had no effects on skeletal development in mice of either sex. PTH treatment caused hypercalcemia and hypophosphatemia and decreased trabecular and cortical bone only in male WT mice. β-arr2 KO in male mice completely abrogated the effects of PTH on bone, while in female β-arr2 KO mice, PTH treatment increased trabecular bone with no effects on cortical bone.

Conclusions

These results demonstrate a profound sex effect on skeletal responses to cPTH treatment, suggesting a protective effect of estrogen on bone loss. β-arr2 plays a role in restraining the anabolic effects of PTH in both male and female mice.

KEYWORDS:

• Hyperparathyroidism
• bone
• β-arrestin 2
• mouse models
• bone cells

Acknowledgments

The authors thank Dr Jean Martin Beaulieu for providing breeding pairs of β-arrestin 2-deficient mice.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Gilberto Li Feng: Experimental data collection and analysis, writing and review.

Marc D Grynpas: Project administration and resources, funding acquisition, data curation, review.

Jane Mitchell: Conceptualization, funding acquisition, data analysis and curation, writing and review.

Additional information

Funding

This work was supported by a grant to Jane Mitchell and Marc Grynpas from the Canadian Institutes of Health Research (PJT-148583).