β‐Arrestin2 Regulates the Differential Response of Cortical and Trabecular Bone to Intermittent PTH in Female Mice

Cytoplasmic arrestins regulate PTH signaling in vitro. We show that female β‐arrestin2 −/− mice have decreased bone mass and altered bone architecture. The effects of intermittent PTH administration on bone microarchitecture differed in β‐arrestin2 −/− and wildtype mice. These data indicate that arrestin‐mediated regulation of intracellular signaling contributes to the differential effects of PTH at endosteal and periosteal bone surfaces. Introduction: The effects of PTH differ at endosteal and periosteal surfaces, suggesting that PTH activity in these compartments may depend on some yet unidentified mechanism(s) of regulation. The action of PTH in bone is mediated primarily by intracellular cAMP, and the cytoplasmic molecule β‐arrestin2 plays a central role in this signaling regulation. Thus, we hypothesized that arrestins would modulate the effects of PTH on bone in vivo. Materials and Methods: We used pDXA, μCT, histomorphometry, and serum markers of bone turnover to assess the skeletal response to intermittent PTH (0, 20, 40, or 80 μg/kg/day) in adult female mice null for β‐arrestin2 (β‐arr2 −/− ) and wildtype (WT) littermates (7‐11/group). Results and Conclusions: β‐arr2 −/− mice had significantly lower total body BMD, trabecular bone volume fraction (BV/TV), and femoral cross‐sectional area compared with WT. In WT females, PTH increased total body BMD, trabecular bone parameters, and cortical thickness, with a trend toward decreased midfemoral medullary area. In β‐arr2 −/− mice, PTH not only improved total body BMD, trabecular bone architecture, and cortical thickness, but also dose‐dependently increased femoral cross‐sectional area and medullary area. Histomorphometry showed that PTH‐stimulated periosteal bone formation was 2‐fold higher in β‐arr2 −/− compared with WT. Osteocalcin levels were significantly lower in β‐arr2 −/− mice, but increased dose‐dependently with PTH in both β‐arr2 −/− and WT. In contrast, whereas the resorption marker TRACP5B increased dose‐dependently in WT, 20‐80 μg/kg/day of PTH was equipotent with regard to stimulation of TRACP5B in β‐arr2 −/− . In summary, β‐arrestin2 plays an important role in bone mass acquisition and remodeling. In estrogen‐replete female mice, the ability of intermittent PTH to stimulate periosteal bone apposition and endosteal resorption is inhibited by arrestins. We therefore infer that arrestin‐mediated regulation of intracellular signaling contributes to the differential effects of PTH on cancellous and cortical bone.