Bouxsein Mary L, Pierroz Dominique D, Glatt Vaida, Goddard Deborah S, Cavat Fanny, Rizzoli Renée, Ferrari Serge L
Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
J Bone Miner Res. 2005 Apr;20(4):635-43. doi: 10.1359/JBMR.041204. Epub 2004 Dec 6.
Cytoplasmic arrestins regulate PTH signaling in vitro. We show that female beta-arrestin2(-/-) mice have decreased bone mass and altered bone architecture. The effects of intermittent PTH administration on bone microarchitecture differed in beta-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.
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 beta-arrestin2 plays a central role in this signaling regulation. Thus, we hypothesized that arrestins would modulate the effects of PTH on bone in vivo.
We used pDXA, muCT, histomorphometry, and serum markers of bone turnover to assess the skeletal response to intermittent PTH (0, 20, 40, or 80 mug/kg/day) in adult female mice null for beta-arrestin2 (beta-arr2(-/-)) and wildtype (WT) littermates (7-11/group).
beta-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 beta-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 beta-arr2(-/-) compared with WT. Osteocalcin levels were significantly lower in beta-arr2(-/-) mice, but increased dose-dependently with PTH in both beta-arr2(-/-) and WT. In contrast, whereas the resorption marker TRACP5B increased dose-dependently in WT, 20-80 mug/kg/day of PTH was equipotent with regard to stimulation of TRACP5B in beta-arr2(-/-). In summary, beta-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.
细胞质抑制蛋白在体外调节甲状旁腺激素（PTH）信号传导。我们发现雌性β - 抑制蛋白2基因敲除（β - arrestin2(-/-)）小鼠的骨量减少且骨结构改变。间歇性给予PTH对骨微结构的影响在β - arrestin2(-/-)小鼠和野生型小鼠中有所不同。这些数据表明，抑制蛋白介导的细胞内信号调节有助于PTH在骨内膜和骨膜骨表面产生不同的作用。
PTH在骨内膜和骨膜表面的作用不同，这表明这些区域中PTH的活性可能依赖于某些尚未明确的调节机制。PTH在骨中的作用主要由细胞内cAMP介导，细胞质分子β - 抑制蛋白2在这种信号调节中起核心作用。因此，我们推测抑制蛋白会在体内调节PTH对骨的作用。
我们使用双能X线吸收法（pDXA）、微观计算机断层扫描（μCT）、组织形态计量学以及骨转换血清标志物，来评估成年雌性β - 抑制蛋白2基因敲除（β - arr2(-/-)）小鼠和野生型（WT）同窝小鼠（每组7 - 11只）对间歇性PTH（0、20、40或80μg/kg/天）的骨骼反应。
与WT小鼠相比，β - arr2(-/-)小鼠的全身骨密度、小梁骨体积分数（BV/TV）和股骨横截面积显著降低。在WT雌性小鼠中，PTH增加了全身骨密度、小梁骨参数和皮质厚度，同时股骨中段髓腔面积有减小的趋势。在β - arr2(-/-)小鼠中，PTH不仅改善了全身骨密度、小梁骨结构和皮质厚度，还剂量依赖性地增加了股骨横截面积和髓腔面积。组织形态计量学显示，与WT相比，PTH刺激的β - arr2(-/-)小鼠骨膜骨形成高出2倍。β - arr2(-/-)小鼠的骨钙素水平显著较低，但在β - arr2(-/-)小鼠和WT小鼠中均随PTH剂量依赖性增加。相反，虽然WT小鼠中骨吸收标志物抗酒石酸酸性磷酸酶5b（TRACP5B）随剂量依赖性增加，但在β - arr2(-/-)小鼠中，20 - 80μg/kg/天的PTH对TRACP5B的刺激作用相同。总之，β - 抑制蛋白2在骨量获取和重塑中起重要作用。在雌激素充足的雌性小鼠中，间歇性PTH刺激骨膜骨沉积和骨内膜吸收的能力受到抑制蛋白的抑制。因此，我们推断抑制蛋白介导的细胞内信号调节有助于PTH对松质骨和皮质骨产生不同的作用。
