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Service of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis Prevention, Department of Rehabilitation and Geriatrics, Geneva University Hospital (S.L.F., D.D.P., E.N.B., D.M.), 1211 Geneva 14, Switzerland; Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School (V.G., D.S.G., M.L.B.), Boston, Massachusetts 02215; and Department of Cell Biology, University of Alabama (F.T.L.), Birmingham, Alabama 35294
Address all correspondence and requests for reprints to: Dr. S. L. Ferrari, Service of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis Prevention, Department of Rehabilitation and Geriatrics, Geneva University Hospital, 1211 Geneva 14, Switzerland. E-mail: serge.ferrari{at}medecine.unige.ch.
Intermittent PTH administration increases bone turnover, resulting in net anabolic effects on bone. These effects are primarily mediated by intracellular cAMP signaling. However, the molecular mechanisms that regulate PTH activity in bone remain incompletely understood. ß-Arrestin2, a G protein-coupled receptor regulatory protein, inhibits PTH-stimulated cAMP accumulation in vitro. Using ß-arrestin2–/– (KO) and wild-type (WT) mice, we investigated the response to PTH in primary osteoblasts (POB) and the effects of intermittent PTH administration on bone mass and microarchitecture in vivo. Compared with that in WT mice, PTH-stimulated intracellular cAMP was increased and sustained in KO POB. Intermittent exposure of POB to PTH significantly decreased the ratio of osteoprotegerin (OPG) receptor activator of nuclear factor-
B ligand (RANKL) mRNA expression in KO POB, whereas it increased this ratio in WT POB. Total body bone mass and cortical and trabecular bone parameters were 5–10% lower in male KO mice compared with WT, and these differences were magnified upon in vivo administration of intermittent PTH (80 µg/kg·d) for 1 month. Thus, PTH significantly increased total body bone mineral content as well as vertebral trabecular bone volume and thickness in WT, but not KO mice. The anabolic response to PTH in cortical bone was also slightly more pronounced in WT than KO mice. Histomorphometry indicated that PTH prominently stimulated indexes of bone formation in both WT and KO mice, whereas it significantly increased indexes of bone resorption (i.e. osteoclast number and surface) in KO mice only. In conclusion, these results suggest that ß-arrestins may specify the activity of intermittent PTH on the skeleton by limiting PTH-induced osteoclastogenesis.
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