Parathyroid hormone 1-84 targets bone vascular structure and perfusion in mice: impacts of its administration regimen and of ovariectomy.
Bone vessel functions during bone remodeling are poorly understood. They depend on both vessel network structure and vasomotor regulation. Parathyroid hormone (PTH) is a systemic vasodilator that may modulate microvascularization. Moreover, although intermittent PTH is anti-osteoporotic, continuous PTH administration can be catabolic for bone. Finally, ovariectomy (OVX) reduces bone perfusion and vessel density in mice. We reasoned that the effects of PTH on bone vascularization might depend on its administration regimen and be impacted by ovariectomy. A 100-µg/kg PTH 1-84 daily dose was administered for 15 days to 4-month-old female C57BL/6 mice, either as daily sc injection (iPTH) or continuously (cPTH; ALZET minipump). Blood pressure (BP) and tibia bone perfusion were measured in vivo with a laser Doppler device. Histomorphometry of bone and barium-contrasted vascular network were performed on the same tibia. Compared with untreated controls, both iPTH and cPTH increased bone formation but had opposite effects on resorption. Both iPTH and cPTH were slightly angiogenic. Intermittent PTH increased microvessel size (+48%, p < 0.001), whereas cPTH decreased it (-29%, p = 0.009). iPTH increased bone perfusion (27%, p < 0.001) with no change in BP, whereas cPTH did not. The vascular effects of a 15-day iPTH treatment were analyzed in OVX mice and compared with sham-operated and OVX untreated controls. Two other anti-osteoporotic drugs, zoledronate (one injection, 70 µg/kg) and propranolol, (5 mg/kg/d) were tested in OVX mice. Although no change in bone mass was observed, iPTH stimulated bone formation and prevented the OVX-induced reduction in bone perfusion and vessel density. Both zoledronate and propranolol strongly lowered bone turnover, but surprisingly, zoledronate prevented OVX-induced reduction in bone perfusion but propranolol did not. Our integrative approach thus demonstrates that the effects of PTH on bone vessel structure and function depend on its mode of administration as well as on the HPG-axis hormonal status, and that OVX-induced vascular changes are prevented by iPTH.
INSERM U1059, Lab Biologie Intégrée du Tissu Osseux, Université de Lyon, Saint-Etienne, France.
Bernard
B
Roche
Arnaud
A
Vanden-Bossche
Luc
L
Malaval
Myriam
M
Normand
Martin
M
Jannot
Robin
R
Chaux
Laurence
L
Vico
Marie-Hélène
MH
Lafage-Proust
D000818:Animals; D004164:Diphosphonates; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010477:Perfusion; D011433:Propranolol / Q000494:pharmacology; D013977:Tibia / Q000033:anatomy & histology / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000187:drug effects; D013997:Time Factors; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D010281:Parathyroid Hormone; D000077211:Zoledronic Acid; D011433:Propranolol
BONE PERFUSION; BONE REMODELING; BONE VASCULARIZATION; PTH; VASCULAR REMODELING