Anabolic Action of Parathyroid Hormone Is Skeletal Site Specific at the Tissue and Cellular Levels in Mice

Abstract

The cellular and molecular events triggering the anabolic response of the skeleton to exogenous parathyroid hormone (PTH) are not well understood. Despite the numerous bone mass studies in rats, few data are available for mice. Therefore, we treated 10-week-old female intact C57BL/6J mice with human PTH(1-34) delivered subcutaneously at a dose of 40 g/kg per day 5 days a week for 3 weeks and 7 weeks. Bone mineral density (BMD) of total bone, femur, tibia, and lumbar vertebrae was measured weekly by PIXImus. Bone turnover was examined by histomorphometry, and gene expression of bone formation and resorption markers and osteoclastogenesis regulators in the excised femur and tibia was assessed by reverse-transcription polymerase chain reaction (RT-PCR) at 3 weeks and 7 weeks. The PTH-stimulated increase in BMD was more prominent in the tibia and femur than in the lumbar vertebrae, with an anabolic effect detected within 1-2 weeks and BMD continuing to increase. The appearance of a detectable PTH-stimulated increase in BMD was slower in the lumbar vertebrae where the increase was only significant after 7 weeks of treatment. Histomorphometric analysis of the proximal tibia at both 3 weeks and 7 weeks indicated significant time-dependent increases in trabecular area, trabecular number, trabecular and cortical widths, and osteoblast and osteoid perimeters. In the lumbar vertebrae, these stimulatory effects of PTH on trabecular area, trabecular number, and cortical width were smaller and not detected until 7 weeks. PTH-stimulated increases in bone turnover were evident by increased gene expression of osteocalcin (

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

“…Interestingly, KO mice had a typical bone formation response to intermittent PTH treatment, suggested by the static and dynamic histomorphometry data and serum osteocalcin levels, but showed an increased osteoclast formation response. Other studies have shown that osteoclast parameters are unchanged in WT mice in response to short-term intermittent PTH treatment (11,28). Our data support these observations.…”

“…Similar to a published study, intermittent PTH treatment caused an anabolic effect on both the cortical and trabecular compartments in a WT strain (11). However, we found that CREM deficiency blunted the anabolic effect in both the cortical and trabecular compartments.…”

“…However, based on the fact that ICER can be induced by PTH in osteoblasts (19) and the involvement of CREM in cAMP signaling, we hypothesized that CREM plays a role in regulating PTH responses in bones. Therefore, we subjected WT and Crem KO mice to an intermittent PTH treatment regimen that has been shown to produce an anabolic effect on bone mass in mice (11,26,27). Our study shows that the Crem gene plays a role in the acquisition of bone mass caused by intermittent PTH treatment and highlights the important role of osteoclastogenesis in shaping the PTH anabolic response.…”

“…The well-described anabolic effect of intermittent PTH on bone mass acquisition has been documented in rats (10), mice (11), monkeys (12) and humans (13). These observations have been pivotal to the development of PTH as an anabolic therapy for treating osteoporosis (14).…”

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

“…Histologic studies have shown that the increase in bone formation is largely due to an increase in the number of matrix-synthesizing osteoblasts [7,8,[10][11][12][13]. Increased osteoblastogenesis, attenuation of osteoblast apoptosis, and activation of quiescent lining cells have been proposed as explanations for this effect of PTH (Fig.…”