Intermittent parathyroid hormone administration counteracts the adverse effects of glucocorticoids on osteoblast and osteocyte viability, bone formation, and strength in mice.
Glucocorticoids act directly on bone cells to decrease production of osteoblasts and osteoclasts, increase osteoblast and osteocyte apoptosis, and prolong osteoclast life span. Conversely, daily injections of PTH decrease osteoblast and osteocyte apoptosis and increase bone formation and strength. Using a mouse model, we investigated whether the recently demonstrated efficacy of PTH in glucocorticoid-induced bone disease results from the ability of this therapeutic modality to counteract at least some of the direct effects of glucocorticoids on bone cells. Glucocorticoid administration to 5- to 6-month-old Swiss-Webster mice for 28 d increased the prevalence of osteoblast and osteocyte apoptosis and decreased osteoblast number, activation frequency, and bone formation rate, resulting in reduced osteoid, wall and trabecular width, bone mineral density, and bone strength. In contrast, daily injections of PTH caused a decrease in osteoblast and osteocyte apoptosis and an increase in osteoblast number, activation frequency, bone formation rate, bone mineral density, and bone strength. The decreased osteocyte apoptosis was associated with increased bone strength. When the two agents were combined, all the adverse effects of glucocorticoid excess on bone were prevented. Likewise, in cultured osteoblastic cells, PTH attenuated the adverse effects of glucocorticoids on osteoblast survival and Wnt signaling via an Akt phosphorylation-dependent mechanism. We conclude that intermittent PTH administration directly counteracts the key pathogenetic mechanisms of glucocorticoid excess on bone, thus providing a mechanistic explanation of its efficacy against glucocorticoid-induced osteoporosis.
Weinstein
Robert S
RS
University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, Little Rock, Arkansas 72205-7199, USA. weinsteinroberts@uams.edu
Jilka
Robert L
RL
Almeida
Maria
M
Roberson
Paula K
PK
Manolagas
Stavros C
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011239:Prednisolone / Q000494:pharmacology
D005938:Glucocorticoids; D010281:Parathyroid Hormone; D011239:Prednisolone
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