Anabolic actions of parathyroid hormone during bone growth are dependent on c-fos.
PTH has anabolic and catabolic actions in bone that are not clearly understood. The protooncogene c-fos and other activating protein 1 family members are critical transcriptional mediators in bone, and c-fos is up-regulated by PTH. The purpose of this study was to examine the mechanisms of PTH and the role of c-fos in PTH-mediated anabolic actions in bone. Mice with ablation of c-fos (-/-) and their wild-type (+/+) and heterozygous (+/-) littermates were administered PTH for 17 d. The +/+ mice had increased femoral bone mineral density (BMD), whereas -/- mice had reduced BMD after PTH treatment. PTH increased the ash weight of +/+ and +/-, but not -/-, femurs and decreased the calcium content of -/-, but not +/+ or +/-, femurs. Histomorphometric analysis showed that PTH increased trabecular bone volume in c-fos +/+, +/- vertebrae, but, in contrast, decreased trabecular bone in -/- vertebrae. Serum calcium levels in +/+ mice were greater than those in -/- mice, and PTH increased calcium in -/- mice. Histologically, PTH resulted in an exacerbation of the already widened growth plate and zone of hypertrophic chondrocytes but not the proliferating zone in -/- mice. PTH also increased calvarial thickness in +/+ mice, but not -/- mice. The c-fos -/- mice had lower bone sialoprotein and osteocalcin (OCN), but unaltered PTH-1 receptor mRNA expression in calvaria, suggesting an alteration in extracellular matrix. Acute PTH injection (8 h) resulted in a decrease in osteocalcin mRNA expression in wild-type, but unaltered expression in -/-, calvaria. These data indicate that c-fos plays a critical role in the anabolic actions of PTH during endochondral bone growth.
Demiralp
Burak
B
Department of Periodontics/Prevention/Geriatrics, Medical School, University of Michigan Ann Arbor 48109, USA.
Chen
Hen-Li
HL
Koh
Amy J
AJ
Keller
Evan T
ET
McCauley
Laurie K
LK
D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D001846:Bone Development / Q000187:drug effects* / Q000502:physiology*; D002118:Calcium / Q000097:blood / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005269:Femur / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006132:Growth Plate / Q000033:anatomy & histology / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008903:Minerals; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010281:Parathyroid Hormone / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000502:physiology*; D012886:Skull / Q000033:anatomy & histology / Q000187:drug effects; D013131:Spine / Q000033:anatomy & histology / Q000187:drug effects
D045930:Anabolic Agents; D016326:Extracellular Matrix Proteins; D008903:Minerals; D010281:Parathyroid Hormone; D016760:Proto-Oncogene Proteins c-fos; D015675:Osteocalcin; C028705:bone ash; D002118:Calcium