title: Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis.
abstract: Both chronic excess of PTH, as in hyperparathyroidism, and intermittent elevation of PTH (by daily injections) increase the number of osteoblasts; albeit, the former is associated with bone catabolism and the later with bone anabolism. Intermittent PTH increases osteoblast number by attenuating osteoblast apoptosis, an effect that requires the transcription factor Runx2. However, chronic elevation of PTH does not affect osteoblast apoptosis because it stimulates the proteasomal degradation of Runx2. Here, we studied the effects of PTH on Sost, a Runx2 target gene expressed in osteocytes (former osteoblasts embedded in the bone matrix), which antagonizes the pro-osteoblastogenic actions of bone morphogenetic proteins and Wnts. We report that continuous infusion of PTH to mice for 4 d decreased Sost mRNA expression in vertebral bone by 80-90%. This effect was accompanied by a comparable reduction of sclerostin, the product of Sost, in osteocytes, as determined by quantitative immunoblot analysis of bone extracts and by immunostaining. In contrast, a single injection of PTH caused a transient 50% reduction in Sost mRNA at 2 h, but four daily injections had no effect on Sost mRNA or sclerostin. PTH strongly decreased Sost expression in osteocytes formed in primary cultures of neonatal murine calvaria cells as well as in osteocytic MLO-A5 cells, demonstrating a direct effect of PTH on this cell type. These results, together with evidence that sclerostin antagonizes bone morphogenetic proteins and Wnts, strongly suggest that suppression of Sost by PTH represents a novel mechanism for hormonal control of osteoblastogenesis mediated by osteocytes.
authors.affiliation: Division of Endocrinology and Metabolism, and Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, Arkansas 72205, USA. tmbellido@uams.edu
authors.forename: T
authors.initials: T
authors.lastname: Bellido
authors.forename: A A
authors.initials: AA
authors.lastname: Ali
authors.forename: I
authors.initials: I
authors.lastname: Gubrij
authors.forename: L I
authors.initials: LI
authors.lastname: Plotkin
authors.forename: Q
authors.initials: Q
authors.lastname: Fu
authors.forename: C A
authors.initials: CA
authors.lastname: O'Brien
authors.forename: S C
authors.initials: SC
authors.lastname: Manolagas
authors.forename: R L
authors.initials: RL
authors.lastname: Jilka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006023:Glycoproteins; D006801:Humans; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins; D008159:Lumbar Vertebrae / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology*; D010011:Osteocytes / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D012886:Skull / Q000166:cytology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; C486030:Sost protein, mouse