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Sustained RANKL response to parathyroid hormone in oncostatin M receptor‐deficient osteoblasts converts anabolic treatment to a catabolic effect in vivo
Author(s) -
Walker Emma C,
Poulton Ingrid J,
McGregor Narelle E,
Ho Patricia WM,
Allan Elizabeth H,
Quach Julie M,
Martin T John,
Sims Natalie A
Publication year - 2012
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.1506
Subject(s) - oncostatin m , parathyroid hormone , medicine , endocrinology , osteoblast , osteoclast , anabolism , rankl , chemistry , bone remodeling , glycoprotein 130 , bone resorption , teriparatide , receptor , cytokine , biology , interleukin 6 , in vitro , activator (genetics) , calcium , biochemistry
Parathyroid hormone (PTH) is the only approved anabolic agent for osteoporosis treatment. It acts via osteoblasts to stimulate both osteoclast formation and bone formation, with the balance between these two activities determined by the mode of administration. Oncostatin M (OSM), a gp130‐dependent cytokine expressed by osteoblast lineage cells, has similar effects and similar gene targets in the osteoblast lineage. In this study, we investigated whether OSM might participate in anabolic effects of PTH. Microarray analysis and quantitative real‐time polymerase chain reaction (qPCR) of PTH‐treated murine stromal cells and primary calvarial osteoblasts identified significant regulation of gp130 and gp130‐dependent coreceptors and ligands, including a significant increase in OSM receptor (OSMR) expression. To determine whether OSMR signaling is required for PTH anabolic action, 6‐week‐old male Osmr −/− mice and wild‐type (WT) littermates were treated with hPTH(1–34) for 3 weeks. In WT mice, PTH increased trabecular bone volume and trabecular thickness. In contrast, the same treatment had a catabolic effect in Osmr −/− mice, reducing both trabecular bone volume and trabecular number. This was not explained by any alteration in the increased osteoblast formation and mineral apposition rate in response to PTH in Osmr −/− compared with WT mice. Rather, PTH treatment doubled osteoclast surface in Osmr −/− mice, an effect not observed in WT mice. Consistent with this finding, when osteoclast precursors were cultured in the presence of osteoblasts, more osteoclasts were formed in response to PTH when Osmr −/− osteoblasts were used. Neither PTH1R mRNA levels nor cAMP response to PTH were modified in Osmr −/− osteoblasts. However, RANKL induction in PTH‐treated Osmr −/− osteoblasts was sustained at least until 24 hours after PTH exposure, an effect not observed in WT osteoblasts. These data indicate that the transient RANKL induction by intermittent PTH administration, which is associated with its anabolic action, is changed to a prolonged induction in OSMR‐deficient osteoblasts, resulting in bone destruction. © 2012 American Society for Bone and Mineral Research.