title: Low-dose PTH increases osteoblast activity via decreased Mef2c/Sost in senescent osteopenic mice.
abstract: Intermittent administration of parathyroid hormone (PTH) 1-34 at a standard dose has been shown to induce anabolic effects in bone. However, whether low-dose PTH promotes bone formation during senescence is unknown. To address this issue, we determined the effects of low-dose PTH and analysed the underlying mechanisms in prematurely senescent mice that display osteopenia. Treatment of 9-week-old Samp6 mice for 6 weeks with PTH at a standard dose (100 μg/kg per day) increased vertebral and femoral bone mass and improved bone microarchitecture as a result of increased bone-forming surfaces and mineral apposition rate (MAR). At a tenfold lower dose (10 μg/kg per day), PTH increased axial bone volume and trabecular thickness, as detected by bone histomorphometry but not by micro-computed tomography analysis. This anabolic effect resulted from increased osteoblast activity, as reflected by increased serum N-terminal propeptide of type 1 procollagen (P1NP) levels and MAR, with unchanged bone-forming surface or osteoblast surface. Mechanistically, low-dose PTH increased the expression of osteoblast markers in bone marrow stromal cells and mature osteoblasts, which was associated with increased expression of the Wnt effector Wisp1. Moreover, low-dose PTH decreased the expression of the Mef2c transcription factor, resulting in decreased Sost expression in osteoblasts/osteocytes. These results indicate that PTH at a low dose is effective at promoting bone formation and increased bone volume in senescent osteopenic mice through increased osteoblast activity and modulation of specific Wnt effectors, which raises the potential therapeutic use of intermittent PTH at low dose to increase bone forming activity and bone mass in skeletal senescence.
authors: UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France.
authors: Zuzana
authors: Z
authors: Saidak
authors: UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France.
authors: Carole
authors: C
authors: Le Henaff
authors: UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France.
authors: Sofia
authors: S
authors: Azzi
authors: UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France.
authors: Caroline
authors: C
authors: Marty
authors: UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France UMR-1132 InsermHôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, FranceUniversité Paris DiderotSorbonne Paris Cité, Paris, France pierre.marie@inserm.fr.
authors: Pierre J
authors: PJ
authors: Marie
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D010281:Parathyroid Hormone; D011518:Proto-Oncogene Proteins; C486030:Sost protein, mouse
keywords: Wnt signalling; low-dose PTH; osteoblast activity; senescent mice