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 mg/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 mg/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.

PTH(1‐34) effects on repairing experimentally drilled holes in rat femur: novel aspects – qualitative vs. quantitative improvement of osteogenesis

“…PTH(1-34), also known as Teriparatide, is an FDA-approved anabolic drug for osteoporosis, increasing bone deposition. It has also been demonstrated that, although PTH(1-34) can also stimulate bone resorption, the net effect of intermittent daily administration is the increase in bone mass (Hock & Gera, 1992;Burr et al 2001;Oswald et al 2014;Saidak et al 2014;Takao-Kawabata et al 2015). Under some conditions, PTH(1-34) can be used to improve fracture healing (Chiang et al 2013), although this may be dependent on the severity and location of bone injury as well as on an individual's overall bone health.…”

A Novel Human PTH Analog [Cys25]hPTH(1–34) Restores Bone Mass in Ovariectomized Mice

“…sion of sclerostin expression (3,4). Furthermore, recent studies revealed that PTH promoted bone anabolism by stimulating aerobic glycolysis in osteoblasts via insulinlike growth factor signaling (5).…”

WISP1i

“…WISP1 can increase osteogenesis through bone morphogenetic protein 2 (BMP-2), and bone formation through parathyroid hormone treatment can progress through WISP1 expression (Saidak et al 2014). Bone formation following growth plate cartilage injury has been demonstrated to involve expression of the WISP1 gene.…”