| Autor: |
Boyce RW; Department of Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States., Brown D; Charles River Laboratories, 4025 Stirrup Creek Drive, Suite 150, Durham, NC 27703, United States., Felx M; Charles River Laboratories, 22022 Transcanadienne, Senneville, QC H9X 3R3, Canada., Mellal N; Charles River Laboratories, 22022 Transcanadienne, Senneville, QC H9X 3R3, Canada., Locher K; Department of Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States., Pyrah I; Department of Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States., Ominsky MS; Department of CardioMetabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States., Taylor S; Department of Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. |
| Abstrakt: |
Sclerostin antibody (Scl-Ab) stimulates bone formation, which with long-term treatment, attenuates over time. The cellular and molecular mechanisms responsible for the attenuation of bone formation are not well understood, but in aged ovariectomized (OVX) rats, the reduction in vertebral cancellous bone formation is preceded by a reduction in osteoprogenitor (OP) number and significant induction of signaling pathways known to suppress mitogenesis and cell cycle progression in the osteocyte (OCy) (Taylor et al., 2016). To determine if the reduction in OP number is associated with a decrease in proliferation, aged OVX rats were administered vehicle or Scl-Ab for 9 or 29 days and implanted with continuous-delivery 5-bromo-2'-deoxyuridine (BrdU) mini-osmotic pumps 5 days prior to necropsy. The total number of BrdU-labeled osteoblasts (OB) was quantified in vertebral cancellous bone to indirectly assess the effects of Scl-Ab treatment on OP proliferation at the time of activation of modeling-based bone formation at day 9 and at the time of maximal mineralizing surface, initial decrease in OP number, and transcriptional changes in the OCy at day 29. Compared with vehicle, Scl-Ab resulted in an increase in the total number of BrdU-positive OB (+260%) at day 9 that decreased with continued treatment (+50%) at day 29. These differences in proliferation occurred at time points when the increase in total OB number was significant and similar in magnitude. These findings suggest that reduced OP proliferation contributes to the decrease in OP numbers, an effect that would limit the OB pool and contribute to the attenuation of bone formation that occurs with long-term Scl-Ab treatment. |
