1. Decreased osteoprogenitor proliferation precedes attenuation of cancellous bone formation in ovariectomized rats treated with sclerostin antibody
- Author
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Rogely W. Boyce, Kathrin Locher, Scott Taylor, Ian Pyrah, Nacera Mellal, Danielle L. Brown, Michael S. Ominsky, and Melanie Felx
- Subjects
0301 basic medicine ,Cell signaling ,lcsh:Diseases of the musculoskeletal system ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,BrdU, 5-bromo-2′-deoxyuridine ,SURS, systematic uniform random sampling ,TP53, tumor protein p53 ,CDKN1A, cyclin-dependent kinase inhibitor 1A ,CE, coefficient of error ,OP, osteoprogenitor(s) ,OCy, osteocyte(s) ,chemistry.chemical_compound ,0302 clinical medicine ,RB1, retinoblastoma protein 1 ,PROBE, precision range of an optimally balanced estimator ,Scl-Ab, sclerostin antibody ,Orthopedics and Sports Medicine ,OVX, ovariectomized ,ANOVA, analysis of variance ,Chemistry ,MYC, v-myc avian myelocytomatosis viral oncogene homolog ,Ob.N, OB number ,Wnt signaling pathway ,medicine.anatomical_structure ,FOXM1, Forkhead box protein M1 ,Osteocyte ,Ovariectomized rat ,Signal transduction ,Cancellous bone ,CDKN2A, CDKN inhibitor 2A ,medicine.medical_specialty ,Osteoprogenitors ,030209 endocrinology & metabolism ,Article ,03 medical and health sciences ,Scl-AbVI, 50 mg/kg of a Scl-Ab ,Internal medicine ,medicine ,Bone ,E2F1, E2F transcription factor 1 ,OB, osteoblast(s) ,Anabolics ,CV, coefficient of variation ,medicine.disease ,Wnt signaling ,VEH, vehicle ,D, day ,030104 developmental biology ,Endocrinology ,MS/BS, mineralizing surface per bone surface ,Sclerostin ,RUNX2, Runt-related transcription factor 2 ,MYCN, MYC neuroblastoma-derived homolog ,lcsh:RC925-935 - Abstract
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., Highlights • Sclerostin antibody stimulates bone formation (BF) that attenuates over time. • Osteoprogenitor (OP) proliferation increases early with treatment. • Attenuation of BF is preceded by a decrease in OP proliferation. • Decrease is coincident with molecular signaling consistent with cell cycle arrest. • Decreased OP proliferation contributes to the attenuation of BF.
- Published
- 2018
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