Decreased osteoprogenitor proliferation precedes attenuation of cancellous bone formation in ovariectomized rats treated with sclerostin antibody.
Decreased osteoprogenitor proliferation precedes attenuation of cancellous bone formation in ovariectomized rats treated with sclerostin antibody.
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DOI：
10.1016/j.bonr.2018.03.001
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发表时间：
2018-06
期刊：
影响因子：
2.5
通讯作者：
Taylor S
中科院分区：
文献类型：
--
作者：
Boyce RW;Brown D;Felx M;Mellal N;Locher K;Pyrah I;Ominsky MS;Taylor S
硬化蛋白抗体（sclr - ab）刺激骨形成，长期治疗后，随着时间的推移会减弱。骨形成衰减的细胞和分子机制尚不清楚，但在老龄卵巢切除（OVX）大鼠中，椎体松质骨形成的减少之前是骨祖细胞（OP）数量的减少和已知抑制骨细胞有丝分裂和细胞周期进展的信号通路的显著诱导（OCy） （Taylor等，2016）。为了确定OP数量的减少是否与增殖的减少有关，在尸检前5 天，给衰老的OVX大鼠注射载药或Scl-Ab 9或29 天，并植入连续输送的5-溴-2 ' -脱氧尿苷（BrdU）微渗透泵。对椎体松质骨中brdu标记成骨细胞（OB）的总数进行量化，以间接评估Scl-Ab治疗对第9天模型骨形成激活时OP增殖的影响，以及第29天最大矿化表面、OP数量初始减少和OCy转录变化时OP增殖的影响。与对照组相比，Scl-Ab导致brdu阳性OB总数在第9天增加（+260%），在第29天继续治疗时减少（+50%）。这些增殖差异发生在OB总数显著增加且幅度相似的时间点上。这些发现表明，OP增殖的减少有助于OP数量的减少，这一效应将限制OB池，并有助于长期Scl-Ab治疗时骨形成的衰减。硬化蛋白抗体刺激骨形成（BF）随着时间的推移而减弱。骨祖细胞（OP）增生随着治疗早期增加。BF的衰减是由OP增殖的减少引起的。减少与与细胞周期阻滞一致的分子信号一致。OP增殖减少有助于BF的衰减。
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. 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.