Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats
Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats
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DOI：
10.1016/j.bone.2016.12.003
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发表时间：
2017-04-01
期刊：
影响因子：
4.1
通讯作者：
Krishnan, Venkatesh
中科院分区：
文献类型：
--
作者：
Ma, Yanfei L.;Hamang, Matthew;Krishnan, Venkatesh
硬化蛋白抗体通过刺激骨形成来增加骨量。然而，人类和动物研究表明，尽管正在进行抗体治疗，但骨形成会短暂增加并恢复到治疗前的水平。为了了解其作用机制，我们研究了骨形成的时间过程，将硬化素抗体治疗后骨量和强度增加的速度和程度关联起来。卵巢切除 (OVX) 大鼠每周皮下注射 20 mg/kg 硬化素抗体 (Scle-ab) 一次，并在基线和治疗后 2、3、4、6 和 8 周处死。在 Scle-ab 治疗的大鼠中，血清 PINP 和 OCN 在第 1 周迅速增加，在第 3 周左右达到峰值，并在第 6 周恢复到 OVX 对照水平。股骨远端的转录本分析显示，骨形成早期增加，随后骨吸收基因持续减少。腰椎 (LV) 成骨细胞表面在第 2 周增加了 88%，骨形成率 (BFR/BS) 在第 4 周增加了 138%。到第 8 周，这两个参数均低于 OVX 控制。骨形成主要是基于建模的形成的结果。皮质内和骨膜 BFR/BS 在第 4 周左右达到峰值，分别为 OVX 对照的 313% 和 585%。然后，到第 8 周，BFR/BS 有所下降，但在两个表面上仍高于 OVX 对照。组织形态计量学分析显示，在第 4 周后，LV-BV/TV 没有进一步增加，而到第 8 周，LV、股骨中段 (MF) 和股骨颈 (FN) 的 BMD 继续增加。生物力学测试显示，MF 和 FN 的骨强度在第 8 周内有类似的改善，但 LV 的骨强度在第 6 周和第 8 周之间趋于稳定。我们的数据表明，Scle-ab 治疗后的骨形成很快，并且在 OVX 大鼠中模型形成占主导地位。虽然短暂，但皮质骨中的骨形成反应比小梁骨中持续时间更长。 (C) 2016 Elsevier Inc. 保留所有权利。
Sclerostin antibodies increase bone mass by stimulating bone formation. However, human and animal studies show that bone formation increases transiently and returns to pre-treatment level despite ongoing antibody treatment. To understand its mechanism of action, we studied the time course of bone formation, correlating the rate and extent of accrual of bone mass and strength after sclerostin antibody treatment. Ovariectomized (OVX) rats were treated with a sclerostin-antibody (Scle-ab) at 20 mg/kg sc once weekly and sacrificed at baseline and 2, 3, 4, 6, and 8 weeks post-treatment. In Scle-ab treated rats, serum PINP and OCN rapidly increased at week 1, peaked around week 3, and returned to OVX control levels by week 6. Transcript analyses from the distal femur revealed an early increase in bone formation followed by a sustained decrease in bone resorption genes. Lumbar vertebral (LV) osteoblast surface increased 88% by week 2, and bone formation rate (BFR/BS) increased 138% by week 4. Both parameters were below OVX control by week 8. Bone formation was primarily a result of modeling based formation. Endocortical and periosteal BFR/BS peaked around week 4 at 313% and 585% of OVX control, respectively. BFR/BS then declined but remained higher than OVX control on both surfaces through week 8. Histomorphometric analyses showed LV-BV/TV did not further increase after week 4, while BMD continued to increase at LV, mid femur (MF), and femoral neck (FN) through week 8. Biomechanical tests showed a similar improvement in bone strength through 8 weeks in MF and FN, but bone strength plateaued between weeks 6 and 8 for LV. Our data suggest that bone formation with Scle-ab treatment is rapid and modeling formation dominated in OVX rats. Although transient, the bone formation response persists longer in cortical than trabecular bone. (C) 2016 Elsevier Inc. All rights reserved.