Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.
Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.
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DOI：
10.1002/jor.20620
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发表时间：
2008-10
影响因子：
2.8
通讯作者：
Schwarz, Edward M.
中科院分区：
文献类型：
--
作者：
Tsutsumi, Ryosuke;Hock, Colleen;Bechtold, C. Dustin;Proulx, Steven T.;Bukata, Susan V.;Ito, Hiromu;Awad, Hani A.;Nakamura, Takashi;O'Keefe, Regis J.;Schwarz, Edward M.
继发于假体周围骨溶解的无菌性松动仍然是一个严重的骨科问题，也是全关节置换术的最大局限性。这一过程是由磨屑诱导的破骨细胞性骨吸收引起的，针对这一过程，已经开发出有效的小分子(双膦酸盐，BPS)和生物(RANK)药物。虽然BP已被证明在非炎症性条件下(如骨质疏松)预防代谢性骨丢失是有效的，但它们在设置炎症性骨丢失方面并不像在假体周围骨溶解中观察到的那样具有相同的疗效。由于这种差异被归因于保护破骨细胞免受BP诱导的凋亡的抗凋亡炎症信号，而不是等级拮抗剂，我们在小鼠颅骨模型中检验了骨保护素(OPG)在预防磨屑诱导的骨溶解方面比唑来膦酸(ZA)或阿伦磷酸(Aln)更有效的假说。基于以往动物研究侧重于2D成像和组织学终点的缺点，以及定量3D-CT的出现，我们发展了适用于小鼠颅骨模型的在体Micro-CT方法，以更严格地验证我们的假设，并将骨溶解结果与传统组织学相关联。尽管这种方法被证明与钛(Ti)颗粒不相容，但由于金属伪影，我们能够证明超高相对分子质量聚乙烯(PE)颗粒在10天内诱导的骨溶解体积是假手术对照组的3.2倍(0.49+/−0.23mm3vs.0.15+/−0.067mm3；p<；0.01)。OPG和高剂量ZA完全抑制PE诱导的骨溶解(p<；0.001)，药理剂量ZA和Aln的作用较弱，但仍有统计学意义(p<；0.05)。对钛和PE处理的小鼠颅骨矢状缝合区的传统组织形态计量学证实，与生理性BP相比，OPG(p<；0.001)显著抑制了吸收。药物对骨溶解作用的差异在很大程度上是由于在钛和聚乙烯处理的颅骨中观察到的OPG和BPS之间的破骨细胞数量的显著差异；线性回归分析表明，骨溶解体积和矢状缝面积与破骨细胞数量之间存在高度显著的相关性(p<；0.001)。综上所述，我们的结果证明了活体3D-CT在检测BPS对磨屑诱导的骨溶解的影响方面的敏感性和实用性，这是组织学无法观察到的；与BPS相比，OPG治疗观察到的对骨吸收的更大抑制是由于其在存在炎症信号的情况下大幅减少破骨细胞数量的能力。
Aseptic loosening secondary to periprosthetic osteolysis remains a serious orthopaedic problem and the greatest limitation of total joint replacement. This process is caused by wear debris-induced osteoclastic bone resorption, for which effective small molecule (bisphosphonates, BPs) and biologic (RANK antagonists) drugs have been developed. While BPs have proven to be effective in preventing metabolic bone loss in non-inflammatory conditions such as osteoporosis, they do not have the same efficacy in the setting of inflammatory bone loss such as that observed in periprosthetic osteolysis. Since this difference has been attributed to the anti-apoptotic inflammatory signals that protect osteoclasts from BP-induce apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris-induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model. Based on the shortcomings of previous animal studies that focused on 2D imaging and histology endpoints, and the emergence of quantitative 3D-CT, we developed in vivo micro-CT methods for the murine calvaria model to more rigorously test our hypothesis and correlate the osteolysis results with traditional histology. Although this approach proved to be incompatible with titanium (Ti) particles, due to metal artifact, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by ultra high molecular weight polyethylene (PE) particles vs. sham controls (0.49 +/− 0.23mm3 vs. 0.15 +/− 0.067mm3; p<0.01). While OPG and high dose ZA completely inhibited this PE-induced osteolysis (p<0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p<0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE treated mice confirmed the remarkable suppression of resorption by OPG (p<0.001) vs. the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG vs. BPs in both Ti and PE treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area vs. osteoclast numbers (p<0.001). Taken together our results demonstrate the sensitivity and utility of in vivo 3D-CT to detect the effects of BPs on wear debris-induced osteolysis that could not be observed by histology alone; and that the greater suppression of bone resorption observed with OPG treatment vs. BPs is due to its ability to dramatically reduce osteoclast numbers in the presence of inflammatory signals.
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影响因子：
6.2
作者：
Li, P;Schwarz, EM;Xing, LP
通讯作者：
Xing, LP
影响因子：
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作者：
Schwarz, EM;Lu, AP;O'Keefe, RJ
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O'Keefe, RJ
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作者：
von Knoch, M;Wedemeyer, C;Löer, F
通讯作者：
Löer, F
影响因子：
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通讯作者：
Schett, G
影响因子：
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作者：
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通讯作者：
Greenfield, EM