Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition.
Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition.
复制标题
硬化蛋白中和可释放 Dkk1 抑制的骨合成代谢作用。
作者：
Phillip C. Witcher;Sara E Miner;D. Horan;Whitney A Bullock;K. Lim;K. S. Kang;A. Adaniya;R. Ross;G. Loots;A. Robling
WNT通路已成为骨骼治疗的一个有吸引力的靶点。在LRP 5/6抑制剂Sost（骨质疏松症）或其下游增强子区域（货车Buchem病）功能缺失突变的患者中，高骨量表型突出了靶向Sost/sclerostin改善骨特性的效用。硬化蛋白中和抗体在动物模型和人体临床试验中具有高度的骨合成代谢作用，但另一种有效的LRP 5/6拮抗剂Dkk 1的基于抗体的抑制对于在未受干扰的成人骨骼中构建骨在很大程度上无效。在这里，我们表明，从骨中有条件地删除Dkk 1对骨量的影响也可以忽略不计。Dkk 1抑制增加Sost表达，这表明可能解释为什么Dkk 1抑制缺乏合成代谢作用的潜在补偿机制。为了测试这个概念，我们删除了骨细胞中的Sost，或者给Dkk 1缺陷骨骼的小鼠施用硬化蛋白中和抗体。只有当Sost/sclerostin受损时，Dkk 1缺失才表现出强大的合成代谢反应。全身DXA扫描、股骨和脊柱的μCT测量、股骨骨形成率的组织形态计量学测量以及全骨的生物力学性质证实了在不存在硬化蛋白的情况下Dkk 1抑制的合成代谢潜力。此外，在WT小鼠中组合施用硬化蛋白和Dkk 1抗体对骨增加产生了协同效应，大大超过了治疗的单独或累加效应，证实了抑制多种WNT拮抗剂对骨骼健康的治疗潜力。总之，如果阻止硬化蛋白上调，则可以实现Dkk 1抑制的骨合成代谢作用。低骨量患者的合成代谢治疗可能受益于解释骨组织中WNT抑制剂的代偿环境的策略。
The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.
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影响因子：
4.1
作者：
Robling AG;Kang KS;Bullock WA;Foster WH;Murugesh D;Loots GG;Genetos DC
通讯作者：
Genetos DC
影响因子：
4.1
作者：
Collette NM;Yee CS;Hum NR;Murugesh DK;Christiansen BA;Xie L;Economides AN;Manilay JO;Robling AG;Loots GG
通讯作者：
Loots GG
影响因子：
4.1
作者：
MacDonald, Bryan T.;Joiner, Danese M.;Hauschka, Peter V.
通讯作者：
Hauschka, Peter V.
影响因子：
11.8
作者：
Mukhopadhyay, M;Shtrom, S;Westphal, H
通讯作者：
Westphal, H
影响因子：
6.2
作者：
Boudin, Eveline;Yorgan, Timur;Van Hul, Wim
通讯作者：
Van Hul, Wim