The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking
The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking
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DOI：
10.1016/j.bone.2011.06.014
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发表时间：
2011-10-01
期刊：
影响因子：
4.1
通讯作者：
Duong, L. T.
中科院分区：
文献类型：
--
作者：
Leung, P.;Pickarski, M.;Duong, L. T.
Odanacatib （ODN）是一种选择性，强效和可逆的组织蛋白酶K （CatK）抑制剂，可抑制绝经后骨质疏松症的骨质流失。经ODN处理的CatK（-/-）小鼠或人类OC祖细胞骨髓破骨细胞（OC）形成的证据表明，CatK抑制对破骨细胞的形成或OC的存活没有影响。虽然ODN对OC活化没有影响，但通过CTx释放（IC50=9.4 nM）或吸收面积（IC50=6.5 nM）测量，ODN降低了吸收活性。未经处理的细胞产生深的径状吸收腔隙，而经过处理的细胞形成小的离散的浅坑。ODN导致细胞内囊泡的大量积累，这些囊泡被CatK和TRAP强烈染色。CatK（+）囊泡定位于基底外侧，极化OC和TRAP（+）囊泡的功能分泌膜均匀分布在细胞质中，表明ODN破坏了多种囊泡运输途径。与未处理对照相比，odn处理的OCs细胞内前体和成熟的TRAP水平增加了2倍，前、前和成熟的CatK水平分别增加了6倍和2倍。ODN处理的OC在含有CatK的囊泡中积累标记的降解骨基质蛋白。综上所述，ODN治疗通过阻断骨吸收腔隙中去矿化胶原蛋白的降解来抑制骨吸收，并阻碍降解蛋白的胞吞进一步加工。(C) 2011爱思唯尔公司版权所有。
Odanacatib (ODN) is a selective, potent and reversible inhibitor of cathepsin K (CatK) that inhibits bone loss in postmenopausal osteoporosis. Evidence from osteoclast (OC) formation from bone marrow of CatK(-/-) mice or human OC progenitors treated with ODN, demonstrated that CatK inhibition has no effect on osteoclastogenesis or survival of OCs. Although having no impact on OC activation, ODN reduces resorption activity as measured by CTx release (IC50=9.4 nM) or resorption area (IC50=6.5 nM). While untreated cells generate deep trail-like resorption lacunae, treated OCs form small discrete shallow pits. ODN leads to significant accumulation of intracellular vesicles intensely stained for CatK and TRAP. CatK (+) vesicles localize toward the basolateral and functional secretory membranes of the polarized OC and TRAP(+) vesicles evenly distribute in the cytoplasm, suggesting that ODN disrupts multiple vesicular trafficking pathways. Intracellular levels of both precursor and mature TRAP were increased by 2-fold and the pre-pro and mature CatK by 6- and 2-fold in ODN-treated OCs compared to untreated controls. ODN treated OC accumulates labeled degraded bone matrix proteins in CatK containing vesicles. In summary, ODN treatment inhibits bone resorption by blocking degradation of demineralized collagen in the resorption lacunae, and retarding transcytosis for further processing of degraded proteins. (C) 2011 Elsevier Inc. All rights reserved.