Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts

BackgroundThe process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. Methodology/Principal FindingsWe found, that in juvenile bone the large conductance, voltage and Ca2+-activated (BK) K+ channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K+ outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK−/−) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK−/− vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca2+ and triiodthyronine as well as osteoclastogenesis were not altered in BK−/− females. Conclusion/SignificanceOur findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK−/− mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity.

背景：破骨细胞介导的骨吸收过程由组织蛋白酶K（Cathepsin K）调控，该溶酶体胶原酶负责骨重塑过程中有机骨基质的降解。近年来，组织蛋白酶K被视为骨质疏松症治疗干预的潜在靶点。然而，导致骨质减少的机制仍有待阐明，且其分子靶点尚待确定——骨质减少在青年女性群体中更为常见，常作为特发性骨质疏松症的临床前期表现。
方法与主要结果：本研究发现，在幼年骨骼中，将膜去极化与胞质钙局部升高关联至超极化性钾外流的大电导钙激活电压门控钾（BK）通道，仅在破骨细胞中特异性表达。与野生型同窝仔鼠相比，幼年BK基因敲除（BK−/−）雌性小鼠的血浆组织蛋白酶K水平升高了两倍。该升高与骨质减少表型相关：通过高分辨率平板容积计算机断层扫描及micro-CT证实，BK−/−小鼠的长骨骨密度降低，椎骨骨小梁网孔隙率升高。然而，BK−/−雌性小鼠的可溶性核因子κB受体活化因子配体（sRANKL）、骨保护素、雌激素、钙及三碘甲状腺原氨酸的血浆水平，以及破骨细胞生成均未发生改变。
结论与意义：本研究结果表明，BK通道通过调控组织蛋白酶K的释放，控制破骨细胞的骨吸收活性。小鼠体内BK通道的定向敲除可引发破骨细胞自主性骨质减少，该表型在幼年雌性小鼠中尤为显著。因此，BK−/−小鼠品系可作为幼年型骨质减少的新型动物模型，并揭示BK通道可作为调控破骨细胞活性的潜在治疗新靶点。