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Radiology and Medical Imaging - Women's Health


Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts
Published: Tuesday, June 14, 2011
Author: Ulrike Sausbier et al.

by Ulrike Sausbier, Christian Dullin, Jeannine Missbach-Guentner, Clement Kabagema, Katarina Flockerzie, Gerd Marten Kuscher, Walter Stuehmer, Winfried Neuhuber, Peter Ruth, Frauke Alves, Matthias Sausbier

Background

The 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 Findings

We 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/Significance

Our 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.

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