Osteopenia due to enhanced Cathepsin K release by BK channel ablation in osteoclasts

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Abstract

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. © 2011 Sausbier et al.

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Sausbier, U., Dullin, C., Missbach-Guentner, J., Kabagema, C., Flockerzie, K., Kuscher, G. M., … Sausbier, M. (2011). Osteopenia due to enhanced Cathepsin K release by BK channel ablation in osteoclasts. PLoS ONE, 6(6). https://doi.org/10.1371/journal.pone.0021168

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