Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts
2011 | journal article. A publication with affiliation to the University of Göttingen.
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Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts
Sausbier, U.; Dullin, C.; Missbach-Guentner, J.; Kabagema, C.; Flockerzie, K.; Kuscher, G. M. & Stühmer, W. et al. (2011)
PLoS ONE, 6(6) art. e21168. DOI: https://doi.org/10.1371/journal.pone.0021168
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- Authors
- Sausbier, Ulrike; Dullin, Christian; Missbach-Guentner, Jeannine; Kabagema, Clement; Flockerzie, Katarina; Kuscher, Gerd Marten; Stühmer, Walter ; Neuhuber, Winfried; Ruth, Peter; Alves, Frauke ; Sausbier, Matthias
- 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.
- Issue Date
- 2011
- Journal
- PLoS ONE
- ISSN
- 1932-6203
- Language
- English