title: Osteopenia due to enhanced cathepsin K release by BK channel ablation in osteoclasts.
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.
  
  
  RESULTS
  We found, that in juvenile bone the large conductance, voltage and Ca(2+)-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, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sausbier
authors.forename: Christian
authors.initials: C
authors.lastname: Dullin
authors.forename: Jeannine
authors.initials: J
authors.lastname: Missbach-Guentner
authors.forename: Clement
authors.initials: C
authors.lastname: Kabagema
authors.forename: Katarina
authors.initials: K
authors.lastname: Flockerzie
authors.forename: Gerd Marten
authors.initials: GM
authors.lastname: Kuscher
authors.forename: Walter
authors.initials: W
authors.lastname: Stuehmer
authors.forename: Winfried
authors.initials: W
authors.lastname: Neuhuber
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: Frauke
authors.initials: F
authors.lastname: Alves
authors.forename: Matthias
authors.initials: M
authors.lastname: Sausbier
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D056657:Cathepsin K / Q000378:metabolism*; D004704:Endocrinology; D005260:Female; D017353:Gene Deletion; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013131:Spine / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013977:Tibia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D055114:X-Ray Microtomography
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D053245:RANK Ligand; D056657:Cathepsin K