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

• Published in: PloS one 2011-06, Vol.6 (6), p.e21168
• Main Authors: Sausbier, Ulrike, Dullin, Christian, Missbach-Guentner, Jeannine, Kabagema, Clement, Flockerzie, Katarina, Kuscher, Gerd Marten, Stuehmer, Walter, Neuhuber, Winfried, Ruth, Peter, Alves, Frauke, Sausbier, Matthias
• Format: Article
• Language: English
• Subjects: Adenosine; Angina pectoris; Animals; Apoptosis; Biocompatibility; Biology; Bone density; Bone Density - drug effects; Bone Diseases, Metabolic - diagnostic imaging; Bone Diseases, Metabolic - metabolism; Bone Diseases, Metabolic - pathology; Bone Diseases, Metabolic - physiopathology; Bone matrix; Bone mineral density; Bone remodeling; Bone resorption; Bones; Calcification; Calcium; Calcium channels (voltage-gated); Calcium conductance; Calcium ions; CAT scans; Cathepsin K; Cathepsin K - secretion; Cathepsins; Collagen; Collagenase; Computed tomography; Computer Science; Depolarization; Endocrinology; Female; Females; Flat panel displays; Gene Deletion; Health aspects; Large-Conductance Calcium-Activated Potassium Channels - deficiency; Large-Conductance Calcium-Activated Potassium Channels - genetics; Long bone; Medicine; Membrane potential; Mice; Molecular biology; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteoclasts - secretion; Osteopenia; Osteoporosis; Osteoprotegerin; Pharmacology; Pharmacy; Phenotypes; Plasma levels; Porosity; Potassium; Potassium channels; Product enhancement; RANK Ligand - chemistry; RANK Ligand - pharmacology; Resistance; Rodents; Solubility; Spine; Spine - diagnostic imaging; Spine - metabolism; Spine - pathology; Spine - physiopathology; Target recognition; Tibia - diagnostic imaging; Tibia - metabolism; Tibia - pathology; Tibia - physiopathology; Toxicology; Vertebrae; X-Ray Microtomography
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021168

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. 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. 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.