Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• PloS one, 2011-06, Vol.6 (6), p.e21168

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.