Abstract
BackgroundThe 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 FindingsWe 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/SignificanceOur 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.
Highlights
Osteopenia, which is discussed to be the clinical pre-stage of idiopathic osteoporosis, is characterized by a reduced bone mineral density and changes in bone micro-architecture leading to a higher risk for fragility fractures in juvenile females [1]
Our data presented in this study establishes for the first time, that BK channels expressed in native osteoclasts control bonedegrading activity by regulating Cathepsin K release
Targeted deletion of BK channel in mice resulted in an osteoclastautonomous osteopenia, being apparent in juvenile females displaying normal bone-influencing endocrinology and osteoclastogenesis, accompanied by increased plasma Cathepsin K levels, reduced bone mineral density and enhanced porosity of trabecular micro-architecture, but without obvious fragility fractures
Summary
Osteopenia, which is discussed to be the clinical pre-stage of idiopathic osteoporosis, is characterized by a reduced bone mineral density and changes in bone micro-architecture leading to a higher risk for fragility fractures in juvenile females [1]. Its prevalence in the juvenile population of western industrialized countries is around 16 per cent and osteopenia occurs more often in young pre-menopausal females than idiopathic osteoporosis, which has a prevalence of lower than one per cent in that group [2]. Mechanisms leading to osteopenia still remain to be elucidated. 75 potassium channel types are known [16]. 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
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