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

Autor: Jeannine Missbach-Guentner, Walter Stuehmer, Gerd Marten Kuscher, Christian Dullin, Frauke Alves, Matthias Sausbier, Ulrike Sausbier, Clement Kabagema, Katarina Flockerzie, Peter Ruth, Winfried Neuhuber
Jazyk: angličtina
Rok vydání: 2011
Předmět:
BK channel
Bone density
Cathepsin K
Osteopenia and Osteoporosis
lcsh:Medicine
Osteoclasts
Biochemistry
Ion Channels
Bone remodeling
Diagnostic Radiology
Mice
0302 clinical medicine
Endocrinology
Bone Density
lcsh:Science
0303 health sciences
Multidisciplinary
biology
Animal Models
medicine.anatomical_structure
Medicine
Female
Radiology
Algorithms
Research Article
musculoskeletal diseases
medicine.medical_specialty
Medizinische Fakultät -ohne weitere Spezifikation
Bone resorption
03 medical and health sciences
Model Organisms
Computed Tomography
Osteoprotegerin
Osteoclast
Internal medicine
medicine
Animals
ddc:610
Large-Conductance Calcium-Activated Potassium Channels
Biology
bone resorption
osteoporosis
030304 developmental biology
Tibia
lcsh:R
RANK Ligand
Proteins
X-Ray Microtomography
medicine.disease
Spine
Osteopenia
Bone Diseases
Metabolic
Solubility
Computer Science
biology.protein
Women's Health
lcsh:Q
030217 neurology & neurosurgery
Gene Deletion
Zdroj: PLoS ONE
PLoS ONE, Vol 6, Iss 6, p e21168 (2011)
Popis: 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 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. 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. peerReviewed
Databáze: OpenAIRE
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