Chloroquine increases osteoclast activity in vitro but does not improve the osteopetrotic bone phenotype of ADO2 mice.

Autor: Alam I; Medicine, Indiana University School of Medicine, IN 46202, USA. Electronic address: ialam@iu.edu., Gerard-O'Riley RL; Medicine, Indiana University School of Medicine, IN 46202, USA., Acton D; Medicine, Indiana University School of Medicine, IN 46202, USA., Hardman SL; Medicine, Indiana University School of Medicine, IN 46202, USA., Hong JM; Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, IN 46202, USA., Bruzzaniti A; Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, IN 46202, USA. Electronic address: abruzzan@iu.edu., Econs MJ; Medicine, Indiana University School of Medicine, IN 46202, USA; Medical and Molecular Genetics, Indiana University School of Medicine, IN 46202, USA.
Jazyk: angličtina
Zdroj: Bone [Bone] 2021 Dec; Vol. 153, pp. 116160. Date of Electronic Publication: 2021 Aug 28.
DOI: 10.1016/j.bone.2021.116160
Abstrakt: Autosomal Dominant Osteopetrosis type II (ADO2) is a bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene. We created mouse models of ADO2 by introducing a knock-in (p.G213R) mutation in the Clcn7 gene, which is analogous to one of the common mutations (G215R) found in humans. The mutation leads to severe osteopetrosis and lethality in homozygous mice but produces substantial phenotypic variability in heterozygous mice on different genetic backgrounds that phenocopy the human disease of ADO2. ADO2 is an osteoclast-intrinsic disease, and lysosomal enzymes and proteins are critical for osteoclast activity. Chloroquine (CQ) is known to affect lysosomal trafficking, intracellular signaling and the lysosomal and vesicular pH, suggesting it might improve ADO2 osteoclast function. We tested this hypothesis in cell culture studies using osteoclasts derived from wild-type (WT or ADO2 +/+ ) and ADO2 heterozygous (ADO2 +/- ) mice and found that CQ and its metabolite desethylchloroquine (DCQ), significantly increased ADO2 +/- osteoclasts bone resorption activity in vitro, whereas bone resorption of ADO2 +/+ osteoclasts was increased only by DCQ. In addition, we exploited our unique animal model of ADO2 on 129 background to identify the effect of CQ for the treatment of ADO2. Female ADO2 mice at 8 weeks of age were treated with 5 doses of CQ (1, 2.5, 5, 7.5 and 10 mg/kg BW/day) via drinking water for 6 months. Bone mineral density and bone micro-architecture were analyzed by longitudinal in vivo DXA and micro-CT at baseline, 3 and 6 months. Serum bone biomarkers (CTX, TRAP and P1NP) were also analyzed at these time points. CQ treatment at the doses tested failed to produce any significant changes of aBMD, BMC (whole body, femur and spine) and trabecular BV/TV (distal femur) in ADO2 mice compared to the control group (water only). Further, levels of bone biomarkers were not significantly changed due to CQ treatment in these mice. Our findings indicate that while CQ increased osteoclast activity in vitro, it did not improve the osteopetrotic bone phenotypes in ADO2 heterozygous mice.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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