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Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism.
- Source :
-
Bone [Bone] 2019 Mar; Vol. 120, pp. 166-175. Date of Electronic Publication: 2018 Oct 25. - Publication Year :
- 2019
-
Abstract
- High-bone-mass (HBM)-causing missense mutations in the low density lipoprotein receptor-related protein-5 (Lrp5) are associated with increased osteoanabolic action and protection from disuse- and ovariectomy-induced osteopenia. These mutations (e.g., A214V and G171V) confer resistance to endogenous secreted Lrp5/6 inhibitors, such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). Cells in the osteoblast lineage are responsive to canonical Wnt stimulation, but recent work has indicated that osteoclasts exhibit both indirect and direct responsiveness to canonical Wnt. Whether Lrp5-HBM receptors, expressed in osteoclasts, might alter osteoclast differentiation, activity, and consequent net bone balance in the skeleton, is not known. To address this, we bred mice harboring heterozygous Lrp5 HBM-causing conditional knock-in alleles to Ctsk-Cre transgenic mice and studied the phenotype using DXA, μCT, histomorphometry, serum assays, and primary cell culture. Mice with HBM alleles induced in Ctsk-expressing cells (TG) exhibited higher bone mass and architectural properties compared to non-transgenic (NTG) counterparts. In vivo and in vitro measurements of osteoclast activity, population density, and differentiation yielded significant reductions in osteoclast-related parameters in female but not male TG mice. Droplet digital PCR performed on osteocyte enriched cortical bone tubes from TG and NTG mice revealed that ~8-17% of the osteocyte population (depending on sex) underwent recombination of the conditional Lrp5 allele in the presence of Ctsk-Cre. Further, bone formation parameters in the midshaft femur cortex show a small but significant increase in anabolic action on the endocortical but not periosteal surface. These findings suggest that Wnt/Lrp5 signaling in osteoclasts affects osteoclastogenesis and activity in female mice, but also that some of the changes in bone mass in TG mice might be due to Cre expression in the osteocyte population.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Absorptiometry, Photon
Alleles
Animals
Biomarkers blood
Bone Marrow Cells metabolism
Bone Resorption blood
Bone Resorption pathology
Bone and Bones diagnostic imaging
Cell Differentiation
Female
Integrases metabolism
Male
Mice, Transgenic
Organ Size genetics
Osteoclasts metabolism
Osteoclasts pathology
Osteogenesis genetics
Periosteum metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Recombination, Genetic genetics
Transgenes
X-Ray Microtomography
Bone and Bones metabolism
Cathepsin K metabolism
Low Density Lipoprotein Receptor-Related Protein-5 genetics
Mutation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2763
- Volume :
- 120
- Database :
- MEDLINE
- Journal :
- Bone
- Publication Type :
- Academic Journal
- Accession number :
- 30409757
- Full Text :
- https://doi.org/10.1016/j.bone.2018.10.007