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Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development
- Source :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, vol 33, iss 10, Yee, CS; Manilay, JO; Chang, JC; Hum, NR; Murugesh, DK; Bajwa, J; et al.(2018). Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development. JOURNAL OF BONE AND MINERAL RESEARCH, 33(10), 1748-1759. doi: 10.1002/jbmr.3467. UC Merced: Retrieved from: http://www.escholarship.org/uc/item/3c4679hb
- Publication Year :
- 2018
- Publisher :
- eScholarship, University of California, 2018.
-
Abstract
- Sclerostin (Sost) is a negative regulator of bone formation and blocking its function via antibodies has shown great therapeutic promise by increasing both bone mass in humans and animal models. Sclerostin deletion in Sost KO mice (Sost-/- ) causes high bone mass (HBM) similar to sclerosteosis patients. Sost-/- mice have been shown to display an up to 300% increase in bone volume/total volume (BV/TV), relative to age-matched controls. It has been postulated that the main source of skeletal sclerostin is the osteocyte. To understand the cell-type specific contributions to the HBM phenotype described in Sost-/- mice, as well as to address the endocrine and paracrine mode of action of sclerostin, we examined the skeletal phenotypes of conditional Sost loss-of-function (SostiCOIN/iCOIN ) mice with specific deletions in (1) the limb mesenchyme (Prx1-Cre; targets osteoprogenitors and their progeny); (2) midstage osteoblasts and their progenitors (Col1-Cre); (3) mature osteocytes (Dmp1-Cre); and (4) hypertrophic chondrocytes and their progenitors (ColX-Cre). All conditional alleles resulted in significant increases in bone mass in trabecular bone in both the femur and lumbar vertebrae, but only Prx1-Cre deletion fully recapitulated the amplitude of the HBM phenotype in the appendicular skeleton and the B-cell defect described in the global KO. Despite WT expression of Sost in the axial skeleton of Prx1-Cre deleted mice, these mice also had a significant increase in bone mass in the vertebrae, but the sclerostin released in circulation by the axial skeleton did not affect bone parameters in the appendicular skeleton. Also, both Col1 and Dmp1 deletion resulted in a similar 80% significant increase in trabecular bone mass, but only Col1 and Prx1 deletion resulted in a significant increase in cortical thickness. We conclude that several cell types within the Prx1-osteoprogenitor-derived lineages contribute significant amounts of sclerostin protein to the paracrine pool of Sost in bone. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
- Subjects :
- Inbred C57BL
Medical and Health Sciences
OSTEOCYTE
MSC
Mice
Engineering
Bone Marrow
Osteogenesis
Animals
Cell Lineage
Femur
Lymphocytes
SCLEROSTIN
OSTEOBLAST
Glycoproteins
Homeodomain Proteins
B-Lymphocytes
Extracellular Matrix Proteins
Lumbar Vertebrae
Osteoblasts
Integrases
Signal Transducing
Adaptor Proteins
Mesenchymal Stem Cells
Organ Size
X-Ray Microtomography
WnT SIGNALING
Biological Sciences
Stem Cell Research
Anatomy & Morphology
WnT
Phenotype
Musculoskeletal
Cancellous Bone
Osteoporosis
Intercellular Signaling Peptides and Proteins
Stem Cell Research - Nonembryonic - Non-Human
Female
CHONDROCYTE
Gene Deletion
Collagen Type X
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, vol 33, iss 10, Yee, CS; Manilay, JO; Chang, JC; Hum, NR; Murugesh, DK; Bajwa, J; et al.(2018). Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development. JOURNAL OF BONE AND MINERAL RESEARCH, 33(10), 1748-1759. doi: 10.1002/jbmr.3467. UC Merced: Retrieved from: http://www.escholarship.org/uc/item/3c4679hb
- Accession number :
- edsair.dedup.wf.001..48e51533f2503376d277e641078b2832