Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development.

Autor: Yee CS; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, CA, USA.; Molecular Cell Biology Unit, School of Natural Sciences, University of California-Merced, Merced, CA, USA., Manilay JO; Molecular Cell Biology Unit, School of Natural Sciences, University of California-Merced, Merced, CA, USA., Chang JC; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, CA, USA.; Molecular Cell Biology Unit, School of Natural Sciences, University of California-Merced, Merced, CA, USA., Hum NR; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, CA, USA., Murugesh DK; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, CA, USA., Bajwa J; Molecular Cell Biology Unit, School of Natural Sciences, University of California-Merced, Merced, CA, USA., Mendez ME; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, CA, USA.; Molecular Cell Biology Unit, School of Natural Sciences, University of California-Merced, Merced, CA, USA., Economides AE; Regeneron, Tarrytown, NY, USA., Horan DJ; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Robling AG; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Loots GG; Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, CA, USA.; Molecular Cell Biology Unit, School of Natural Sciences, University of California-Merced, Merced, CA, USA.
Jazyk: angličtina
Zdroj: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2018 Oct; Vol. 33 (10), pp. 1748-1759. Date of Electronic Publication: 2018 Jun 29.
DOI: 10.1002/jbmr.3467
Abstrakt: 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 (Sost iCOIN/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.
(© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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