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Title: Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development: DELETION OF Sost IN MSC-DERIVED LINEAGES

Journal Article · · Journal of Bone and Mineral Research
DOI: https://doi.org/10.1002/jbmr.3467 · OSTI ID:1512582
 [1];  [2];  [1];  [3];  [3];  [2];  [1];  [4];  [5];  [5];  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California, Merced, CA (United States)
  2. Univ. of California, Merced, CA (United States)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  4. Regeneron, Tarrytown NY (United States)
  5. Indiana Univ. School of Medicine, Indianapolis, IN (United States)
+ Show Author Affiliations

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.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA)
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
1512582
Report Number(s):
LLNL-JRNL-739165; 892575
Journal Information:
Journal of Bone and Mineral Research, Vol. 33, Issue 10; ISSN 0884-0431
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 37 works
Citation information provided by
Web of Science

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Cited By (4)

Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies journal March 2019
The Effects of Sclerostin on the Immune System journal January 2020
The role of osteoblasts in energy homeostasis journal August 2019
Cytoprotective Effect of Taurine against Hydrogen Peroxide-Induced Oxidative Stress in UMR-106 Cells through the Wnt/β-Catenin Signaling Pathway journal November 2018

Figures / Tables (14)

Table 1(p. 24)table Table 1
Table 2(p. 25)table Table 2
Table 3(p. 26)table Table 3
Fig. 1(p. 27)figure Fig. 1
Fig. 2(p. 28)figure Fig. 2
Fig. 3(p. 29)figure Fig. 3
Fig. 4(p. 30)figure Fig. 4
Fig. 5(p. 31)figure Fig. 5
Supplementary Fig. 1(p. 32)figure Supplementary Fig. 1
Supplementary Fig. 2 Parts A and B(p. 33)figure Supplementary Fig. 2 Parts A and B
Supplementary Fig. 2 Part C(p. 34)figure Supplementary Fig. 2 Part C
Supplementary Fig. 3(p. 35)figure Supplementary Fig. 3
Supplementary Fig. 4(p. 36)figure Supplementary Fig. 4
Supplementary Fig. 5(p. 37)figure Supplementary Fig. 5

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