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Parathyroid hormone regulates fates of murine osteoblast precursors in vivo
Deepak H. Balani, … , Noriaki Ono, Henry M. Kronenberg
Deepak H. Balani, … , Noriaki Ono, Henry M. Kronenberg
Published September 1, 2017; First published July 31, 2017
Citation Information: J Clin Invest. 2017;127(9):3327-3338. https://doi.org/10.1172/JCI91699.
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Categories: Research Article Bone biology Stem cells

Parathyroid hormone regulates fates of murine osteoblast precursors in vivo

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Abstract

Teriparatide, a recombinant form of parathyroid hormone (PTH), is the only approved treatment for osteoporosis that increases the rate of bone formation. Teriparatide increases osteoblast numbers by suppressing osteoblast apoptosis and activating bone-lining cells. No direct evidence for teriparatide’s actions on early cells of the osteoblast lineage has been demonstrated. Here, we have employed a lineage-tracing strategy that uses a tamoxifen-dependent, promoter-driven cre to mark early cells of the osteoblast lineage in adult mice. We show that teriparatide increases the numbers of osteoblast precursors and drives their differentiation into mature osteoblasts. Unexpectedly, following withdrawal of teriparatide therapy, bone marrow adipocytes increased dramatically in number. Some of these adipocytes derived from cells marked by Sox9-cre expression weeks earlier. Continued therapy with teriparatide prevented the appearance of adipocytes. Selective, inducible deletion of the PTH receptor in Sox9-cre cells demonstrated that PTH receptor expression is required for teriparatide-mediated increases in early osteoblast precursors. The increase in early precursors after teriparatide administration was associated with robust suppression of precursor apoptosis without affecting their rate of proliferation. Thus, teriparatide increases the numbers of early cells of the osteoblast lineage, hastens their differentiation into osteoblasts, and suppresses their differentiation into adipocytes in vivo.

Authors

Deepak H. Balani, Noriaki Ono, Henry M. Kronenberg

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Figure 1

Sox9-creERT2+ cells label early cells of the osteoblast lineage in postnatal mice in vivo.

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Sox9-creERT2+ cells label early cells of the osteoblast lineage in post...
(A and B) Representative long bone section from Sox9-creERT2; R26RTomato; Ocn-GFPtpz mice at 4 days (A) and 27 days (B) after tamoxifen injection. Sox9-creERT2; R26RTomato cells at P7 were seen as articular chondrocytes (no. 1), in the metaphysis (no. 2), and at endocortical (no. 3) and periosteal (no. 4) surfaces and did not overlap with Ocn-GFPtpz. At P30, several Sox9-creERT2; R26RTomato cells coincided with Ocn-GFPtpz cells in the metaphysis and at endocortical and periosteal surfaces, shown as yellow cells (arrows). Scale bars: 0.5 mm. (C and D) The number of Sox9-creERT2; R26RTdTomato+ (TOM+) cells counted in the metaphysis and cortical diaphyseal bone in standard regions described in Supplemental Figure 11 on day 4 and day 27 after tamoxifen injection. (E and F) The number of Sox9-creERT2; R26RTomato+ (TOM+GFPtpz+) cells that also colocalized Ocn-GFPtpz protein in the metaphysis and cortical bone in diaphysis counted on day 4 and day 27 after tamoxifen injection. Data represent mean ± SD from 3 independent experiments with 3 mice/experiment. (G) Representative confocal image of Sox9-creERT2; R26RTdTomato+ and perilipin-positive adipocytes (arrows) in the distal tibia after 57 days of tamoxifen administration. Data represent 3 independent experiments with 3 mice/experiment.
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