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.

中文翻译：

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甲状旁腺激素在体内调节鼠成骨细胞前体的命运

特立帕肽是甲状旁腺激素（PTH）的重组形式，是批准的唯一可提高骨形成速率的骨质疏松症治疗方法。特立帕肽通过抑制成骨细胞凋亡和激活骨衬细胞来增加成骨细胞数量。没有直接证据表明teriparatide对成骨细胞谱系的早期细胞有作用。在这里，我们采用了谱系追踪策略，该策略使用他莫昔芬依赖性，启动子驱动的cre标记成年小鼠成骨细胞谱系的早期细胞。我们表明，teriparatide增加了成骨细胞前体的数量，并驱动其分化为成熟的成骨细胞。出乎意料的是，在停用特立帕肽治疗之后，骨髓脂肪细胞的数量急剧增加。这些脂肪细胞中的一些来源于标有的细胞Sox9 -cre表达在数周前完成。特立帕肽的持续治疗阻止了脂肪细胞的出现。Sox9 -cre细胞中PTH受体的选择性诱导性缺失表明，特立帕肽介导的早期成骨细胞前体增加需要PTH受体表达。给予特立帕肽后早期前体细胞的增加与前体细胞凋亡的强烈抑制有关，而不影响其增殖速率。因此，在体内，特立帕肽增加了成骨细胞谱系的早期细胞的数量，加速了它们向成骨细胞的分化，并抑制了它们向脂肪细胞的分化。