Parathyroid Hormone Shifts Cell Fate of a Leptin Receptor‐Marked Stromal Population from Adipogenic to Osteoblastic Lineage
Parathyroid Hormone Shifts Cell Fate of a Leptin Receptor‐Marked Stromal Population from Adipogenic to Osteoblastic Lineage
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DOI：
10.1002/jbmr.3811
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发表时间：
2019-10
影响因子：
6.2
通讯作者：
Mengyu Yang;A. Arai;N. Udagawa;Lijuan Zhao;Daisuke Nishida;Kohei Murakami;T. Hiraga;R. Takao-Kawabata;K. Matsuo;T. Komori;Yasuhiro Kobayashi;N. Takahashi;Y. Isogai;T. Ishizuya;A. Yamaguchi;T. Mizoguchi
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文献类型：
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作者：
Mengyu Yang;A. Arai;N. Udagawa;Lijuan Zhao;Daisuke Nishida;Kohei Murakami;T. Hiraga;R. Takao-Kawabata;K. Matsuo;T. Komori;Yasuhiro Kobayashi;N. Takahashi;Y. Isogai;T. Ishizuya;A. Yamaguchi;T. Mizoguchi
间歇性甲状旁腺激素（iPTH）治疗诱导骨合成代谢作用，导致骨质疏松性骨质流失的恢复。人类甲状旁腺激素通常用于骨质疏松症患者，因为它能诱导成骨细胞发生。然而，PTH刺激基质细胞群扩张和向成骨细胞谱系成熟的机制尚未阐明。小鼠遗传谱系追踪显示，iPTH治疗诱导骨髓间充质干细胞和祖细胞（MSPCs）成骨分化，其中携带瘦素受体（LepR）‐Cre。尽管这些发现表明PTH诱导的部分骨合成代谢作用是由于MSPCs的成骨承诺而发挥的，但对这些过程的体内机制细节知之甚少。在这里，我们发现LepR+MSPCs在iPTH治疗下分化为I型胶原(Col1)+成熟成骨细胞。随着成骨细胞的形成，骨表面周围Col1+成熟成骨细胞的数量增加，尽管它们大多数表现为静止细胞。然而，iPTH治疗后，骨组织附近LepR - Cre标记谱系细胞增殖状态的数量也有所增加。在iPTH治疗下，LepR+MSPCs群体中，作为成骨细胞标志物的SP7/osterix （Osx）和Col1的表达水平也有所增加。相反，脂肪细胞标志物Cebpb、Pparg和Zfp467的表达水平在该人群中下降。与这些结果一致，iPTH治疗抑制了5 -氟尿嘧啶或卵巢切除术（OVX）诱导的BM中LepR+MSPC衍生的脂肪生成，并增加了LepR+MSPC衍生的成骨细胞，即使在脂肪细胞诱导的条件下也是如此。iPTH对OVX大鼠骨质疏松性骨组织和BM脂肪组织的扩张有显著影响。这些结果表明，iPTH诱导了LepR+MSPCs的短暂增殖，并使它们的谱系从脂肪细胞向成骨细胞分化，导致成骨细胞群体扩大、静止和成熟。©2019美国骨与矿物研究学会。
Intermittent parathyroid hormone (iPTH) treatment induces bone anabolic effects that result in the recovery of osteoporotic bone loss. Human PTH is usually given to osteoporotic patients because it induces osteoblastogenesis. However, the mechanism by which PTH stimulates the expansion of stromal cell populations and their maturation toward the osteoblastic cell lineage has not be elucidated. Mouse genetic lineage tracing revealed that iPTH treatment induced osteoblastic differentiation of bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs), which carried the leptin receptor (LepR)‐Cre. Although these findings suggested that part of the PTH‐induced bone anabolic action is exerted because of osteoblastic commitment of MSPCs, little is known about the in vivo mechanistic details of these processes. Here, we showed that LepR+MSPCs differentiated into type I collagen (Col1)+ mature osteoblasts in response to iPTH treatment. Along with osteoblastogenesis, the number of Col1+ mature osteoblasts increased around the bone surface, although most of them were characterized as quiescent cells. However, the number of LepR‐Cre‐marked lineage cells in a proliferative state also increased in the vicinity of bone tissue after iPTH treatment. The expression levels of SP7/osterix (Osx) and Col1, which are markers for osteoblasts, were also increased in the LepR+MSPCs population in response to iPTH treatment. In contrast, the expression levels of Cebpb, Pparg, and Zfp467, which are adipocyte markers, decreased in this population. Consistent with these results, iPTH treatment inhibited 5‐fluorouracil‐ or ovariectomy (OVX)‐induced LepR+MSPC‐derived adipogenesis in BM and increased LepR+MSPC‐derived osteoblasts, even under the adipocyte‐induced conditions. Treatment of OVX rats with iPTH significantly affected the osteoporotic bone tissue and expansion of the BM adipose tissue. These results indicated that iPTH treatment induced transient proliferation of the LepR+MSPCs and skewed their lineage differentiation from adipocytes toward osteoblasts, resulting in an expanded, quiescent, and mature osteoblast population. © 2019 American Society for Bone and Mineral Research.