Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice.
Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice.
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DOI：
10.1172/jci15543
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发表时间：
2003-09
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影响因子：
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通讯作者：
Xue-Bin Wu;Yanan Li;A. Schneider;Wanqin Yu;G. Rajendren;J. Iqbal;Matsuo Yamamoto;Mohammad Alam;L. Brunet;H. Blair;M. Zaidi;E. Abe
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作者：
Xue-Bin Wu;Yanan Li;A. Schneider;Wanqin Yu;G. Rajendren;J. Iqbal;Matsuo Yamamoto;Mohammad Alam;L. Brunet;H. Blair;M. Zaidi;E. Abe
我们描述了骨形态发生蛋白(BMP)抑制剂noggin的过表达对成骨细胞分化和骨形成的影响。成骨细胞和软骨细胞系的细胞，以及骨髓巨噬细胞，在noggin基因缺失的地方插入了LacZ转基因的成年noggin+/-小鼠中，显示出强烈的β-半乳糖组织或细胞染色。然而，尽管BMP水平相同，20个月大的C57BL/6J和4个月大的加速衰老小鼠(SAM-P6小鼠)的成骨细胞noggin的表达水平分别比4个月大的C57BL/6J小鼠和SAM-R1(对照)小鼠高出近四倍。过度表达noggin基因的U-33前成骨细胞表现出成熟缺陷，同时RUNX-2、骨涎蛋白、骨钙素和RANK-L的表达降低。Noggin不能抑制BMP受体1A型，ca-ALK-3的无配体信号和促分化作用。在成熟的骨钙素阳性的成骨细胞中过表达noggin的转基因小鼠在4个月和8个月时骨密度和骨形成率显著下降，组织学证据显示小梁骨和CFU成骨细胞集落减少。总之，这些结果提供了令人信服的证据，证明在成熟的成骨细胞中表达的noggin可以抑制成骨细胞的分化和骨形成。因此，在生物老化过程中，noggin的过量产生可能会导致成骨细胞的形成和功能受损，从而导致净骨丢失。
We describe the effects of the overexpression of noggin, a bone morphogenetic protein (BMP) inhibitor, on osteoblast differentiation and bone formation. Cells of the osteoblast and chondrocyte lineages, as well as bone marrow macrophages, showed intense beta-gal histo- or cytostaining in adult noggin+/- mice that had a LacZ transgene inserted at the site of noggin deletion. Despite identical BMP levels, however, osteoblasts of 20-month-old C57BL/6J and 4-month-old senescence-accelerated mice (SAM-P6 mice) had noggin expression levels that were approximately fourfold higher than those of 4-month-old C57BL/6J and SAM-R1 (control) mice, respectively. U-33 preosteoblastic cells overexpressing the noggin gene showed defective maturation and, in parallel, a decreased expression of Runx-2, bone sialoprotein, osteocalcin, and RANK-L. Noggin did not inhibit the ligandless signaling and pro-differentiation action of the constitutively activated BMP receptor type 1A, ca-ALK-3. Transgenic mice overexpressing noggin in mature osteocalcin-positive osteoblasts showed dramatic decreases in bone mineral density and bone formation rates with histological evidence of decreased trabecular bone and CFU-osteoblast colonies at 4 and 8 months. Together, the results provide compelling evidence that noggin, expressed in mature osteoblasts, inhibits osteoblast differentiation and bone formation. Thus, the overproduction of noggin during biological aging may result in impaired osteoblast formation and function and hence, net bone loss.