Nuclear Factor-κB p65 facilitates longitudinal bone growth by inducing growth plate chondrocyte proliferation and differentiation and by preventing apoptosis (Retracted article. See vol. 295, pg. 13691, 2020)
Nuclear Factor-κB p65 facilitates longitudinal bone growth by inducing growth plate chondrocyte proliferation and differentiation and by preventing apoptosis (Retracted article. See vol. 295, pg. 13691, 2020)
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DOI：
10.1074/jbc.m702991200
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发表时间：
2007-11-16
影响因子：
4.8
通讯作者：
De Luca, Francesco
中科院分区：
文献类型：
--
作者：
Wu, Shufang;Flint, Janna K.;De Luca, Francesco
核因子-kappaB是一组参与细胞增殖、分化和凋亡的转录因子。缺乏核因子-kappa B亚单位p50和p52的小鼠生长迟缓，这表明核因子-kappa B参与了骨生长。然而，目前尚不清楚这些小鼠骨骼生长的减少是否取决于生长板软骨细胞中缺乏核因子-kappaB的活性。利用培养的大鼠跖骨和分离的生长板软骨细胞，研究了两种核因子-kappaB抑制剂(吡咯烷二硫代氨基甲酸酯(PDTC)或BAY11-7082(Bay))、p65短干扰RNA(SiRNA)和p65过表达对软骨细胞增殖、分化和凋亡的影响。为了进一步确定其潜在的机制，我们研究了软骨细胞中核因子-kappa B p65和骨形态发生蛋白-2之间的功能相互作用。PDTC和Bay抑制了跖骨的线形生长。这种生长抑制是由于软骨细胞增殖和分化减少以及软骨细胞凋亡增加所致。在培养的软骨细胞中，抑制NF-kappa B p65的激活(由PDTC和Bay)和表达(由p65 siRNA)导致了在培养的跖骨中观察到的相同结果。相反，p65在培养的软骨细胞中过表达，可诱导软骨细胞的增殖和分化，并阻止细胞凋亡。虽然PDTC、Bay和p65 siRNA降低了培养的生长板软骨细胞BMP-2的表达，但p65的过表达增加了BMP-2的表达。BMP-2拮抗剂Noggin的加入中和了p65对软骨细胞增殖和分化的刺激作用及其抗凋亡作用。总之，我们的研究结果表明，在生长板软骨细胞中表达的核因子-kappa B p65通过诱导BMP-2的表达和活性来促进生长板软骨的形成和纵向骨的生长。
NF-kappa B is a group of transcription factors involved in cell proliferation, differentiation, and apoptosis. Mice deficient in the NF-kappa B subunits p50 and p52 have retarded growth, suggesting that NF-kappa B is involved in bone growth. Yet, it is not clear whether the reduced bone growth of these mice depends on the lack of NF-kappa B activity in growth plate chondrocytes. Using cultured rat metatarsal bones and isolated growth plate chondrocytes, we studied the effects of two NF-kappa B inhibitors ( pyrrolidine dithiocarbamate ( PDTC) or BAY11-7082 (BAY)), p65 short interference RNA ( siRNA), and of the overexpression of p65 on chondrocyte proliferation, differentiation, and apoptosis. To further define the underlying mechanisms, we studied the functional interaction between NF-kappa B p65 and BMP-2 in chondrocytes. PDTC and BAY suppressed metatarsal linear growth. Such growth inhibition resulted from decreased chondrocyte proliferation and differentiation and from increased chondrocyte apoptosis. In cultured chondrocytes, the inhibition of NF-kappa B p65 activation (by PDTC and BAY) and expression (by p65 siRNA) led to the same findings observed in cultured metatarsal bones. In contrast, overexpression of p65 in cultured chondrocytes induced chondrocyte proliferation and differentiation and prevented apoptosis. Although PDTC, BAY, and p65 siRNA reduced the expression of BMP-2 in cultured growth plate chondrocytes, the overexpression of p65 increased it. The addition of Noggin, a BMP-2 antagonist, neutralized the stimulatory effects of p65 on chondrocyte proliferation and differentiation, as well as its anti-apoptotic effect. In conclusion, our findings indicate that NF-kappa B p65 expressed in growth plate chondrocytes facilitates growth plate chondrogenesis and longitudinal bone growth by inducing BMP-2 expression and activity.