Interference by adrenaline with chondrogenic differentiation through suppression of gene transactivation mediated by Sox9 family members.
Interference by adrenaline with chondrogenic differentiation through suppression of gene transactivation mediated by Sox9 family members.
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DOI：
10.1016/j.bone.2009.05.004
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发表时间：
2009-09
期刊：
影响因子：
4.1
通讯作者：
T. Takarada;H. Hojo;Mika Iemata;K. Sahara;Ayumi Kodama;N. Nakamura;E. Hinoi;Y. Yoneda
中科院分区：
文献类型：
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作者：
T. Takarada;H. Hojo;Mika Iemata;K. Sahara;Ayumi Kodama;N. Nakamura;E. Hinoi;Y. Yoneda
与成骨细胞相比，肾上腺素能信号转导机制在软骨细胞中的功能表达受到的关注较少。首次发现不同肾上腺素能受体(ADR)亚型在软骨ATDC5细胞和血管化前分离的小鼠跖骨中表达，但不表达其他与肾上腺素能信号相关的分子。在新生小鼠胫骨切片中，原位杂交发现β2AdR和α2aAdR在不同发育阶段的软骨细胞中均有表达。肾上腺素可通过β2AdR激活的cAMP/蛋白激酶A途径显著抑制多种成熟标志物的表达，而不影响培养的ATDC5细胞和跖骨的细胞增殖。肾上腺素还显著抑制软骨分化所必需的sry-type HMG box 9(Sox9)家族成员的基因反式激活，这种作用可被β受体拮抗剂普萘洛尔所阻断，并伴随着Sox6mRNA及相应蛋白水平的显著降低。全身应用心得安可显著促进小鼠股骨骨折骨痂中I型和X型胶原基因的表达，但对II型胶原基因的表达无明显影响。这些结果提示，在软骨细胞表达的β2AdR被激活后，肾上腺素可能通过下调SOX6的表达，进而抑制SOX9家族成员介导的基因反式激活，从而干扰软骨细胞的分化。
In contrast to osteoblasts, little attention has been paid to the functional expression of adrenergic signaling machineries in chondrocytes. Expression of mRNA was for the first time demonstrated for different adrenergic receptor (AdR) subtypes in chondrogenic ATDC5 cells and mouse metatarsals isolated before vascularization in culture, but not for other molecules related to adrenergic signaling. In neonatal mouse tibial sections, β2AdR and α2aAdR mRNA expression was found in chondrocytes at different developmental stages by in situ hybridization. Exposure to adrenaline significantly suppressed expression of several maturation markers through the cAMP/protein kinase A pathway activated by β2AdR without affecting cellular proliferation in both cultured ATDC5 cells and metatarsals. Adrenaline also significantly inhibited gene transactivation by sry-type HMG box 9 (Sox9) family members essential for chondrogenic differentiation in a manner prevented by the general βAdR antagonist propranolol, with a concomitant significant decrease in the levels of Sox6 mRNA and corresponding protein, in ATDC5 cells and primary cultured mouse costal chondrocytes. Systemic administration of propranolol significantly promoted the increased expression of mRNA for collagen I and collagen X, but not for collagen II, in callus of fractured femur in mice. These results suggest that adrenaline may interfere with chondrogenic differentiation through downregulation of Sox6 expression for subsequent suppression of gene transactivation mediated by Sox9 family members after activation of β2AdR expressed by chondrocytes.