The TrkA agonist gambogic amide augments skeletal adaptation to mechanical loading.
The TrkA agonist gambogic amide augments skeletal adaptation to mechanical loading.
复制标题
TrkA激动剂藤黄酰胺增强骨骼对机械负荷的适应。
DOI：
10.1016/j.bone.2021.115908
复制
发表时间：
2021-06
期刊：
影响因子：
4.1
通讯作者：
Tomlinson RE
中科院分区：
文献类型：
--
作者：
Fioravanti G;Hua PQ;Tomlinson RE
成熟骨的骨膜和骨内膜表面密集地分布着表达神经生长因子(NGF)高亲和力受体TrkA的感觉神经。在以前的工作中，我们证明了外源性NGF通过激活Wnt信号显著增加了负荷诱导的骨形成。然而，NGF的翻译潜力受到诱导小鼠和人类严重的机械和热痛敏的限制。在这里，我们测试了最近发现的一种强大的TrkA小分子激动剂--伽玛能胺(GA)在痛觉过敏和负荷诱导骨形成中的作用。行为分析用于评估轴向前肢加压后一周内的疼痛。与我们的预期相反，GA治疗与减少负荷前肢的使用或对热刺激的敏感性无关。此外，动态组织形态计量学显示，与赋形剂治疗相比，相对骨膜成形率显著增加。此外，我们发现GA处理与负重肢体每骨表面的成骨细胞数量增加以及NGF、Wnt7b和Axin2mRNA表达的折叠变化显著增加(与对照组相比)。为了直接检测GA对成骨细胞的影响，我们在含有NGF、GA或载体(对照组)的成骨分化培养液中培养MC3T3-E1细胞长达21天。含有GA的培养液以剂量依赖的方式诱导成骨细胞分化标志物Runx2、Bglap2和SP7显著上调，而NGF处理与这些标志物的显著上调无关。此外，与我们在体内的研究结果一致，我们观察到50 nM的GA在第3天和第7天都上调了NGF的表达。然而，最高剂量的GA(500 NM)处理的细胞显著增加了凋亡和抑制了细胞增殖。总之，我们的研究表明，GA可能有助于增强骨骼对机械力的适应，而不会导致痛觉过敏。
The periosteal and endosteal surfaces of mature bone are densely innervated by sensory nerves expressing TrkA, the high-affinity receptor for nerve growth factor (NGF). In previous work, we demonstrated that administration of exogenous NGF significantly increased load-induced bone formation through the activation of Wnt signaling. However, the translational potential of NGF is limited by the induction of substantial mechanical and thermal hyperalgesia in mice and humans. Here, we tested the effect of gambogic amide (GA), a recently identified robust small molecule agonist for TrkA, on hyperalgesia and load-induced bone formation. Behavioral analysis was used to assess pain up to one week after axial forelimb compression. Contrary to our expectations, GA treatment was not associated with diminished use of the loaded forelimb or sensitivity to thermal stimulus. Furthermore, dynamic histomorphometry revealed a significant increase in relative periosteal bone formation rate as compared to vehicle treatment. Additionally, we found that GA treatment was associated with an increase in the number of osteoblasts per bone surface in loaded limbs as well as a significant increase in the fold change of Ngf, Wnt7b, and Axin2 mRNA expression as compared to vehicle (control). To test the effect of GA on osteoblasts directly, we cultured MC3T3-E1 cells for up to 21 days in osteogenic differentiation media containing NGF, GA, or vehicle (control). Media containing GA induced the significant upregulation of the osteoblastic differentiation markers Runx2, Bglap2, and Sp7 in a dose-dependent manner, whereas treatment with NGF was not associated with any significant increases in these markers. Furthermore, consistent with our in vivo findings, we observed that administration of 50 nM of GA upregulated expression of Ngf at both Day 3 and Day 7. However, cells treated with the highest dose of GA (500 nM) had significantly increased apoptosis and impaired cell proliferation. In conclusion, our study indicates GA may be useful for augmenting skeletal adaptation to mechanical forces without inducing hyperalgesia.
登录
查看更多内容
影响因子：
3.3
作者：
Castañeda-Corral G;Jimenez-Andrade JM;Bloom AP;Taylor RN;Mantyh WG;Kaczmarska MJ;Ghilardi JR;Mantyh PW
通讯作者：
Mantyh PW
DOI：
10.1073/pnas.061020198
发表时间：
2001-03-13
影响因子：
11.1
作者：
Lee, FS;Chao, MV
通讯作者：
Chao, MV
影响因子：
4.1
作者：
Kelly, Natalie H.;Schimenti, John C.;van der Meulen, Marjolein C. H.
通讯作者：
van der Meulen, Marjolein C. H.
影响因子：
6.2
作者：
Hens, JR;Wilson, KM;Wysolmerski, JJ
通讯作者：
Wysolmerski, JJ
DOI：
10.1111/ejn.12462
发表时间：
2014-02
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Mantyh PW
通讯作者：
Mantyh PW