Szegeczki Vince, Pálfi Andrea, Fillér Csaba, Hinnah Barbara, Tóth Anna, Kovács Lili Sarolta, Jüngling Adél, Zákány Róza, Reglődi Dóra, Juhász Tamás
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
Department of Anatomy, HUN-REN-PTE PACAP Research Team, Medical School, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
Int J Mol Sci. 2025 May 26;26(11):5088. doi: 10.3390/ijms26115088.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that plays significant regulatory roles in the differentiation of the central nervous system and peripheral organs. A lack of the neuropeptide can lead to abnormalities in long bone development. In callus formation, a possible signaling balance shift in PACAP KO mice has been demonstrated, but Notch signalization, with its potential connection with PACAP 1-38, has not been investigated in ossification. Our main goal was to show connections between PACAP and Notch signaling in osteogenesis. Notch signalization showed an elevation in the long bones of PACAP-gene-deficient mice, and it was also elevated during the PACAP 1-38 treatment of UMR-106 and MC3T3-E1 osteogenic cells. Moreover, the inhibition of Notch signaling was compensated by the addition of PACAP 1-38 in vitro. The inorganic and organic matrix production of UMR-106 cells was increased during PACAP 1-38 treatment under the inhibition of Notch signaling. As a possible common target, the expression and nuclear translocation of NFATc1 transcription factor was increased during the disturbance of PACAP and Notch signaling. Our results indicate a possible synergistic regulation during bone formation by PACAP and Notch signalization. The crosstalk between Notch and PACAP signaling pathways highlights the complexity of bone development and homeostasis.
垂体腺苷酸环化酶激活多肽（PACAP）是一种神经肽，在中枢神经系统和外周器官的分化中发挥着重要的调节作用。缺乏这种神经肽会导致长骨发育异常。在骨痂形成过程中，已证实PACAP基因敲除小鼠可能存在信号平衡转移，但尚未在骨化过程中研究Notch信号及其与PACAP 1-38的潜在联系。我们的主要目标是揭示PACAP与Notch信号在骨生成中的联系。Notch信号在PACAP基因缺陷小鼠的长骨中升高，并且在UMR-106和MC3T3-E1成骨细胞的PACAP 1-38处理过程中也升高。此外，在体外添加PACAP 1-38可补偿Notch信号的抑制。在Notch信号抑制下，PACAP 1-38处理期间UMR-106细胞的无机和有机基质生成增加。作为一个可能的共同靶点，在PACAP和Notch信号紊乱期间，NFATc1转录因子的表达和核转位增加。我们的结果表明，PACAP和Notch信号在骨形成过程中可能存在协同调节。Notch和PACAP信号通路之间的相互作用凸显了骨发育和稳态的复杂性。
