Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil; Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas - SBFis/UNESP, Brazil; Department of Basic Sciences, São Paulo State University (UNESP), School of Dentistry of Araçatuba, São Paulo, Brazil.
Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil.
Eur J Pharmacol. 2021 Nov 15;911:174515. doi: 10.1016/j.ejphar.2021.174515. Epub 2021 Sep 20.
The sympathetic nervous system regulates bone remodeling via adrenergic receptors on the surface of bone cells. Herein, we evaluated the role of beta-adrenergic receptors (ADRBs) in osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs) derived from normotensive (Wistar) and spontaneously hypertensive rats (SHRs). BMSCs were cultured in a proliferation medium or osteogenic medium (OM). Cells cultured in OM were treated with carvedilol (Cv) or nebivolol (Nb).In OM, cell proliferation was decreased in both strains. In Wistar rats, Cv increased BMSC proliferation and increased alkaline phosphatase (ALP) activity in OM. Both Cv and Nb decreased ALP activity. In addition, Cv and Nb reduced mineral deposition in Wistar rats. Moreover, NB decreased mineralization in SHRs, exhibiting superior efficacy. In OM, cells from Wistar rats and SHRs showed Adrb1 and Adrb2 expression. On day 7, Nb, but not Cv, reduced Adrb1 levels in BMSCs from Wistar rats. Nb inhibited Adrb2 in both strains, and Cv demonstrated superior efficacy. In BMSCs from Wistar rats, both antagonists inhibited Runx2, osterix, and β-catenin; in SHRs, Cv and Nb inhibited only osterix. Cv decreased osteopontin (Opn), osteocalcin (Ocn), and bone morphogenetic protein (Bmp2) in BMSCs from Wistar rats, inhibiting only Opn in SHRs. Nb effectively inhibited Ocn, bone sialoprotein, and Bmp2, but not Ocn, in BMSCs from Wistar rats, while suppressing Opn in BMSCs from SHRs. In addition, Nb inhibited p-p38 in BMSCs from Wistar rats; Cv inhibited p-p38 in BMSCs from SHRs. In Wistar rats, both antagonists inhibited p-ERK and reduced p-JNK; Cv reduced these expressions only in SHRs. In conclusion, ADRB1, but not ADRB2, could be involved in the osteogenic differentiation of BMSCs from Wistar rats and SHRs. The high ADRB1 expression might suppress the effect of ADRB2 on BMSCs.
交感神经系统通过骨细胞表面的肾上腺素能受体调节骨重塑。在此，我们评估了β-肾上腺素能受体（ADRB）在来自正常血压（Wistar）和自发性高血压大鼠（SHR）的骨髓间充质干细胞（BMSC）成骨分化中的作用。将 BMSC 在增殖培养基或成骨培养基（OM）中培养。在 OM 中培养的细胞用卡维地洛（Cv）或奈比洛尔（Nb）处理。在 OM 中，两种品系的细胞增殖均减少。在 Wistar 大鼠中，Cv 增加 BMSC 增殖并增加 OM 中的碱性磷酸酶（ALP）活性。Cv 和 Nb 均降低 ALP 活性。此外，Cv 和 Nb 减少了 Wistar 大鼠的矿物质沉积。此外，NB 降低了 SHR 的矿化作用，显示出更好的疗效。在 OM 中，Wistar 大鼠和 SHR 的细胞均表达 Adrb1 和 Adrb2。在第 7 天，Nb 而不是 Cv 降低了 Wistar 大鼠 BMSC 中的 Adrb1 水平。Nb 抑制了两种品系的 Adrb2，而 Cv 则显示出更好的疗效。在 Wistar 大鼠的 BMSC 中，两种拮抗剂均抑制了 Runx2、osterix 和 β-连环蛋白；在 SHR 中，Cv 和 Nb 仅抑制了 osterix。Cv 降低了 Wistar 大鼠 BMSC 中的骨桥蛋白（Opn）、骨钙素（Ocn）和骨形态发生蛋白（Bmp2），而在 SHR 中仅降低了 Opn。Nb 有效抑制了 Wistar 大鼠 BMSC 中的 Ocn、骨唾液蛋白和 Bmp2，但不抑制 Ocn，而在 SHR 的 BMSC 中抑制了 Opn。此外，Nb 抑制了 Wistar 大鼠 BMSC 中的 p-p38；Cv 抑制了 SHR 中 BMSC 的 p-p38。在 Wistar 大鼠中，两种拮抗剂均抑制了 p-ERK 并降低了 p-JNK；Cv 仅在 SHR 中降低了这些表达。总之，ADRB1 而不是 ADRB2，可能参与了 Wistar 大鼠和 SHR 的 BMSC 成骨分化。高 ADRB1 表达可能抑制了 ADRB2 对 BMSC 的作用。
