Reactivities of a Prostanoid EP2 Agonist, Omidenepag, Are Useful for Distinguishing between 3D Spheroids of Human Orbital Fibroblasts without or with Graves' Orbitopathy.

Abstract

BACKGROUND:

To obtain new insights into the activation of the thyroid-stimulating hormone (TSH) and insulin-like growth factor 1 (IGF-1) receptors in human orbital fibroblasts (n-HOFs), the effects of the prostanoid EP2 agonist, omidenepag (OMD), and a rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, ripasudil (Rip) were evaluated using three-dimension (3D) n-HOFs spheroids in the absence and presence of the recombinant human TSH receptor antibodies, M22 and IGF-1.

METHODS:

The effects of 100 nM OMD or 10 μM Rip on the physical properties, size, stiffness, and mRNA expression of several extracellular matrix (ECM) molecules, their regulator, inflammatory cytokines, and endoplasmic reticulum (ER) stress-related factors were examined and compared among 3D spheroids of n-HOFs, M22-/IGF-1-activated n-HOFs and GO-related human orbital fibroblasts (GHOFs).

RESULTS:

The physical properties and mRNA expressions of several genes of the 3D n-HOFs spheroids were significantly and diversely modulated by the presence of OMD or Rip. The OMD-induced effects on M22-/IGF-1-activated n-HOFs were similar to the effects caused by GHOHs, but quite different from those of n-HOFs.

CONCLUSIONS:

The findings presented herein indicate that the changes induced by OMD may be useful in distinguishing between n-HOFs and GHOFs.

• Authors: Yosuke Ida, Hanae Ichioka, Masato Furuhashi, Fumihito Hikage, Megumi Watanabe, Araya Umetsu, Hiroshi Ohguro
• Journal: Cells (Cells) Vol. 10 Issue 11 (11 16 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34831419 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Isoquinolines
• K-115
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• RNA, Messenger
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Thyrotropin
• Sulfonamides
• Receptor, IGF Type 1
• rho-Associated Kinases
• omidenepag isopropyl
• Glycine

Topics

• Cell Size (drug effects)
• Cytokines (metabolism)
• Endoplasmic Reticulum Stress (drug effects, genetics)
• Extracellular Matrix (genetics, metabolism)
• Fibroblasts (drug effects, pathology)
• Gene Expression Regulation (drug effects)
• Glycine (analogs & derivatives, pharmacology)
• Graves Ophthalmopathy (diagnosis, genetics, pathology)
• Humans
• Isoquinolines (pharmacology)
• Orbit (pathology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Receptor, IGF Type 1 (metabolism)
• Receptors, Prostaglandin E, EP2 Subtype (agonists, metabolism)
• Receptors, Thyrotropin (metabolism)
• Spheroids, Cellular (drug effects, pathology)
• Sulfonamides (pharmacology)
• rho-Associated Kinases (antagonists & inhibitors, metabolism)