Minoxidil weakens newly synthesized collagen in fibrotic synoviocytes from osteoarthritis patients

Stefan Sarkovich; Peter P Issa; Andrew Longanecker; Davis Martin; Kaitlyn Redondo; Patrick McTernan; Jennifer Simkin; Luis Marrero

doi:10.1186/s40634-023-00650-8

Minoxidil weakens newly synthesized collagen in fibrotic synoviocytes from osteoarthritis patients

J Exp Orthop. 2023 Aug 21;10(1):84. doi: 10.1186/s40634-023-00650-8.

Authors

Affiliations

¹ Department of Orthopaedic Surgery, Louisiana State University Health Sciences Center, 2021 Perdido St., Center for Advanced Learning and Simulation, 7th floor, New Orleans, LA, 70112, USA.
² School of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier St., Lions Building, 5th floor, New Orleans, LA, 70112, USA.
³ Morphology and Imaging Core, Louisiana State University Health Sciences Center, 533 Bolivar St., Clinical Sciences Research Building, 5th floor, New Orleans, LA, 70112, USA.
⁴ Department of Physiology, Louisiana State University Health Sciences Center, 533 Bolivar St., Clinical Sciences Research Building, 4th floor, New Orleans, LA, 70112, USA.
⁵ Department of Orthopaedic Surgery, Louisiana State University Health Sciences Center, 2021 Perdido St., Center for Advanced Learning and Simulation, 7th floor, New Orleans, LA, 70112, USA. lmarre@lsuhsc.edu.
⁶ School of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier St., Lions Building, 5th floor, New Orleans, LA, 70112, USA. lmarre@lsuhsc.edu.
⁷ Morphology and Imaging Core, Louisiana State University Health Sciences Center, 533 Bolivar St., Clinical Sciences Research Building, 5th floor, New Orleans, LA, 70112, USA. lmarre@lsuhsc.edu.

^# Contributed equally.

Abstract

Purpose: Synovial fibrosis (SFb) formation and turnover attributable to knee osteoarthritis (KOA) can impart painful stiffness and persist following arthroplasty. To supplement joint conditioning aimed at maximizing peri-operative function, we evaluated the antifibrotic effect of Minoxidil (MXD) on formation of pyridinoline (Pyd) cross-links catalyzed by Plod2-encoded lysyl hydroxylase (LH)2b that strengthen newly synthesized type-I collagen (COL1) in fibroblastic synovial cells (FSCs) from KOA patients. MXD was predicted to decrease Pyd without significant alterations to Col1a1 transcription by FSCs stimulated with transforming growth factor (TGF)β1.

Methods: Synovium from 10 KOA patients grouped by SFb severity was preserved for picrosirius and LH2b histology or culture. Protein and RNA were purified from fibrotic FSCs after 8 days with or without 0.5 µM MXD and/or 4 ng/mL of TGFβ1. COL1 and Pyd protein concentrations from ELISA and expression of Col1a1, Acta2, and Plod2 genes by qPCR were compared by parametric tests with α = 0.05.

Results: Histological LH2b expression corresponded to SFb severity. MXD attenuated COL1 output in KOA FSCs but only in the absence of TGFβ1 and consistently decreased Pyd under all conditions with significant downregulation of Plod2 but minimal alterations to Col1a1 and Acta2 transcripts.

Conclusions: MXD is an attractive candidate for local antifibrotic pharmacotherapy for SFb by compromising the integrity of newly formed fibrous deposits by FSCs during KOA and following arthroplasty. Targeted antifibrotic supplementation could improve physical therapy and arthroscopic lysis strategies aimed at breaking down joint scarring. However, the effect of MXD on other joint-specific TGFβ1-mediated processes or non-fibrotic components requires further investigation.

Keywords: Arthroplasty; Collagen type I; Fibrosis; Knee; Lysyl hydroxylase; Minoxidil; Osteoarthritis; Pyridinoline; Synovial fibroblasts; Synovium.

Grants and funding

U54 GM104940/GM/NIGMS NIH HHS/United States