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Vol. 21. Issue 3.
(March 2025)
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Vol. 21. Issue 3.
(March 2025)
Brief report
Effect of Plasminogen Activator Inhibitor-1 on extracellular matrix homeostasis in scaffold-free spheroids from human chondrocytes
Efecto del inhibidor del activador del plasminógeno-1 sobre la homeostasis de la matriz extracelular en esferoides sin andamio de condrocitos humanos
Carlos Suarez-Ahedoa,b,c, Carlos Martinez-Armentaa,
Corresponding author
c.armenta1208@gmail.com

Corresponding authors.
, Laura E. Martínez-Gómeza, Oswaldo González-Mendozaa, María de Jesús Hernández Rochad, Gabriela A. Martínez-Navaa, Carlos Pinedad, Alberto López-Reyesa,
Corresponding author
allorey@yahoo.com

Corresponding authors.
a National Rehabilitation Institute of Mexico, Geroscience Laboratory, Mexico City, Mexico
b National Rehabilitation Institute of Mexico, Adult Hip and Knee Reconstruction Department, Mexico City, Mexico
c American Hip Institute, Chicago, IL, USA
d National Rehabilitation Institute of Mexico, Mexico City, Mexico
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Abstract
Introduction

New trends in osteoarthritis research focus on the use of biological therapy; in this context, the use of Plasminogen Activator Inhibitor-1 (PAI-1) is considered a potential therapeutic strategy to prevent extracellular matrix (ECM) degradation in osteoarthritis (OA) management. However, in vitro studies have not demonstrated its effect on the expression of ECM homeostasis-related genes.

Methods

Human OA cartilage-derived chondrocytes were used to generate scaffold-free spheroids under hypoxia conditions. The spheroids were exposed to PAI-1 for 24h, and cell viability was measured. Then qRT-PCR was used to analyze the expression of ECM components and degradative enzymes, including COL2A1, SOX9, ACAN, COL1A1, MMP3, MMP9, MMP13, ADAMTS4, ADAMTS5, TIMP1, TIMP2, TIMP3, uPA and tPA.

Results

PAI-1 treatment consistently maintained cell viability and chondrocyte spheroid integrity. At the 50ng/mL concentration, PAI-1 increased the gene expression of COL2A1 and reduced SOX9, ACAN, MMP3, MMP9, TIMP2, and tPA. Moreover, the functional COL2A1/COL1A1 ratio was significantly increased in PAI-1-treated spheroids.

Conclusion

Our results suggest that PAI-1 treatment exerts a complex and multifaceted influence on spheroids’ ECM. While it supports matrix integrity by reducing the gene expression of ECM remodeling enzymes, such as MMPs and ADAMTS5, it also induces unfavorable changes in chondrogenesis-related marker genes, such as SOX9 and ACAN. These findings indicate that the cellular response to PAI-1 is not unidirectional, warranting further investigation to understand its precise biological implications.

Keywords:
Plasminogen Activator Inhibitor-1 (PAI-1)
Extracellular matrix (ECM) degradation
Gene expression modulation
Chondrocytes
Arthrosis
Resumen
Introducción

Las nuevas tendencias en la investigación de la osteoartritis (OA) se centran en el uso de terapias biológicas; en este contexto, el uso del inhibidor del activador del plasminógeno-1 (PAI-1) se considera una estrategia terapéutica potencial para prevenir la degradación de la matriz extracelular (ECM) en el manejo de la OA. Sin embargo, los estudios in vitro no han demostrado su efecto en la expresión de genes relacionados con la homeostasis de la ECM.

Métodos

Se utilizaron condrocitos derivados de cartílago humano con OA para generar esferoides sin andamios bajo condiciones de hipoxia. Los esferoides fueron expuestos a PAI-1 durante 24h y se midió la viabilidad celular. Posteriormente, se utilizó qRT-PCR para analizar la expresión de componentes de la ECM y enzimas de degradación, incluidos COL2A1, SOX9, ACAN, COL1A1, MMP3, MMP9, MMP13, ADAMTS4, ADAMTS5, TIMP1, TIMP2, TIMP3, uPA y tPA.

Resultados

El tratamiento con PAI-1 mantuvo consistentemente la viabilidad celular y la integridad del esferoide de condrocitos. A una concentración de 50ng/ml, el PAI-1 aumentó la expresión génica de COL2A1 y redujo la expresión de SOX9, ACAN, MMP3, MMP9, TIMP2 y tPA. Además, la relación funcional COL2A1/COL1A1 aumentó significativamente en los esferoides tratados con PAI-1.

Conclusión

Nuestros resultados sugieren que el tratamiento con PAI-1 ejerce una influencia compleja y multifacética sobre la ECM de los esferoides. Si bien promueve la integridad de la matriz al reducir la expresión génica de enzimas que remodelan la ECM, como las MMPs y ADAMTS5, también induce cambios desfavorables en marcadores relacionados con la condrogénesis como SOX9 y ACAN. Estos hallazgos indican que la respuesta celular al PAI-1 no es unidireccional, lo que justifica una mayor investigación para entender sus implicaciones biológicas precisas.

Palabras clave:
Inhibidor del activador del plasminógeno-1
Degradación de la matriz extracelular
Modulación de la expresión génica
Condrocitos
Artrosis

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