Restoration of the Phenotype of Dedifferentiated Rabbit Chondrocytes by Sesquiterpene Farnesol

Abstract

Osteoarthritis (OA) is a joint disorder characterized by the progressive degeneration of articular cartilage. The phenotype and metabolism behavior of chondrocytes plays crucial roles in maintaining articular cartilage function. Chondrocytes dedifferentiate and lose their cartilage phenotype after successive subcultures or inflammation and synthesize collagen I and X (COL I and COL X). Farnesol, a sesquiterpene compound, has an anti-inflammatory effect and promotes collagen synthesis. However, its potent restoration effects on differentiated chondrocytes have seldom been evaluated. The presented study investigated farnesol’s effect on phenotype restoration by examining collagen and glycosaminoglycan (GAG) synthesis from dedifferentiated chondrocytes. The results indicated that chondrocytes gradually dedifferentiated through cellular morphology change, reduced expressions of COL II and SOX9, increased the expression of COL X and diminished GAG synthesis during four passages of subcultures. Pure farnesol and hyaluronan-encapsulated farnesol nanoparticles promote COL II synthesis. GAG synthesis significantly increased 2.5-fold after a farnesol treatment of dedifferentiated chondrocytes, indicating the restoration of chondrocyte functions. In addition, farnesol drastically increased the synthesis of COL II (2.5-fold) and GAG (15-fold) on interleukin-1β-induced dedifferentiated chondrocytes. A significant reduction of COL I, COL X and proinflammatory cytokine prostaglandin E2 was observed. In summary, farnesol may serve as a therapeutic agent in OA treatment.

Synergistic prevention and reparative effects of sesquiterpene farnesol in a rabbit model of surgical resection-induced osteoarthritis

“…Wu et al also indicated that GAG production resumes and increases in the presence of 0.4 mM farnesol or 0.8 mM Farn/HA. 22 In the present in vivo study, H&E staining revealed that 0.8 mM Farn/HA led to a greater increase in the number of chondrocytes without significant hypertrophy than did 0.4 mM farnesol or HA nanoparticles [ Fig. 3(a) ].…”

“…We previously noted that farnesol restores the production of chondrogenic COL II and suppress the production of COL I in IL-1β-stimulated dedifferentiated chondrocytes. 22 In addition, treatment with farnesol significantly reduces PGE2 secretion to a level similar to that secreted the normal chondrocytes. PGE2, involved in inflammation and OA symptom development, modulates PGE2-derived signaling and influences chondrocyte metabolism, affecting ECM structure.…”

“…As the treatment progressed, Farn/HA gradually formed because of hydrophobic and hydrophilic interactions between the HA nanoparticles and farnesol molecules in the electrostatic field environment, yielding HA nanoparticle-farnesol aggregates (i.e., Farn/HA). 22 At the treatment temperature (20–25 °C), which enabled the mobility of HA nanoparticles and farnesol molecules, the structure of the formed Farn/HA was nonuniform; initially (i.e., in the short-term), it was relatively loose, and as the treatment progressed, it became denser. The experiments on and mechanisms underlying the preparation of Farn/HA are not covered in this study.…”

“…After treatment with farnesol, these dedifferentiation- and inflammation-related proteins decreased the IL-1β-stimulated chondrocytes to levels similar to those in normal chondrocytes. 22 …”

“…The authors suggested that farnesol restores the phenotype of the chondrocytes and salvages their ECM COL II and glycosaminoglycan (GAG) production capacity in vitro. 22 Therefore, this study investigated whether intraarticularly administered farnesol could prevent further cartilage degeneration in a rabbit model with anticipated cartilage degeneration, and further investigated if they have a therapeutic effect.…”