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Piezo1-Fstl1 Axis in Fracture Healing: Modulation of the Chondrocyte Inflammation-ROS-Mitochondrial Damage Cascade
Tao Zhang1,2,3,4, Haoran Wang1,2,3,4, Guangzhao Hou1,2,3
1Department of Orthopaedic Surgery, Hebei Medical University Third Hospital; Shijiazhuang, Hebei 050051, China.
Abstract:
This study investigated the regulatory role of an intelligent drug delivery system in promoting fracture healing via Piezo1-Fstl1 signaling axis. It also verified its modulation of chondrocyte inflammatory response, mitochondrial oxidative stress, and osteoblast differentiation. Inflammation triggers the accumulation of pro-inflammatory factors, and reactive oxygen species (ROS) in chondrocytes. This leads to oxidative damage in mitochondria, a decrease in mitochondrial membrane potential (MMP), and the induction of mitochondrial permeability transition pore (mPTP) opening, thereby hindering fracture healing. Single-cell RNA sequencing revealed that Piezo1 deficiency markedly upregulated the expression of follistatin-like protein 1 (Fstl1) in chondrocytes. This upregulation exacerbated chondrocyte inflammation and impaired the chondrocyte-to-osteoblast differentiation. Inhibition of Fstl1 attenuated the inflammatory response and ROS accumulation associated with Piezo1 deficiency, alleviated mitochondrial oxidative stress, and improved mitochondrial function and homeostasis. It also restored mitochondrial cristae ultrastructure, thereby improving MMP and mitochondrial activity. This intervention concurrently upregulated osteogenic markers and accelerated endochondral ossification. Based on these, we developed a HA-PBA/TA self-healing hydrogel incorporating chondrocyte-targeting lipid nanoparticles (C-LNP@Fstl1) to suppress Fstl1 expression. Local injection of this hydrogel into murine femoral fracture sites significantly reduced inflammatory cytokines in callus tissue and promoted fracture healing, offering new insights and therapeutic strategies for fracture treatment.
Insights
An intelligent hydrogel delivery system targeting Follistatin-like protein 1 (Fstl1) promotes fracture healing by reducing inflammation and oxidative stress in chondrocytes, enhancing osteoblast differentiation.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Molecular Biology
Background:
- Inflammation and oxidative stress in chondrocytes impede fracture healing by damaging mitochondria and hindering osteoblast differentiation.
- Piezo1 deficiency upregulates follistatin-like protein 1 (Fstl1), exacerbating chondrocyte inflammation and impairing differentiation.
- Mitochondrial dysfunction, including decreased membrane potential and increased permeability transition pore opening, is a key factor in delayed fracture healing.
Purpose of the Study:
- To investigate the regulatory role of an intelligent drug delivery system in fracture healing via the Piezo1-Fstl1 signaling axis.
- To assess the system's modulation of chondrocyte inflammatory response, mitochondrial oxidative stress, and osteoblast differentiation.
- To develop and evaluate a novel hydrogel-based therapeutic for enhanced fracture repair.
Main Methods:
- Single-cell RNA sequencing to identify Piezo1-Fstl1 interactions in chondrocytes.
- Development of a hyaluronic acid-polyboronic acid/tannic acid (HA-PBA/TA) self-healing hydrogel with chondrocyte-targeting lipid nanoparticles (C-LNP@Fstl1) to suppress Fstl1.
- Local injection of the hydrogel into murine femoral fracture sites for therapeutic intervention.
Main Results:
- Piezo1 deficiency significantly upregulated Fstl1, increasing inflammation and impairing chondrocyte-to-osteoblast differentiation.
- Inhibition of Fstl1 via the hydrogel system attenuated inflammation, reduced reactive oxygen species (ROS), and alleviated mitochondrial oxidative stress.
- The treatment improved mitochondrial function, restored mitochondrial ultrastructure, enhanced osteogenic marker expression, and accelerated endochondral ossification, promoting fracture healing in mice.
Conclusions:
- The Piezo1-Fstl1 signaling axis is a critical regulator of chondrocyte function and fracture healing.
- The developed HA-PBA/TA hydrogel system effectively suppresses Fstl1, mitigating chondrocyte inflammation and mitochondrial dysfunction.
- This intelligent drug delivery system offers a promising therapeutic strategy for accelerating fracture healing and improving bone regeneration.
