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A Metabo-Reprogramming Niche Remodeling System Halts Osteoarthritis by Restoring the FGF21-Arginine Axis

Hao Pan1,2, Haoze Zhu1, Siman Huang1

  • 1Department of Orthopaedic Surgery, Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Advanced Materials (Deerfield Beach, Fla.)
|August 5, 2026
PubMed

Insights

Researchers identified a key metabolic pathway involving FGF21 and arginine in osteoarthritis (OA). They developed a novel treatment (MetaRemod) that restores this pathway, effectively halting OA progression and preserving joint health in mice.

Area of Science:

  • Biochemistry
  • Regenerative Medicine
  • Orthopedics

Background:

  • Osteoarthritis (OA) is a leading cause of chronic pain and disability, with no current treatments targeting its core pathogenesis.
  • A specific chondrocyte subpopulation crucial for cartilage health is depleted in OA, linked to reduced levels of Fibroblast Growth Factor 21 (FGF21).

Purpose of the Study:

  • To investigate the role of the FGF21-arginine metabolic axis in OA pathogenesis.
  • To develop and evaluate a novel drug delivery system (MetaRemod) for targeted FGF21 delivery to reprogram chondrocyte metabolism and treat OA.

Main Methods:

  • Single-cell RNA sequencing (scRNA-seq) of human OA cartilage to identify key cellular and molecular changes.
  • Mechanistic studies elucidating the FGF21-arginine biosynthesis pathway in chondrocytes.
  • Development of a hydrogel-based system (MetaRemod) for localized FGF21 delivery.
  • Preclinical evaluation of MetaRemod in a mouse model of OA.

Main Results:

  • scRNA-seq revealed a depleted chondrocyte subpopulation with high arginine metabolism in OA, associated with downregulated FGF21.
  • FGF21 was found to rescue chondrocyte dysfunction by promoting arginine biosynthesis via the ASS1/ASL pathway.
  • MetaRemod effectively delivered FGF21 in a mouse OA model, restoring chondrocyte metabolism, preserving cartilage and subchondral bone, and reducing synovitis.
  • Treated cartilage showed restoration of the depleted high-arginine-metabolism chondrocyte subpopulation, confirming metabolic defect reversal.

Conclusions:

  • The FGF21-arginine metabolic axis is a critical therapeutic target for osteoarthritis.
  • MetaRemod, a bioinspired niche remodeling system, demonstrates a promising strategy for OA treatment by synergizing targeted FGF21 delivery and metabolic reprogramming.
  • This approach provides a strong foundation for the clinical translation of metabolic reprogramming-based disease-modifying osteoarthritis drugs (DMOADs).
Keywords:
FGF21‐arginine metabolic axismetabolic reprogrammingmultifunctional hydrogelosteoarthritistargeted FGF21 delivery

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