Pyrroloquinoline quinone alleviates age-related osteoarthritis via nuclear factor erythroid 2-related factor...

Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C₁₄H₆N₂O₈) is a naturally bioactive compound that has been reported to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective gene expression. However, its effects on age-related OA and the underlying mechanisms remain unclear.

Twelve‑month‑old mice received dietary PQQ (4 mg/kg feed) for 12 months and joint pathology was assessed by Safranin O-Fast Green staining, osteoarthritis research society international (OARSI) grading, osteophyte and synovitis scoring, and micro‑computed tomography (μCT). Oxidative damage, senescence and extracellular matrix markers were analyzed. Human and mouse chondrocytes and cartilage explants were treated with interleukin-1β (IL‑1β) to model OA in vitro; effects of PQQ on oxidative stress, proliferation, senescence and matrix proteins were measured. Nrf2 signaling activation was examined. Mechanistic assays investigated how Nrf2 regulates the insulin‑like growth factor 1 receptor (IGF1R). Nrf2 or IGF1R loss‑of‑function evaluated pathway dependence.

Long‑term dietary PQQ markedly reduced spontaneous, age‑related OA in mice. It lowered OARSI scores and reduced osteophyte formation and synovitis, while preserving cartilage and subchondral bone structure. PQQ also decreased oxidative DNA damage in cartilage, reduced senescence markers and senescence‑associated secretory phenotype (SASP) factors, and restored Lamin B1. In addition, it reduced matrix metalloproteinase‑13 (MMP13) and maintained COL2A1 expression. In IL‑1β‑challenged human chondrocytes and explants, PQQ suppressed oxidative stress, rescued proliferation, diminished senescence and prevented matrix degradation. PQQ enhanced Nrf2 nuclear accumulation, antioxidant response element (ARE) activity and antioxidant genes expression. Mechanistic assays identified IGF1R as a direct Nrf2 target; IGF1R knockdown blocked PQQ‑induced extracellular signal‑regulated kinase (ERK) signaling and COL2A1 upregulation. PQQ failed to protect Nrf2‑deficient chondrocytes and joints, demonstrating Nrf2 dependence.

PQQ mitigates age‑related OA by activating Nrf2‑mediated antioxidant/anti‑senescence responses and transcriptionally upregulating IGF1R to support matrix anabolism. The PQQ-Nrf2-IGF1R axis is a promising therapeutic target for preventing or slowing age‑related OA progression.