Table 2 Anti-senescence drugs for OA

β-Hydroxybutyrate

Upregulated PTEN expression and inhibited the downstream P13K/Akt signaling pathway

Improved H₂O₂-induced senescent phenotype and proliferative activity of chondrocytes derived from OA patients

Improved COL2A1 expression and maintained cartilage morphology in OA rats

Inhibited MMP13, P16 and P21 expression

–

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Gastrodin

Upregulated Sirtuin3(SIRT3) expression and downregulated protein phosphorylation of the PI3K-AKT pathway

Attenuated IL1-β-induced chondrocyte senescence, mitochondrial homeostasis imbalance

Ameliorated cartilage erosion, chondrocyte senescence and OA injury in rat knee joints

–

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Vildagliptin

upregulated SIRT1 expression and attenuated AMPK-SIRT-p53 acetylation

Attenuated chondrocyte senescence and senescence-associated protein expression induced by TNF-α and ameliorated chondrocyte cell cycle arrest in G1 phase

–

(1) Validation of in vivo models was absent

(2) Single stimulus source cannot fully model OA pathogenesis

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Parathyroid hormone-related protein-derived peptide C-terminal fraction

Reduced activation of NF-κB

Reduced senescence marker expression levels, number of γH2AX foci, and inflammatory response in IL-1β-induced OA osteoblasts, and enhanced osteoblast mineralization

–

Lack of comparison of OA and healthy osteoblasts from same-age donors

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Exosomes from umbilical cord mesenchymal stem cell sources

Involved in regulating the p53 signaling pathway

Inhibited the expression of OA chondrocyte senescence genes, restored the viability of senescent OA chondrocytes, and promoted the synthesis of cartilage matrix

"Two-Phase" release system enhanced exosome therapeutic efficiency and retention time

(1) Exosomes have a complex composition and their therapeutic role still needs to be explored

(2) Intelligent release needs to be matched to disease

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Butorphanol tartrate

Inactivated NF-κB and STAT3

Reduced percentage of SA-β-gal positivity and G0/G1 phase in TNF-α-induced human articular chondrocytes, reduced p21 protein levels, elevated telomerase activity, and neutralized TNF-α-induced inflammatory response

–

Effects of drugs in vivo not explored

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Heme oxygenase-1

Reduced production of relevant inflammatory and catabolic mediators involved in OA pathophysiology

Upregulated osteogenic differentiation and mineralization gene expression, downregulated MMP and senescence-related gene expression, and inhibited NF-κB activation

–

Validation of in vivo models was absent

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Ceria Nanoparticles

scavenged ROS and inactivated the NF-κB signaling pathway

Removed synoviocyte senescence and inhibited SASP triggered by H₂O₂, attenuated senescence and inhibited SASP in multiple passaged synoviocytes, and inhibited NF-κB pathway activation in senescent synoviocytes

Reduced ROS content attenuates synovial cell senescence and SASP expression in a rat OA model constructed by ACLT surgery

(1) Failed to measure intra-articular SASP protein concentrations

(2) Failure to study effects on other tissues such as chondrocytes

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multi-kinase inhibitor YKL-05-099

Inhibited MAPK and NF-κB signaling activation

Suppressed IL-1β-induced inflammation and catabolism, promoted chondrocyte anabolism, and inhibited senescence inducer and SASP factor expression

Attenuated histological damage to cartilage in mice models of OA, inhibited subchondral bone loss and osteoclast formation

(1) Lack of cartilage-targeted type

(2) Failed to study the mechanical properties of hydrogels

(3) Failed to evaluate hydrogel drug delivery systems system in vivo safety systematically

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senolytic

Induced apoptosis selectively in some senescent chondrogenic progenitor cells

Increased proliferation of senescent chondrogenic progenitor cells, accelerated cartilage regeneration from chondrogenic progenitor cells, and significantly reduced supernatant IL-1β levels

Significant restore of articular cartilage integrity and corrected abnormal subchondral bone sclerosis in combination with arthrodesis

(1) Failed to use synovial fluid to assess levels of inflammatory factors

(2) Failed to explore other mechanisms of action of the drug

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Navitoclax (ABT263)

Induced apoptosis in senescent cells

Removed senescent rat chondrocytes induced by ionizing radiation in a dose-dependent manner, eliminated SA-β-gal-positive senescent cells in chondrocytes and cellular microcolonies, and promoted the chondrogenic phenotype

Attenuated cartilage and subchondral bone damage in a rat model of post-traumatic OA

(1) Failed to study potential effects on other tissues such as synovium

(2) The period of in vivo experiments was short

(3) Failed to elucidate the apoptosis signaling pathway

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Navitoclax (ABT263)

Induced apoptosis in senescent OA synovial MSCs cells

Significantly reduced SA-β-gal positivity in synovial MSCs derived from OA patients and expression of B-cell lymphoma 2

–

(1) Failed to validate in vivo therapeutic efficacy

(2) Absence of quantification of released SASP factors

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anti-beta-2-microglobulin antibodies

Induced apoptosis in senescent chondrocytes by peroxidase-like activity

Targeting senescent chondrocytes for elimination and upregulated cartilage-related gene expression

Removed senescent cells in the joints of OA mice constructed by DMM surgery and promoted cartilage regeneration

–

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Rapamycin

Upregulated autophagy

Induced autophagy in primary human articular chondrocytes, reduced the percentage of senescent cells induced by H₂O₂, and maintained the production of sulfated glycosaminoglycans in pressurized microcosm cultures

Effectively attenuated cartilage damage and inflammation in a post-traumatic model of OA in mice

–

²¹⁰

Rapamycin

Activated autophagy

Induced chondrocyte autophagy in a dose-dependent manner, prevented chondrocyte senescence under two stress conditions, and maintained sulfated glycosaminoglycan production in 3D cultures

Microcarrier platform increased drug residence time in the joints

Failed to test effects in preclinical models of OA

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Fibroblast growth factor 21

Upregulated chondrocyte autophagic fluxes

attenuated apoptosis, senescence and extracellular matrix catabolism in chondrocytes, which involved activation of the SIRT1-mTOR signaling pathway

Inhibited pathology in DMM surgically constructed OA mouse models

(1) In vitro experiments can only partially respond to OA pathology

(2) The mechanism of action on chondrocytes was unclear

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Spermidine

Increased expression of acetyltransferase EP300 and enhanced cellular autophagy

Activated autophagy in human and mouse chondrocytes, increased chondrogenic markers in mouse chondrocytes and human OA chondrocytes

–

–

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Strontium

Improved autophagy in fibroblast-like synoviocytes via the AMPK/mTOR/LC3B-II signaling axis

Inhibited fibroblast-like synoviocyte senescence and significantly reduced mRNA levels of SASP

Attenuated pain-related behaviors and inhibited pathological processes in DMM-constructed OA mice

Failed to explore ion concentrations and different intracellular signaling pathways

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Metformin

activated the AMPK/mTOR-dependent autophagy pathway

Increased survival and reduced senescence of adipose-derived mesenchymal stem cells, reversed excessive ROS production and DNA damage induced by H2O2

Inhibited pathologic progression and reduced pain in DMM surgically constructed OA mice

Inherent shortcomings of stem cell therapy, including frequency of injections and number of cells

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