Table 2 Mechanisms of non-coding RNA in mesenchymal stromal cell-based therapy for knee osteoarthritis

Human AT-MSCs

In vitro

400 µg/mL

miR-145 and miR-221

Downregulated the expression of pro-inflammatory markers IL-6, NF-κB, and TNF-α, while upregulated the expression of the anti‐inflammatory cytokine IL‐10

[109]

Human OA cartilage-derived MSCs and BM-MSCs

Mice

NR

miR-365

Activation of aggrecan and collagen type 2a1 gene expression. MiR-365 expression was activated by chondrogenic induction in both OA-MSCs and BM-MSCs

[139]

Human BM-MSCs-Exos

In vitro

NR

miR-520d-5p/HDAC1

MiR-520d-5p promoted MSCs chondrogenesis and regulates chondrocyte metabolism through targeting HDAC1

[140]

Human BM-MSCs

In vitro

NR

miR-410/Wnt3a

MiR-410 was elevated during TGF-β3-induced chondrogenic differentiation of MSCs, and regulated the Wnt signaling pathway

[135]

Rat BM-MSCs-Exos

Rat

NR

miR-9-5p/syndecan 1

Anti-inflammatory and chondroprotective effects of BM-MSC-derived exosomal miR-9-5p on KOA via regulation of syndecan 1

[110]

Human BM-MSCs-Exos

Rat

250 ng/5 µL

miR-26a-5p/Cox2

Human BM-MSC-Exos overexpressing miR-26a-5p serve as a repressor for damage of synovial fibroblasts via Cox2 in KOA

[112]

Human SMSCs-Exos

Rat

30 µL, 10¹¹ particles/mL

miR-26a-5p/PTEN/IL-1β

SMSC-exos enhanced IL-1β-induced cell proliferation, whereas inhibited apoptosis and inflammation. MiR-26a-5p targeted PTEN, for which overexpression spoiled the protection of exosomes against IL-1β-induced cell damage

[111]

SMSCs-Exos

Mice

5 µL

miR-31/KDM2A/E2F1/PTTG1

SMSC-Exos and Exos from miR-31-overexpressed SMSCs alleviated cartilage damage and inflammation in KOA in vivo

[91]

Human AT-MSCs-Exos

Mice

10 µL, 10¹⁰ particles/mL

miR-100-5p/mTOR

The level of miR-100-5p decreased the luciferase activity of mTOR 3′UTR, while inhibition of miR-100-5p could reverse the MSC-Exos-decreased mTOR signaling pathway

[97]

Rat BM-MSCs-Exos

Nude mice

20 µg

miR-127-3p/ CDH11/Wnt/β-catenin

MiR-127-3p targeted CDH11 and over-expressed CDH11 in chondrocytes weakened the therapeutic effect of exosomes. IL-1β treatment resulted in the activation of the Wnt/β-catenin pathway in chondrocytes

[96]

Rat BM-MSCs-Exos

Rat

100 µL, 10¹¹ particles/mL

miR-135b/MAPK6

MiR-135b promoted M2 polarization of synovial macrophages through targeting MAPK6

[117]

Rat MSCs-Exos

Rat

100 µL, 10¹¹ particles/mL

miR-135b/Sp1/TGF-β1

TGF-β1 stimulation enhanced miR-135b expression in MSC-exosomes, and MSC-exosomes-derived miR-135b increased the cell viability of C5.18 cells via downregulated Sp1 expression

[92]

Human BM-MSCs-Exos

Mice

100 µL, 10¹¹ particles/mL

miRNA-136-5p/ELF3

An increased ELF3 expression and reduced miR-136-5p expression were detected in the clinical samples of traumatic OA cartilage tissues. BM-MSC-derived exosomal miR-136-5p could promote chondrocyte migration in vitro and inhibit cartilage degeneration in vivo

[101]

Human AT-MSCs-Exos

Mice

NR

miR-124/NF-κB and miR-143/ ROCK1/TLR9

MiR-143 and miR-124 inhibited the expression of NF-κB and ROCK1 in OA cells. In addition, the 3’ UTRs of NF-κB and ROCK1 were proven to contain the binding sites for miR-143 and miR-124, respectively

[138]

Rat BM-MSCs-Exos

Rat

200 µg

miR-216a-5p/JAK2/STAT3

Hypoxic-Exos promoted the proliferation and migration of chondrocytes and inhibited their apoptosis by targeting functional miR-216a-5p to chondrocytes and then downregulating JAK2. In addition, HIF-1α induces hypoxic BM-MSCs to release Exos

[93]

Human BM-MSCs-Exos

Rat

2 µg

miR-361-5p/DDX20/NF-κB

MiR-361-5p was verified to directly target DDX20. Additionally, human BM-MSC-Exos-transferred miR-361-5p alleviates chondrocyte damage and inhibits the NF-κB signaling pathway

[137]

Human SMSCs-Exos

BALB/C mouse

30 µL, 10¹¹ particles/mL

miR-155-5p/Runx2

The SMSC-155-5p-Exos prevented KOA. Overexpression of Runx2 partially reversed the effect of the SMSC-155-5p-Exos

[136]

MSCs-Exos

In vitro, co-culture with mouse chondrocytes

NR

circRNA_HIPK3/miR-124-3p/MYH9

MSCs-Exos overexpressing circHIPK3 improved IL-1β-induced chondrocyte injury. Mechanistically, circHIPK3 could directly bind to miR-124-3p and subsequently elevate the expression of the target gene MYH9

[143]

Human MSCs

In vitro

NR

lncRNA HOTAIRM1-1/miR-125b/ BMPR2; JNK/MAPK/ERK pathway

HOTAIRM1-1 was downregulated in KOA cartilages and may inhibit MSCs viability, induce apoptosis, and suppress differentiation via regulating miR-125b/BMPR2 axis JNK/MAPK/ERK pathway may be a possible downstream mechanism to mediate the role of HOTAIRM1-1 in OA development

[146]

Human BM-MSCs-Exos

In vitro

NR

lncRNA HOTTIP/miR-455-3p/CCL3

HOTTIP negatively regulated miR-455-3p and increased CCL3 levels in human chondrocytes

[147]

Human AT-MSCs

In vitro

NR

circRNA_ATRNL1/miR‐145‐5p/SOX9

Circ_ATRNL1 regulated the promotion of SOX9 expression to promote chondrogenic differentiation of human AT-MSCs mediated by miR‐145‐5p

[141]

Human BM-MSCs-Exos

Mice

10 µL, 500 µg/mL

circRNA_0001236/miR-3677-3p/Sox9

Exosomal circRNA_0001236 enhanced the expression of Col2α1 and SOX9, but inhibited MMP13 in chondrogenesis via targeting miR-3677-3p and Sox9

[142]

Human BM-MSCs

In vitro

NR

lncRNA GRASLND

Silencing of lncRNA GRASLND resulted in lower accumulation of cartilage-like extracellular matrix, while GRASLND overexpression significantly enhanced cartilage matrix production

[144]

Human SMSCs

In vitro

NR

lncRNA MEG3/EZH2-mediated H3K27me3/TRIB2

LncRNA MEG3 regulated chondrogenic differentiation by inhibiting TRIB2 expression through EZH2-mediated H3K27me3

[145]

Human and mouse MSCs

In vitro

NR

lncRNA EPB41L4A‐AS1 and lncRNA SNHG7/miR‐146a

MiR‐146a significantly inhibited BM-MSCs proliferation partly interacting with lncRNA EPB41L4A‐AS1 and lncRNA SNHG7

[148]

Human BM-MSCs-Exos

In vitro

NR

lncRNA LYRM4-AS1/GRPR/miR-6515-5p

IL-1β significantly decreased cell viability, promoted apoptosis, and upregulated the expression of MMP3, AKT, and GRPR, while Exos reversed the changes

[149]