Bone marrow mesenchymal stromal cell-derived exosomes in knee osteoarthritis: Bridging mechanistic understanding to clinical applications

Table 1 Selected bone marrow mesenchymal stromal cell-exosomal microRNAs and long noncoding RNAs relevant to knee osteoarthritis

Cargo species	Principal targets/pathways (examples)	Main joint-level effects (preclinical)	Ref.
miR-140-5p	ADAMTS5, MMP-13, IGFBP5, Notch and Wnt components	Promotes chondrogenesis and matrix synthesis; suppresses catabolic enzymes and hypertrophic signalling	[34,35]
miR-127-3p	Cadherin-11 and Wnt/β-catenin signalling	Inhibits chondrocyte hypertrophy and cartilage calcification	[34,45]
miR-92a-3p	WNT5A and associated kinases	Increases COL2A1 and aggrecan; reduces MMP expression	[34,46]
miR-129-5p	HMGB1 and TLR4/NF-κB axis	Dampens synovial inflammation and chondrocyte apoptosis	[35,41]
miR-223	NLRP3 inflammasome components	Inhibits pyroptosis in chondrocytes and macrophages	[35,43]
miR-100-5p	mTOR	Enhances autophagy and survival in stressed chondrocytes	[35,47]
lncRNA KLF3-AS1	Sponges miR-206, maintains GIT1	Supports PI3K/Akt signalling; promotes chondrocyte proliferation and survival	[47]
lncRNA SNHG7	miR-485-5p/FSP1 axis	Anti-ferroptotic and anti-senescent effects in cartilage	[36]

ADAMTS5: A disintegrin and metalloproteinase with thrombospondin motifs 5; MMP-13: Matrix metalloproteinase-13; IGFBP5: Insulin-like growth factor-binding protein 5; COL2A1: Collagen type II alpha 1; HMGB1: High mobility group B1; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor kappa B; NLRP3: Nod-like receptor protein 3; mTOR: Mechanistic target of rapamycin; GIT1: G protein-coupled receptor kinase-interactor 1; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; FSP1: Ferroptosis suppressor protein 1.

Table 2 Comparative features of exosomes from mesenchymal stromal cell sources in osteoarthritis models

Source	Main advantages in osteoarthritis context	Principal limitations or concerns
Bone marrow[59-61]	Strong chondrogenic lineage; rich ECM-related proteome; extensive mechanistic data and historical use in cartilage repair	Donor age dependence; invasive harvest; intermediate performance in comparative exosome meta-analysis; variable outcomes in MSC trials
Adipose tissue[63,64]	Abundant, minimally invasive harvest; high cell yield; strong immunomodulatory profile; good pain relief in MSC trials	Some preparations favour fibrocartilage over hyaline repair; structural regeneration less consistent; potential influence of donor metabolic status
Umbilical cord[65]	Neonatal cells with high proliferative capacity; off-the-shelf allogeneic banking; robust anti-inflammatory and chondroprotective actions; early clinical data in KOA	Fewer long-term joint safety data; regulatory complexity of allogeneic products
Synovium/synovial fluid[34,60]	Joint-specific tissue origin; excellent targeting and regenerative potency, especially with miR-140-5p enrichment; top rankings in rodent network analyses	Arthroscopic retrieval for autologous use; scalability challenges; limited clinical-grade products

ECM: Extracellular matrix; MSC: Mesenchymal stromal cell; KOA: Knee osteoarthritis.

Table 3 Human studies of mesenchymal stromal cell-derived extracellular vesicles relevant to knee osteoarthritis

EV source	Indication/design	Intervention and comparator	Main outcomes	Key limitations
Placental MSC exosomes[83-85]	Bilateral KOA, triple-blind randomised placebo-controlled trial	Single intra-articular exosome injection to one knee, saline to contralateral knee	Good short-term safety; no significant advantage over saline in pain, function or MRI cartilage metrics	Single-dose regimen; short follow up; partial EV characterisation; no dose-finding
Umbilical cord MSC small EVs[86]	KOA, first-in-human open-label phase I study	Intra-articular small EVs, single or repeated dosing, no control group	Acceptable 12-month safety; symptomatic improvement; MRI signs of cartilage regeneration; evidence of M2-like macrophage polarisation	Non-randomised; small sample; potential placebo and regression effects
BM-MSC-derived EV product (for example, ExoFlo)[87,88]	Osteoarthritis and joint injuries, observational cohorts	Intra-articular injection, no formal comparator	Symptomatic improvement reported; no major acute toxicity	Non-randomised; heterogeneous pathology; limited EV characterisation; lack of long-term imaging and independent replication

EV: Extracellular vesicle; MSC: Mesenchymal stromal cell; KOA: Knee osteoarthritis; MRI: Magnetic resonance imaging; BM-MSC: Bone marrow mesenchymal stromal cell.