MicroRNAs as Key Regulators of Degeneration and Inflammation in Osteoarthritis: A Narrative Review

Abstract

Osteoarthritis (OA) is the most prevalent degenerative joint disease and a leading cause of chronic pain and disability worldwide, particularly among aging populations. It is characterized by progressive degeneration of articular cartilage, synovial inflammation, subchondral bone remodeling, and metabolic alterations in the infrapatellar fat pad, reflecting pathology across the entire joint microenvironment. The onset and progression of OA are driven by complex interactions among mechanical stress, aging, obesity, and metabolic dysregulation, which collectively disrupt joint homeostasis. Mechanical injury and cartilage damage induce the release of damage-associated molecular patterns, activating innate immune receptors on chondrocytes and synovial cells. This promotes the production of pro-inflammatory mediators, including interleukin-1β, tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-17, which contribute to extracellular matrix degradation and cartilage deterioration. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, have emerged as key modulators in OA pathogenesis. They regulate chondrocyte proliferation, apoptosis, extracellular matrix turnover, inflammation, and osteochondral remodeling. Notably, certain miRNAs exhibit mechanosensitive properties, responding to altered biomechanical loading and translating mechanical stimuli into gene regulatory responses. This review synthesizes current evidence on the roles of miRNAs in OA, focusing on their regulatory functions across joint tissues, including cartilage, synovium, subchondral bone, and the infrapatellar fat pad. Key miRNAs such as miR-140, miR-146a, miR-27b, miR-34a, miR-155, and mechanosensitive miR-365 are discussed, along with their interactions with major inflammatory and degenerative signaling pathways. Their potential as diagnostic biomarkers and therapeutic targets is also highlighted.

INTRODUCTION

Osteoarthritis (OA) is a joint disorder marked by the gradual breakdown of cartilage and inflammation in the synovial tissue. It also includes hardening of the bone beneath the cartilage, the formation of bone spurs, damage to the meniscus, and scarring in the infrapatellar fat pad, which can impact the entire joint.[1] OA is a major source of pain, stiffness, and disability in middle-aged and older adults, with hip and knee OA ranking among the top global causes of disability[2] where over 590 million people around the world are affected.[3] The development of OA is complicated and involves several risk factors, including aging, obesity, joint misalignment, mechanical stress, genetic factors, and inflammation with aging and obesity among the most significant contributors.[4,5,6] Recently, more focus has been placed on microRNAs (miRNAs), which are non-coding RNAs that regulate gene expression after transcription. These molecules play a key role in OA.[7] Changes in miRNA expression have been linked to the development of OA.[8]

This review summarizes the current evidence on the role of miRNAs in cartilage degeneration and inflammation in OA. It focuses on how miRNAs regulate key signaling pathways, including NF-κB, MAPK and TGF-β. It also highlights their potential as targets for diagnosis and treatment. Relevant information was found by searching Scopus, Web of Science, Google Scholar, and PubMed using keywords like osteoarthritis, microRNAs, signaling pathways, inflammation, and cartilage degeneration. Selected articles were screened and combined to give an updated overview of miRNA involvement in OA.

PATHOPHYSIOLOGY OF OSTEOARTHRITIS

OA is a multifactorial joint disease characterized by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation, and osteophyte formation. Although once considered a purely mechanical disorder, increasing evidence highlights the critical role of inflammatory and metabolic factors in its progression.[9] OA starts when factors such as mechanical stress, aging, obesity, and metabolic imbalance throw off the balance between pro-and anti-inflammatory signals, promoting a degenerative joint environment. This imbalance causes damage to the cartilage and subchondral bone at the microstructural level, which causes chondrocytes to release damage-associated molecular patterns (DAMPs).[10] These molecules interact with toll-like receptors (TLRs) on chondrocytes and synovial cells, activating signaling pathways that increase the production of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6, and IL-17, thereby perpetuating local inflammation.[11] In addition to cartilage and subchondral bone, the infrapatellar fat pad (IFP) is increasingly recognized as a key contributor to OA pathophysiology. In diseased joints, the IFP undergoes inflammation and fibrosis, leading to structural changes that modify its biomechanical properties and promote the release of pro-inflammatory cytokines and adipokines. Furthermore, the IFP operates as a functional unit with the synovial membrane, jointly driving synovial inflammation and disease progression.[12]

The cytokine-rich milieu recruits and activates synovial macrophages and fibroblasts, amplifying inflammation through chemokines such as CCL2, CCL3, CCL4, CCL5, and CXCL10, thereby sustaining synovitis and immune cell infiltration.[13] Persistent signaling upregulates matrix-degrading enzymes, including MMP-13 and ADAMTS-5, driving cartilage breakdown and synovial hyperplasia.[14] Concurrently, dysregulated TGF-β signaling favors ALK1-Smad1/5/8 over ALK5-Smad2/3 pathways, promoting catabolic activity and enhancing MMP-13-mediated extracellular matrix degradation.[15] In parallel, pro-inflammatory cytokines induce COX-2 and PGE-2 production, reinforcing inflammation and osteophyte formation, while oxidative stress accelerates chondrocyte senescence and impairs repair capacity.[16] Persistent inflammation induces chondrocyte hypertrophy via RUNX2, increasing COL1A1 and VEGF expression and promoting angiogenesis and osteophyte formation.[17] Although anti-inflammatory cytokines such as IL-4 and IL-10 are upregulated, they fail to counterbalance the dominant catabolic response.[18] Concurrently, subchondral bones undergo active remodeling driven by TGF-β, bone morphogenetic proteins (BMPs), and RANKL-mediated osteoclast activation, leading to structural changes that disrupt joint biomechanics and accelerate cartilage degradation.[19] These combined molecular and structural alterations ultimately drive progressive cartilage loss and functional impairment.

As OA advances, sustained inflammation and injury to the synovium and IFP activate neurogenic pathways that contribute to pain. These highly innervated tissues release mediators such as nerve growth factor (NGF), bradykinin, and substance P, promoting peripheral sensitization and nociceptive signaling,[20] clinically this manifesting with persistent pain, stiffness, swelling, and reduced joint mobility.[21] Radiographic progression is graded using the Kellgren-Lawrence scale (stages 1-4), reflecting increasing joint space narrowing, osteophyte formation, and subchondral sclerosis.[22] Collectively, mechanical stress, inflammation, protease activity, oxidative damage, chondrocyte phenotypic changes, and bone remodeling interact to sustain a self-perpetuating cycle that drives OA progression and highlights potential therapeutic targets.

MicroRNAS IN OSTEOARTHRITIS

MicroRNAs are ~22-nucleotide non-coding RNAs that regulate gene expression by binding target messenger RNAs (mRNAs), resulting in mRNA degradation or translational repression.[23] They are generated through a multi-step process in which primary transcripts (pri-miRNAs) are processed by Drosha into precursor miRNAs (pre-miRNAs) in the nucleus, exported to the cytoplasm, and further cleaved by Dicer to produce mature miRNAs [Figure 1]. These mature forms are incorporated into the RNA-induced silencing complex to mediate sequence-specific gene regulation.[24]

Figure 1.

MicroRNAs biogenesis and their biological mechanism. miRNAs are transcribed as primary miRNAs by RNA polymerase II (RNA Pol II) and processed in the nucleus by the Drosha-DGCR8 complex into precursor miRNAs (pre-miRNAs). These pre-miRNAs are exported to the cytoplasm by Exportin-5 in a Ran-GTP-dependent manner, where they are further cleaved by Dicer and TAR RNA-binding protein into ~22-nucleotide miRNA duplexes. The guide strand is then incorporated into the RNA-induced silencing complex, together with Argonaute proteins, to mediate gene silencing through mRNA degradation or translational repression. miRNA – MicroRNAs; pri-miRNAs – Primary miRNAs; pre-miRNAs – Precursor miRNAs; TRBP – TAR RNA-binding protein; RISC – RNA-induced silencing complex

Aberrant miRNA expression has been linked to a wide range of diseases, including cancer, cardiovascular and neurodegenerative disorders, and OA. Circulating miRNAs (c-miRNAs), detectable in body fluids, exhibit high stability and specificity, making them attractive candidates for diagnostic and prognostic biomarkers.[25] In OA, miRNAs regulate key processes such as chondrocyte activity, extracellular matrix (ECM) remodeling, and inflammatory responses, with dysregulation contributing to cartilage degradation, altered differentiation, and increased cytokine production. They also target genes involved in ECM turnover, including matrix metalloproteinases (MMPs) and ADAMTS enzymes, and modulate signaling pathways such as NF-κB, Wnt, and TGF-β.[26]

Mechanical loading is a key regulator of cartilage physiology, with chondrocytes responding to biomechanical stimuli to control ECM synthesis, inflammation, and tissue remodeling. Several miRNAs are mechanosensitive and respond to mechanical stress, acting as mediators that translate biomechanical signals into gene regulatory responses.[27] Under normal loading, this process maintains cartilage homeostasis by promoting ECM synthesis and limiting inflammation. In contrast, abnormal or excessive mechanical stress disrupts miRNA expression, activating catabolic pathways, increasing ECM-degrading enzymes, and enhancing inflammatory signaling, thereby contributing to OA progression.[28] Emerging evidence further highlights the dual role of miRNAs in either promoting or inhibiting disease processes, supporting their potential as therapeutic targets.[29] In addition to mechanical factors, obesity-related metabolic dysregulation also influences miRNA expression in OA. Obesity alters miRNA profiles through metabolic and inflammatory pathways, particularly in response to high-fat diets. In knee cartilage, several miRNAs correlate with body mass index, with miR-22 and miR-103 upregulated, and miR-25, miR-29a, and miR-337 downregulated in obese OA patients.[30] These alterations highlight a shift toward inflammatory and catabolic condition, linking systemic metabolic dysfunction to cartilage degeneration and disease progression.

MicroRNAS REGULATION OF EXTRACELLULAR MATRIX HOMEOSTASIS AND DEGENERATION IN OSTEOARTHRITIS

OA is characterized by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation, and osteophyte formation, ultimately resulting in pain and impaired joint function.[31] Articular cartilage, composed mainly of type II collagen (COL2) and proteoglycans, depends on chondrocytes to maintain ECM homeostasis.[32] Disruption by mechanical stress or inflammation increases matrix-degrading enzymes such as MMPs and ADAMTS, accelerating cartilage loss. Moreover, OA involves not only cartilage but also the infrapatellar fat pad (IFP) and menisci, which actively contribute to disease progression.[12] The meniscus maintains load distribution and joint stability; its damage increases focal cartilage stress and promotes degeneration.[32] Inflammation of the IFP further amplifies disease by releasing cytokines and adipokines that reinforce catabolic signaling. Structural ECM components such as COL2A1 and ACAN, regulated by transcription factors SOX9 and SOX5, are essential for cartilage integrity.[33] Their dysregulation, together with increased MMP-1, MMP-13, and ADAMTS-4/5 activity, disrupts ECM balance and drives OA progression.[34] Loss of COL2A1 and ACAN alters cartilage biomechanics, reducing water retention, compressive stiffness, and shock absorption, thereby increasing mechanical stress and reinforcing a self-perpetuating cycle of degeneration.[35]

miRNAs are key regulators of these processes, modulating ECM synthesis, inflammation, and signaling pathways including NF-κB, MAPK, and TGF-β/Smad. Among them, miR-140 is critical for cartilage homeostasis; its loss leads to spontaneous OA, while its overexpression or MSC-mediated delivery protects cartilage by suppressing ADAMTS-5 and inflammatory signaling.[36] miR-140 is also mechanosensitive, linking mechanical loading to ECM regulation.[37] Similarly, miR-365 mediates mechanotransduction by targeting HDAC4 and regulating cartilage maturation pathways.[38]

Additional miRNAs (miR-140-5, miR-145, miR-127-5p, miR -140, miR-675, miR-15a, miR-26a, miR-142-3p, miR-204/211, miR-320a, miR-455-5P, miR-24, miR-27a, miR-27b, miR-17 and miR-29b) maintain cartilage integrity by suppressing MMPs, ADAMTS enzymes, inflammatory signaling and chondrocyte hypertrophy [Figure 2].[39,40,41,42,43,44,45,46,47,48,49,50,51,52,53] Conversely, degenerative miRNAs such as miR-34a, miR-495, miR-5581, miR-155, miR-146a and miR-181a-5p promote apoptosis, inflammation, and ECM breakdown through pathways involving SIRT1, AKT/mTOR, KRAS, and TGFBR3 [Figure 2].[54,55,56,57,58,59] Although miR-146a shows context-dependent effects, acting as both an anti-inflammatory regulator and a contributor to altered ECM signaling under OA conditions.[55] Collectively, these miRNAs are key regulators of cartilage homeostasis, balancing anabolic and catabolic processes [Figure 2]. Some of these miRNAs are mechanosensitive, linking biomechanical stress to pathways governing inflammation, ECM turnover, and chondrocyte survival. Their dysregulation under abnormal mechanical loading contributes to OA progression, highlighting their therapeutic potential for restoring cartilage integrity.

Figure 2.

MicroRNA regulation of cartilage homeostasis and degeneration in osteoarthritis (OA). This schematic illustrates the role of microRNAs (miRNAs) in regulating extracellular matrix (ECM) homeostasis and OA progression. Under physiological conditions, protective miRNAs, including miR-140-5p, miR-145, miR-127-5p, miR-675, miR-15a, miR-26a, miR-142-3p, miR-204/211, miR-455, miR-17, miR-320a, miR-24, miR-29b, miR-27a, and miR-27b, maintain cartilage integrity by promoting ECM synthesis, inhibiting matrix-degrading enzymes such as matrix metalloproteinase-13 (MMP-13), MMP-3, and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and upregulating anabolic genes including collagen type II alpha 1 chain (COL2A1) and SRY-box transcription factor 9. These effects occur through suppression of inflammatory signaling pathways and transcription factors, including nuclear factor kappa B, mitogen-activated protein kinase (MAPK), Toll-like receptor 4, high mobility group box 1, RUNX2, BMI-1, and p16INK4a, thereby preventing chondrocyte apoptosis and senescence. In contrast, pathogenic miRNAs, including miR-34a, miR-146a, miR-5581, miR-495, and miR-181a-5p, promote cartilage degeneration, synovial and Infrapatellar fat pad inflammation and subchondral bone remodeling, by enhancing inflammatory signaling, apoptosis, and catabolic enzyme expression (MMPs, ADAMTS, and C-C motif chemokine ligand 4), while suppressing protective genes such as sirtuin 1, B-cell lymphoma 2, and COL2A1. These effects are mediated through regulation of signaling pathways including nuclear factor erythroid 2-related factor 2 (NRF2), p53, phosphoinositide 3-kinase/protein kinase, nuclear respiratory factor 1, Kirsten rat sarcoma viral oncogene homolog, AKT1, and transforming growth factor beta receptor 3. MMP-13 – Matrix metalloproteinase-13; SOX9 – SRY-box transcription factor 9; COL2A1 – Collagen type II alpha 1 chain; KRAS – Kirsten rat sarcoma viral oncogene homolog; TGFBR3 – Transforming growth factor beta receptor 3; NRF1 – Nuclear respiratory factor 1, PI3K/AKT – Phosphoinositide 3-kinase/protein kinase B; SIRT1 – Sirtuin 1; BCL-2 – B-cell lymphoma 2; CCL4 – C-C motif chemokine ligand 4; NF-κB – Nuclear factor kappa B; TLR4 – Toll-like receptor 4; HMGB1 – High mobility group box 1

MicroRNAS REGULATION OF INFLAMMATION IN OSTEOARTHRITIS

Inflammation is a key immune response triggered by pathogens, toxins, and tissue injury. Although essential for host defense and repair, persistent inflammation is a major driver of OA progression.[60] The balance between pro-and anti-inflammatory signals across joint tissues including synovium and infrapatellar fat pad,[12] articular cartilage,[43] menisci[61] and subchondral bone determines whether inflammation resolves or becomes chronic and destructive.[62]

In OA, multiple joint components contribute to the inflammatory milieu. Synovial macrophages and fibroblast-like synoviocytes, stressed chondrocytes, activated osteoblasts and osteoclasts, as well as adipocytes and infiltrating immune cells in the infrapatellar fat pad, collectively sustain inflammation.[63] Clinical signs such as swelling, pain, redness, heat and reduced function result from increased vascular permeability and leukocyte infiltration in synovial and periarticular tissues. These cells, together with resident joint cells, produce pro-inflammatory cytokines including IL-1β, IL-6, IL-15, TNF-α, and IL-17, which amplify inflammatory signaling and activate matrix-degrading pathways.[64]

Increasing evidence shows that miRNAs are key regulators of inflammatory and catabolic signaling in OA [Figure 3]. Several miRNAs act as pro-inflammatory mediators that enhance cartilage degradation. For example, miR-155 is upregulated in OA and amplifies IL-1β-induced inflammatory and catabolic responses in chondrocytes by targeting PIK3R1 and disrupting PI3K/Akt signaling, thereby promoting apoptosis and matrix degradation [Figure 3].[65] Similarly, miR-34a contributes to the development and progression of OA by increasing chondrocyte death and cellular aging through the inhibition of Delta-like ligand 1 (DLL1) and subsequent downregulation of the PI3K/AKT signaling pathway.[54] miR-9-5p, a mechanosensitive miRNA, promotes synovial inflammation by enhancing M1 macrophage polarization through SIRT1 suppression and activation of NF-κB while inhibiting AMPK signaling.[66] In addition, miR-21-5p, delivered via synovial fibroblast-derived extracellular vesicles, suppresses KLF6 and increases MMP-3 and MMP-13 expression, thereby promoting cartilage breakdown.[67] Other miRNAs, including miR-5581 and miR-495, also contribute to OA progression by modulating inflammatory and catabolic pathways [Figure 3].[57,58]

Figure 3.

MicroRNA (miRNA)-mediated regulation of inflammatory signaling in osteoarthritis (OA). This schematic illustrates the role of miRNAs in regulating inflammatory signaling during OA progression. Multiple joint tissues, including the synovium, articular cartilage, infrapatellar fat pad, menisci and subchondral bone are affected in OA and exhibit increased inflammatory activity characterized by elevated levels of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), tumor necrosis factor alpha, interleukin-6 (IL-6), IL-17 and IL-15. Pro-inflammatory miRNAs, including miR-155, miR-34a, miR-9-5p, miR-21-5p, miR-5581, and miR-495, promote inflammatory signaling and increase expression of matrix-degrading enzymes such as matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), ADAMTS-5, cyclooxygenase-2, and prostaglandin E2, contributing to cartilage and synovial degeneration, osteophyte formation, and joint inflammation. In contrast, anti-inflammatory miRNAs, including miR-146a, miR-140, miR-92a-3p, miR-26a, miR-124, miR-320a, miR-455-3p/5p, miR-17, and miR-27a, suppress nuclear factor kappa B and signal transducer and activator of transcription 3 signaling, reduce cytokine production, and maintain cartilage homeostasis. miRNA – MicroRNAs; OA – Osteoarthritis; IL – Interleukin; TNF-α – Tumor necrosis factor alpha; MMP – Matrix metalloproteinase; ADAMTS: A disintegrin and metalloproteinase with thrombospondin motifs; COX-2 – Cyclooxygenase-2; PGE2 – Prostaglandin E2

In contrast, several miRNAs exert anti-inflammatory and chondroprotective effects. miR-146a suppresses NF-κB signaling by targeting TRAF6 and IRAK1, reducing cytokine production,[68] although sustained dysregulation may impair cartilage homeostasis in later stages. miR-140 is a key protective regulator that inhibits inflammatory mediators (IL-1β, IL-6, TNF-α, COX-2, MMPs) while promoting ECM synthesis and suppressing aggrecanases, thereby supporting cartilage repair.[36] Additional anti-inflammatory miRNAs include miR-92a-3p, which inhibits WNT5A signaling,[69] and miR-26a and miR-124, which suppress NF-κB and STAT3 pathways, respectively.[44,70] Other previously discussed miRNAs, including miR-320a, miR-455-3p/5p, miR-17 and miR-27a, also contribute to cartilage protection by limiting inflammatory and catabolic signaling [Figure 3].[47,48,49,50] Collectively, these miRNAs form a complex regulatory network that derives synovial inflammation and cartilage degradation in OA. Therefore, by either amplifying or suppressing inflammatory pathways, they critically influence disease progression, highlighting their potential as therapeutic targets for modulating joint inflammation and slowing OA progression.

TISSUE-SPECIFIC MicroRNAs IN THE SYNOVIUM, SUBCHONDRAL BONE, AND INFRAPATELLAR FAT PAD IN OSTEOARTHRITIS

Although cartilage degeneration is a hallmark of OA, the disease involves the entire joint as an integrated organ. Multiple tissues including the synovium, articular cartilage, infrapatellar fat pad (IFP), menisci, and subchondral bone contribute to OA progression through inflammatory signaling, biomechanical alterations, and ECM remodeling.[12,61,62] miRNAs act as key post-transcriptional moderators within these compartments, regulating pathways involved in inflammation, tissue degeneration, and joint remodeling.

In the synovium, miRNAs regulate inflammatory signaling and fibroblast activation. Pro-inflammatory miRNAs such as miR-155 enhance cytokine production and matrix-degrading enzymes via NF-κB activation, promoting cartilage degeneration.[56] In contrast, miR-146a suppresses inflammation by targeting TRAF6 and IRAK1, thereby inhibiting NF-κB signaling.[68] Additional protective miRNAs, including miR-26a, miR-92a-3p and miR-124 limit inflammatory responses through regulation of NF-κB, STAT3, and Wnt signaling pathways.[44,69,71] Conversely, miR-9-5p and miR-21-5p promote synovial inflammation by enhancing MMP expression and macrophage polarization, respectively.[66,67] In subchondral bone, miRNAs regulate osteoblast differentiation, osteoclast activity and osteochondral remodeling, which are critical for joint integrity.[71] miR-204 and miR-211 inhibit RUNX2 to limit osteogenic differentiation and chondrocyte hypertrophy,[46] while miR-320a similarly regulates RUNX2 and BMI-1 signaling.[47] miR-29b further contributes to osteochondral remodeling by targeting Wnt5a, influencing ECM turnover and bone-cartilage interactions.[53] These miRNAs collectively link abnormal bone remodeling to cartilage degeneration. The IFP also contributes to OA through the secretion of adipokines and inflammatory mediators.[12] Although less characterized, miRNAs in adipose-derived cells appear to regulate inflammatory signaling and immune responses within this tissue, indirectly promoting synovial inflammation and cartilage degradation.[72] Overall, miRNAs coordinate inflammatory and degenerative processes across multiple joint tissues. Their tissue-specific regulation highlights OA as a whole-joint disease and supports the potential of miRNA-targeted therapies to modulate inflammation and slow disease progression. However, further studies are needed to fully elucidate their regulatory networks and therapeutic potential in OA, with particular emphasis on tissue-specific miRNA functions.

MicroRNAs SIGNALING PATHWAYS IN OSTEOARTHRITIS

The pathogenesis of OA involves mechanical stress, biochemical mediators, and dysregulated intracellular signaling pathways that regulate chondrocyte homeostasis, ECM turnover, inflammation, and apoptosis.[73] Disruption of these pathways shifts the balance toward cartilage catabolism, driving OA progression. These signaling mechanisms are discussed in detail in the following sections, and a summary of associated miRNAs is provided in Table 1.

Table 1.

miRNAs involved in osteoarthritis: Functions, targets, and pathways

miRNA	Primary function(s) in OA	Target genes	Pathways involved	References
miR-140	Maintains cartilage homeostasis, inhibits MMP-13 and ADAMTS-5, reduces inflammation	MMP-13, ADAMTS-5, HDAC4, TLR4	TGF-β/Smad	[37]
miR-127-5p	Reduces ECM degradation	ADAMTS-5	NF-kB	[41]
miR-675	Supports chondrocyte differentiation by upregulating Col2a1	Col2a1 (indirect)	Not specified	[42]
miR-15a	Suppresses SASP markers, ameliorates inflammation and cartilage damage	HMGB1, TNF-α	NF-κB, β1,4-GalT-I axis	[43]
miR-26a	Reduces cartilage damage and synovial inflammation	NF-κB components, PGE2 COX-2	NF-κB	[44]
miR-142-3p	Inhibits chondrocyte apoptosis and inflammation	HMGB1	NF-kB	[45]
miR-204/211	Preserves cartilage integrity by suppressing chondrocyte hypertrophy	Runx2, MMP-13, ADAMTS-5	PI3K/Akt	[46]
miR-320a	Protects cartilage by regulating RUNX2 and BMI-1	MMP-13, ADAMTS-5 RUNX2, BMI-1	NF-κB/RUNX2, BMI-1	[47]
miR-34a	Induces chondrocyte senescence and MMP expression	MMP-13, MMP-1, COL-X, DLL1	PI3K/AKT	[54]
MiR-19b-3p	Enhances cell viability, reduces apoptosis, and decreased ECM degradation	Suppresses GRK6	NF-kB	[74]
miR-107	Prevents apoptosis and promotes autophagy	Inhibits TRAF3	NF-κB	[75]
MiR-210	Decreases chondrocyte inflammation and apoptosis	DR6, IκBα, p65	NF-κB	[76]
miR-93	Inhibits inflammatory and degenerative responses in LPS-induced OA	TLR4	TLR4/NF-κB	[77]
miR-410-3p	Attenuates pro-inflammatory cytokine production and cell death	HMGB1	NF-κB	[78]
miR-125b-5p	Reduces inflammation and degeneration	TRAF6, MMP-13 COX-2, iNOS, TNF-α, IL-6, ADAMTS5, and MMP9	NF-κB/YAP1	[79]
miR-214-3p	Mitigates inflammatory and degenerative responses	IKBKB	NF-κB	[80]
miR-181a-5p/miR-4454	Inhibits inflammation and degeneration	ZNF440	NF-κB	[81]
miR-455-3p	Prevents of cartilage breakdown and Inflammation	Supress PAK2, MMPs, IL-1, IL-6, and TNF-α	TGF-β/Smad, HMGB1, NF-kB	[82]
MiR-16-5P	Promotes IL-1β-induced inflammation and cartilage catabolism;	IL-6, TNF-α, COX-2, MMPs, ADAMTS; Collagen, Aggrecan	p38 MAPK, NF-κB	[83]
MiR-296-5P	Promotes chondrocyte proliferation, inhibits apoptosis and ECM degradation	TGF-β1; MMP-13, ADAMTS-5, COL2A1, Aggrecan	TGF-β1 / p38 MAPK	[84]
MiR-199a-5p	Promotes inflammatory responses and cartilage degradation	MAPK4; IL-1β, IL-6, IL-18, MMP-13, ADAMTS-5; COL2A1	MAPK	[85]
MiR-144-3p	Suppresses IL-1β production and reduces synovial inflammation in OA	IL-1β	MAPK, PI3K/Akt, NF-κB	[86]
MiR-27a-3p	Protective regulator of cartilage ECM; inhibits cartilage matrix degradation	ADAMTS5	MAPK, NF-κB	[87]
MiR-186-5p	Regulates IL-1β-induced inflammatory injury and apoptosis in chondrocytes	MAPK1; TNF-α, IL-6, IL-8	MAPK signaling pathway	[88]
miR-574-3p	Suppresses chondrocyte hypertrophy and reduces the inflammatory response in (KOA)	CRIM1	CRIM1/BMP	[89]
miR-378a-3p	Facilitates proliferation and chondrogenic differentiation	BMP2	BMP/Smad	[90]

OA – Osteoarthritis; KOA – Knee OA; ECM – Extracellular matrix; MMP – Matrix metalloproteinases; IL – Interleukin, TNF-α – Tumor necrosis factor-α; BMP – Bone morphogenetic proteins; MAPK – Mitogen-activated protein kinase; ADAMTS – A disintegrin and metalloproteinase with thrombospondin motifs; HMGB 1 – High mobility group box 1; NF-κB – Nuclear factor kappa B; DR – Death receptor-6; SASP – Senescence-associated secretory phenotype

NF-κB signaling is a key mediator of inflammatory and catabolic responses in OA, where NF-κB dimers (RelA, RelB, c-Rel, p50, and p52) are normally sequestered by IκB proteins but become activated following IκB degradation, translocating to the nucleus to induce the expression of pro-inflammatory cytokines and extracellular matrix-degrading enzymes.[91] In OA studies, NF-κB inhibition reduces cytokine production and matrix degradation.[92] This pathway is further moderated by multiple miRNAs targeting upstream NF-κB signaling components, thereby reducing inflammation, apoptosis, and ECM breakdown [Table 1].[74,75,76,77,78,79,80,81,82] The MAPK pathway, including ERK, JNK, and p38 MAPK, regulates chondrocyte apoptosis, inflammatory mediator production and expression of matrix-degrading enzymes such as MMP-13 and ADAMTS.[93] miRNAs regulate MAPK signaling directly or via upstream regulators, thereby influencing inflammation, cell survival, and ECM homeostasis in OA [Table 1].[83,84,85,86,87,88,88] The TGF-β/Smad pathway is essential for maintaining cartilage homeostasis by promoting ECM synthesis and preserving the stable chondrocyte phenotype.[94] Under physiological conditions, canonical TGF-β signaling through Smad2/3 maintains cartilage integrity by preventing chondrocyte hypertrophic differentiation, whereas in osteoarthritic cartilage this balance shifts toward Smad1/5/8 signaling, promoting chondrocyte hypertrophy, catabolic activity, and progressive cartilage degradation.[95] Several miRNAs contribute to this imbalance by targeting key regulators such as Smad3, IL-6/STAT3, TRAF6, and PAK2, thereby modulating inflammatory and anabolic responses involved in cartilage remodeling [Table 1].[37,82,84]

BMP signaling, a member of the TGF-β superfamily, regulates chondrogenesis and cartilage repair by promoting chondrocyte differentiation and ECM synthesis. In OA, BMPs such as BMP-2 and BMP-7 are upregulated and contribute to both regenerative and degenerative processes, including structural alterations and subchondral bone remodeling.[95] Although BMP signaling promotes cartilage regeneration under physiological conditions, its dysregulation is associated with abnormal differentiation, ECM remodeling, and cartilage degeneration. miRNAs; such as miR-574-3p and miR-378a-3p modulate this pathway by targeting BMP ligands, receptors, and downstream effectors, thereby influencing chondrogenesis, hypertrophy, and matrix homeostasis in OA cartilage [Table 1].[89,90] Collectively, these findings indicate that miRNAs regulate key signaling pathways in OA, including NF-κB, MAPK, TGF-β/Smad, and BMP pathways. Through modulation of inflammation, chondrocyte apoptosis, and ECM metabolism, they contribute to the imbalance between cartilage degradation and repair, highlighting their potential as diagnostic biomarkers and therapeutic targets in OA.

FUTURE PERSPECTIVES: CIRCULATING MicroRNAs IN DIAGNOSIS AND THERAPY OF OSTEOARTHRITIS

Circulating microRNAs are emerging non-invasive biomarkers for OA, which can be detectable in synovial fluid, serum, and plasma, and reflect joint pathology. Several miRNA signatures are associated with OA onset, severity, and progression [Table 2]. For example, miR-140-5p/3p are downregulated and correlate with cartilage degeneration,[96] whereas miR-210 is elevated in early OA, indicating hypoxic adaptation.[97] Inflammatory and degenerative processes are linked to increased miR-146a, miR-365, miR-146b, and miR-27b,[98,99] while miR-335-5p exhibits protective effects through autophagy and anti-inflammatory activity.[100]

Table 2.

Circulating MicroRNAs in diagnosis and therapy of osteoarthritis

miRNA	Expression pattern in OA	Biological source	Functional/clinical relevance	Supporting evidence	Reference
miR-140-5p/miR-140-3p	Downregulated	Synovial fluid	Correlates with OA severity and cartilage degeneration	Reduced levels reported in OA synovial fluid samples	[96]
miR-210	Upregulated in early OA	Serum/synovial fluid	Potential early diagnostic marker	Elevated expression reported in early-stage OA	[97]
miR-146a	Upregulated	Plasma	Diagnostic biomarker; regulates inflammatory responses	Elevated plasma levels observed in OA patients	[98]
miR-365	Upregulated	Plasma	Associated with inflammatory factors and OA severity	Increased plasma levels correlated with inflammation	[98]
miR-146b	Altered expression	Serum/synovial fluid	Potential early biomarker of OA	Altered expression detected in clinical samples	[99]
miR-27b	Reduced in OA progression	Serum/synovial fluid	Regulates MMP-13 and cartilage degradation	Functional role in cartilage homeostasis	[99]
miR-335-5p	Upregulated in OA chondrocytes	Blood/chondrocytes	Enhances autophagy, improves viability, reduces inflammation	Functional studies in OA chondrocytes	[100]
let-7e	Decreased (inverse correlation)	Serum/plasma	Lower levels associated with severe knee and hip OA	Potential predictive biomarker for OA severity and progression	[101]
miR-454	Decreased (inverse correlation)	Serum/plasma	Reduces expression associated with severe OA	May reflect cartilage degeneration and disease progression	[101]
miR-885-5p	Increased (positive correlation)	Serum/plasma	Higher levels associated with severe knee and hip OA	Potential marker of advanced disease	[101]
miR-126-3p	Elevated	Plasma	Correlates with radiographic OA severity	Identified as reproducible circulating biomarker	[102]
miR-23a-3p	Increased	Plasma	Correlates with pain scores and clinical severity	Plasma analysis in hand OA	[103]
miR-652-3p	Increased	Plasma	Associated with OA symptoms and inflammatory activity	Identified in hand OA plasma samples	[103]
miR-222-3p	Inversely correlated with radiographic score	Plasma	Associated with structural disease severity	Negative correlation with radiographic progression	[103]
miR-16	Differentially expressed	Plasma	Component of circulating OA biomarker signature	Identified through plasma miRNA profiling	[104]
miR-29c	Increased	Plasma	Associated with cartilage metabolism and OA progression	Detected in circulating OA miRNA signature	[104]
miR-93	Altered expression	Plasma	Linked to inflammation and cartilage homeostasis	Plasma profiling studies in OA	[104]
miR-576-5p	Downregulated	Serum	Correlates with OA severity (KL grade); improves chondrocyte viability and reduces apoptosis and inflammation via KLF10 targeting	Serum levels reduced in OA patients; functional studies in IL-1β-stimulated chondrocytes show protective effects of miR-576–5p overexpression	[105]

OA – Osteoarthritis; MMP – Matrix metalloproteinases; miRNA – MicroRNAs; IL – Interleukin

Longitudinal studies further identify miRNAs associated with disease progression, including let-7e, miR-454, and miR-885-5p, with let-7e showing predictive potential for severe OA.[101] Additional biomarkers such as miR-126-3p, miR-23a-3p, miR-652-3p, and miR-222-3p demonstrate diagnostic relevance across different OA phenotypes.[102,103] Collectively, circulating miRNAs represent promising diagnostic and prognostic indicators of inflammatory and degenerative processes in OA [Table 2].[96,97,98,99,100,101,102,103,104,105]

Next-generation sequencing enables comprehensive miRNA profiling and has identified differentially expressed miRNAs involved in inflammation, cartilage degeneration, and ECM remodeling.[106] Building on this, specific circulating miRNA panels have been shown to differentiate early from late OA, highlighting their diagnostic potential.[107] Consistent with these findings, tissue-based studies reveal widespread miRNA dysregulation in cartilage and subchondral bone, implicating pathways related to apoptosis, angiogenesis, and chondrocyte differentiation.[108] Furthermore, integrated analyses of miRNA-mRNA interactions have revealed key regulatory interactions involving targets such as SMAD3 and WNT5A, reinforcing their roles in OA pathogenesis and pain.[109]

Beyond diagnosis, miRNAs are promising therapeutic targets due to their regulation of inflammation, ECM turnover, and chondrocyte survival. Therapeutic strategies include restoring protective miRNAs (e.g. miR-140,[36] miR-144-3p[86]) and inhibiting pathogenic miRNAs (e.g., miR-34a,[54] miR-21-5p[67]), which have been identified to reduce inflammation, preserve cartilage integrity, and slow disease progression. Additional regulators such as miR-411 and miR-590-5p further modulate autophagy and apoptosis, highlighting the broader therapeutic potential of miRNA networks.[110,111] Regulatory RNA interactions also contribute to OA pathogenesis. For instance, modulation of the lncRNA-UFC1/miR-34a/MMP-13 axis reduces ECM degradation and promotes chondrocyte survival, partly through effects on inflammatory signaling pathways.[112] Overall, miRNA-based strategies offer promising potential for OA management by targeting key mechanistic pathways of inflammation, cartilage degradation, and cell survival. Integration of diagnostic miRNA panels with targeted therapies within a theranostic framework, alongside advanced delivery systems such as nanoparticles or exosomes, may enhance treatment specificity. However, large-scale longitudinal studies are required to validate circulating miRNAs as reliable biomarkers and therapeutic targets, supporting precision medicine approaches in OA.

CONCLUSION

MiRNAs play central roles in OA by regulating inflammation, apoptosis, cartilage homeostasis, and ECM remodeling. Circulating miRNAs offer minimally invasive biomarkers for early diagnosis, while therapeutic modulation via mimics or inhibitors holds promise for disease modification. Integrating miRNA profiling with clinical data could enable personalized OA management, shifting care from late-stage symptom control to early detection and targeted intervention, pending clinical validation and safe delivery strategies.

Peer review

This article was peer-reviewed by two independent and anonymous reviewers.

Data availability statement

Data sharing is not applicable for this article, as no new data were created or analyzed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

This review was funded by the Fundamental Research Grant Scheme from the Ministry of Higher Education Malaysia (FRGS/1/2023/SKK10/ USM/02/18).