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Review
. 2022 Jul 22;24(1):174.
doi: 10.1186/s13075-022-02859-x.

Senescence in osteoarthritis: from mechanism to potential treatment

Yikai Liu  1 , Zian Zhang  1 , Tao Li  1 , Hao Xu  1 , Haining Zhang  2
Affiliations
Review

Senescence in osteoarthritis: from mechanism to potential treatment

Yikai Liu et al. Arthritis Res Ther. .

Abstract

Osteoarthritis (OA) is an age-related cartilage degenerative disease, and chondrocyte senescence has been extensively studied in recent years. Increased numbers of senescent chondrocytes are found in OA cartilage. Selective clearance of senescent chondrocytes in a post-traumatic osteoarthritis (PTOA) mouse model ameliorated OA development, while intraarticular injection of senescent cells induced mouse OA. However, the means and extent to which senescence affects OA remain unclear. Here, we review the latent mechanism of senescence in OA and propose potential therapeutic methods to target OA-related senescence, with an emphasis on immunotherapies. Natural killer (NK) cells participate in the elimination of senescent cells in multiple organs. A relatively comprehensive discussion is presented in that section. Risk factors for OA are ageing, obesity, metabolic disorders and mechanical overload. Determining the relationship between known risk factors and senescence will help elucidate OA pathogenesis and identify optimal treatments.

Keywords: Cellular senescence; Immunotherapy; Killer cells; Natural; Osteoarthritis; SASP (senescence-associated secretory phenotype).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Signalling mechanisms leading to senescence. Mechanical stress, DNA damage, ROS, oxidative stress and other adverse conditions induce cellular senescence. p53-p21-CDK2 and p16-CDK4/6 are two pathways involved in senescence. CDK2/4/6 inhibit RB and promote S phase entry, leading to cell cycle arrest and cellular senescence. ROS, reactive oxygen species; CDK, cyclin-dependent kinases; RB, retinoblastoma protein
Fig. 2
Fig. 2
The effects of mechanical stress on chondrocytes. Under mechanical stress conditions, Piezo1 and TRPV4 channels are activated, leading to Ca2+ influx into the cytoplasmand triggering endoplasmic reticulum stress and mitochondrial dysfunction. mtROS and mtDNA are released from damaged mitochondria, which results in DNA damage, active catabolism and cartilage degeneration. NF-κB is usually activated during senescence and promotes SASP factor transcription. Mechanical stress inhibits FBXW7-dependent MKK7 degradation, which leads to JNK pathway activation and cellular senescence. JNK also has anti-senescence effect by regulating p16. The Rac1-ROS pathway participates in NF-κB activation under mechanical stress and promotes the production of gremlin-1. Gremlin-1 in turn activates NF-κB via VEGF2 in an autocrine or paracrine manner. TRPV4, transient receptor potential vanilloid 4; mtROS, mitochondrial reactive oxygen species; NF-κB, nuclear factor kappa-B; SASP, senescence-associated secretory phenotype; FBXW7, F-box and WD repeat domain containing 7; MKK7, mitogen-activated protein kinase kinase 7; JNK, mitogen-activated protein kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; VEGF2, vascular endothelial growth factor 2
Fig. 3
Fig. 3
The relationship between energy shortage and chondrocyte senescence. Energy deficiency caused by damaged mitochondria activates AMPK, and SIRTs including SIRT1, SIRT3 and SIRT6. SIRT1 protects cartilage by promoting the transcription of Sox9 and collagen 2. Several factors such miR-34a and leptin inhibit SIRT1 and exacerbate chondrocyte senescence and cartilage damage. Damaged mitochondria are eliminated by p62-mediated autophagy. Activated in an inflammatory environment, NF-κB promotes SASP factor transcription. SASP factors activate NF-κB in an autocrine manner, forming a positive feedback loop. Energy deficiency activates mTOR via AMPK. mTOR inhibits ZFP36L1 by activating MKK. ZFP36L1 and some miRNAs, such as miR-204 participate in the degradation of SASPs. Decreased NAD + /NADH also activates SIRT3 and SIRT6 in addition to SIRT1. SIRT3 deacetylates SOD2 and increases SOD2-specific activity, thus protecting chondrocytes against oxidative stress. SIRT6 can inhibit DNA damage and cellular senescence. SIRT, sirtuin; AMPK, adenosine 5′-monophosphate (AMP)-activated protein kinase; mTOR, mammalian target of rapamycin; ZFP36L1, ZFP36 ring finger protein like 1; SOD2, superoxide dismutase 2
Fig. 4
Fig. 4
Interactions between NK cells and senescent cells. In response to DNA damage, MICA is selectively expressed on senescent cells rather than proliferative cells. MICA interacts with NKG2D and activates NK cells via ITAM. Activated NK cells produce and secrete granzyme B and perforin to kill senescent cells. Shedding MICA from the senescent cell membrane surface leads to NK cells off-target and senescent cell evasion. HLA-E is upregulated by the p38 pathway. HLA-E binds to NKG2A and inhibits NK cell activation via the ITIM on the NKG2A intracellular segment. CD155 exerts dual effects as its combination with DNAM-1 activates NK cells while its combination with CD94 or TIGHT inhibits NK cell activation. Shedding CD155 participates is involved in the evasion of senescent cells as its binding affinity to DNAM-1 is higher than that to TIGHT and CD94. The expression of MICA and CD155 is directly regulated by transcriptional factor E2F1. uPAR is specifically expressed on the senescent cell membrane surface, and CAR-T therapy targeting uPAR has been designed to eliminate senescence. DPP4 has been treated as a target of immunotherapy via ADCC. NKG2D, natural killer group 2, member D; HLA-E, human leukocyte antigen-E; IL-6, interleukin-6; CAR-T cell, chimeric antigen receptor T cell; uPAR, urokinase-type plasminogen activator receptor; ADCC, antibody-dependent cell-mediated cytotoxicity; DPP4, dipeptide peptidase 4; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif
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