An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization
Abstract
:1. Introduction
2. The Development Stage of Osteoarthritis (OA)
- (a)
- The activity of osteoclasts in the joints increases, which disrupts the balance between bone formation and bone resorption, and eventually makes the thickness of subchondral bone significantly thinner than normal [15].
- (b)
- The depletion of phagocytic synovial lining cells causes a decrease in the influx of polymorphonuclear neutrophils, which inhibits proteoglycan degradation. Overall, the above changes lead to the death of articular cartilage cells (collagen-induced arthritis (CIA) model). Besides, the reduction of synovial macrophages attenuates the formation of joint osteophytes (in the OA mouse model) [16].
- (c)
- Elevated cholesterol promotes the formation of ectopic bone (CIA model) [17].
- (a)
- Cartilage is mostly degraded, accompanied by severe pain. At the mechanism level, pain is mainly caused by the following phenomenon: the synovium in the joints of advanced OA patients is infiltrated by macrophages. Subsequently, the activated macrophages release pro-inflammatory cytokines, causing chronic pain and inflammation. From a diagnostic point of view, the levels of three pro-inflammatory mediators in the synovial tissue are significantly up-regulated, which could be considered as a diagnostic marker for OA. The three types of pro-inflammatory mediators are (1) interleukin-1b (IL-1β), (2) IL-6, and (3) nerve growth factor (NGF). Therefore, these indicators may be promising clinical markers for monitoring the progression of OA [18].
- (b)
- The production of IRF5 (interferon regulatory factor 5, IRF5) in the synovial macrophages of OA patients is markedly enhanced, indicating that IRF5 is positively correlated with the severity of OA. Additionally, on the synovial macrophages of OA patients, the IRF5 level in Stage 4 OA patients is significantly higher than that in Stage 2 and Stage 3 [19].
- (c)
- The subchondral plate of OA patients becomes significantly thicker, and the thickness of the unmineralized articular cartilage is significantly thinner than average [15].
3. Macrophage Polarization
4. Macrophages Are an Emerging Target for OA Treatment
4.1. Physical Stimuli
Low-Intensity Pulsed Ultrasound (LIPUS)
4.2. Chemical Compounds
4.2.1. Kinsenoside
4.2.2. Quercetin
4.2.3. Dexamethasone
4.2.4. Pravastatin
4.2.5. Rapamycin
4.3. Biological Molecules
4.3.1. Cells
Mesenchymal Stem Cells
TissueGene-C
4.3.2. Proteins
R-Spondin-2
Interferon Regulatory Factor 5
Pro-Resolving Lipid Mediator
Lumican
Bone Morphogenetic Protein 7
Squid Type II Collagen
Modified ZIF-8 Nanoparticles
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Abbreviation | Full name |
ACLT | Anterior cruciate ligament transection |
ADAMTS-4 | A disintegrin and metalloproteinase with thrombospondin motifs 4 |
Akt | Protein kinase B |
Arg-1 | Arginase-1 |
BMP-7 | Bone morphogenetic protein 7 |
CIA | Collagen-induced arthritis |
CIOA | Collagenase-induced osteoarthritis |
CL | Clodronate-loaded liposomes |
CM | Conditioned medium |
COX2 | Cyclooxygenase 2 |
DMOADs | Disease-modifying osteoarthritis drugs |
DXMS | Dexamethasone |
ERK | Extracellular regulated protein kinase |
H2O2 | Hydrogen peroxide |
IFN-γ | Interferon-γ |
IL-1 | Interleukin-1 |
IL-1β | Interleukin-1β |
IL-4 | Interleukin-4 |
IL-6 | Interleukin-6 |
IL-10 | Interleukin-10 |
IL-12 | Interleukin-12 |
IL-13 | Interleukin-13 |
IL-23 | Interleukin-23 |
iNOS | Inducible nitric oxide synthase |
IRF5 | Interferon regulatory factor 5 |
IκBα | Inhibitor of NF-κB |
JNK | C-Jun N-terminal kinase |
Kin | Kinsenoside |
LIPUS | Low-intensity pulsed ultrasound |
LPS | Lipopolysaccharide |
LUM | Lumican |
MAPK | Mitogen-activated protein kinase |
MIA | Monosodium iodoacetate |
MMP-13 | Matrix metalloproteinase-13 |
MR | Mannose receptor |
MSCs | Mesenchymal stem cells |
mTOR | Mammalian target of rapamycin |
NF-κB | Nuclear factor kappa B |
NGF | Nerve growth factor |
NO | Nitric oxide |
O2 | Oxygen |
OA | Osteoarthritis |
PTOA | Post-traumatic osteoarthritis |
ROS | Reactive oxygen species |
Rspo2 | R-spondin-2 |
RvD1 | Retinoid D1 |
SCII | Squid type II collagen |
STAT6 | Signal transducer and activator of transcription 6 |
TAM | Tumor-associated macrophages |
TCR+ | T-cell receptor-positive |
TGF-β | Transforming growth factor-beta |
TGF-β1 | Transforming growth factor-beta 1 |
TGF-β3 | Transforming growth factor-beta 3 |
TLR | Toll-like receptor |
TLR4 | Toll-like receptor 4 |
TNF-α | Tumor necrosis factor α |
YM1 | Chitinase-like protein |
ZIF-8 | Zeolitic imidazolate framework-8 |
ZIF-8 NPs | ZIF-8 nanoparticles |
Appendix A
Type | Name | OA Sample—Cells | OA Sample—Animal | Signaling Pathway | Function | Research Stage/Application Schedule | Mechanism | Refs. | |
---|---|---|---|---|---|---|---|---|---|
Physical stimuli | Low-intensity pulsed ultrasound (LIPUS) | THP-1 cells; RAW 264.7; synovial macrophages | Mouse medial meniscus instability (DMM) arthritis | JNK NF-κB | Inhibit the expression of related genes in M1 macrophages and promote the expression of related genes in M2 macrophages | Preclinical stage/NA | LIPUS regulates the polarization of synovial macrophages, thus inhibiting osteoarthritis. | [27] | |
Chemical compounds | Kinsenoside (Kin) | RAW264.7 | Anterior cruciate ligament transection (ACLT) mouse model | NF-κB JNK MAPK ERK | Transform M1 macrophages into M2 macrophages; reduce the infiltration of M1 in mouse joints and promote the infiltration of M2 in mouse synovitis | Preclinical stage/NA | Kinsenoside relieves the symptoms of osteoarthritis by inactivating NF-κB/MAPK signaling and promoting macrophage repolarization. | [15] | |
Quercetin | RAW264.7 | IL-1β-induced rat osteoarthritis model | Akt/NF-κB | Promote the formation of M2 macrophages | Preclinical stage/NA | Quercetin repairs damaged cartilage by promoting the conversion of synovial macrophages into M2 macrophages, and finally alleviates OA symptoms. | [34] | ||
Dexamethasone (DXMS) | Synovial macrophages | Patients with osteoarthritis | NA | Inhibit the activity of M1 macrophages and promote the formation of M2 macrophages | Preclinical stage/NA | DXMS promotes the conversion of macrophages into M2 macrophages to relieve OA symptoms. | [16] | ||
Pravastatin | Primary human monocytes | Patients with osteoarthritis | NA | Promote the formation of M2 macrophages | Preclinical stage/NA | DXMS promotes the conversion of macrophages into M2 macrophages to relieve OA symptoms. | [16] | ||
Rapamycin | Primary human monocytes | Patients with osteoarthritis | mTOR | Enhance the function of M1 macrophages and inhibit the activity of M2 macrophages | Preclinical stage/NA | DXMS promotes the conversion of macrophages into M2 macrophages to relieve OA symptoms. | [16,47] | ||
Biological molecules | Cell | Mesenchymal stem cell (MSC) | Synovial macrophages of OA patients | In vitro co-culture OA model consisting of patient-matched cartilage and macrophages | NA | Inhibit the activity of M1 macrophages and induce polarization of M2 macrophages | Preclinical stage/NA | MSCs promote the formation of M2 macrophages, thereby relieving OA symptoms | [46,51] |
TissueGene-C | Human joint macrophages | Patients with osteoarthritis | NA | Promote the formation of M2 macrophages | Phase III of a clinical trial/NA | TissueGene-C induces the formation of M2 macrophages, thereby relieving pain in patients with OA. | [52,53] | ||
Protein | R-spondin-2 | NA | NA | Wnt/β-catenin | NA | Preclinical stage/NA | The formation of M1 macrophages promoted the secretion of rspo2 in chondrocytes, thereby exacerbating the symptoms of experimental OA. | [47] | |
Interferon regulatory factor 5 (IRF5) | Synovial macrophages | Patients with osteoarthritis | NA | Promote the formation of M1 macrophages | Preclinical stage/NA | M1 macrophage-secreted IRF5 is positively correlated with the severity of OA symptoms. | [19,58] | ||
Pro-resolving lipid mediator | Synovial macrophages | Obesity-induced osteoarthritis | NA | Reduce the number of M1 macrophages and increase the formation of M2 macrophages | Preclinical stage/NA | CL attenuates obesity-induced OA by regulating the polarization of macrophages. | [59] | ||
Lumican (LUM) | Human primary chondrocytes and macrophages | NA | NF-κB | LUM+LPS induces the differentiation of macrophages into M1 type | Preclinical stage/NA | In the TLR4-mediated OA model, the expression of LUM is up-regulated, which promotes the formation of M1 macrophages and aggravates OA symptoms. | [23,61,62,63,64] | ||
Bone morphogenetic protein 7 (BMP-7) | Primary human monocytes | Patients with osteoarthritis | NA | NA | Preclinical stage/NA | BMP-7 regulates the inflammatory state of joints by changing the phenotype of OA synovium (polarizing monocytes into M2 type). | [16] | ||
Squid type II collagen (SCII) | RAW264.7 cells; mouse chondrocytes | Mouse OA model induced by anterior cruciate ligament transection (ACLT) and partial meniscus resection (pMMx) | STAT6 | Promote the conversion of M1 macrophages into M2 macrophages | Preclinical stage/NA | SCII improves the symptoms of OA by promoting the polarization of M2 macrophages. | [68] | ||
Modified ZIF-8 nanoparticles | RAW264.7 cells | A mouse model of OA with anterior cruciate ligament transection (ACLT). | MAPK NF-κB JNK | Promote the transformation of M1 macrophages into M2 macrophages | Preclinical stage/NA | Modified ZIF-8 nanoparticles transform macrophages from M0 to M2 for OA treatment. | [73] |
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Sun, Y.; Zuo, Z.; Kuang, Y. An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization. Int. J. Mol. Sci. 2020, 21, 8513. https://doi.org/10.3390/ijms21228513
Sun Y, Zuo Z, Kuang Y. An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization. International Journal of Molecular Sciences. 2020; 21(22):8513. https://doi.org/10.3390/ijms21228513
Chicago/Turabian StyleSun, Yulong, Zhuo Zuo, and Yuanyuan Kuang. 2020. "An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization" International Journal of Molecular Sciences 21, no. 22: 8513. https://doi.org/10.3390/ijms21228513
APA StyleSun, Y., Zuo, Z., & Kuang, Y. (2020). An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization. International Journal of Molecular Sciences, 21(22), 8513. https://doi.org/10.3390/ijms21228513