Adiponectin, May Be a Potential Protective Factor for Obesity-Related Osteoarthritis

Figures & data

Figure 1 Possible mechanisms of obesity leading to osteoarthritis. IL-1β, interleukin 1 β. TNF-α, tumor necrosis factor-α.

Figure 2 Possible mechanisms by which adiponectin regulates risk factors for OA in obese patients.

Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; PPAR, peroxisome proliferator-activated receptor; NF-κB, nuclear factor kappa-B; Mgl-1, macrophage galactose N-acetyl-galactosamine specific lectin-1; ERK, extracellular regulated protein kinases; LPL, lipoprotein lipase; HSL, hormone-sensitive lipase; ATGL, adipose triglyceride lipase; Apo-CIII, apolipoprotein-CIII; TIMP-2, tissue inhibitor of matrix metalloproteinases-2; MMP-13, matrix metalloproteinase.

Table 1 Inflammatory Factor Involved in the Pathophysiology of OA

Inflammatory Factor	Activities in OA
TNF-α and IL-1	Be observed synovial fluid, synovium, cartilage and subchondral bone layer.^Citation32 Increases MMPs.^Citation33 Promotes the expression of ADAMTS.^Citation37 Promotes iNOS activity. Leading to overexpression of NO in chondrocytes.^Citation40,Citation41
TNF-α	Enhances the activity of NF-κB and stress-activated protein kinase/c-Jun N-terminal kinase.^Citation43
IL-6	Detected in knee synovial fluid and surrounding tissues.^Citation44 Associated with JSN and cartilage loss.^Citation45 Increases MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5.^Citation46 Blocking the effect of IL-6 to reduce OA cartilage damage, osteophyte formation, and synovial inflammation.^Citation46 Inhibits the differentiation of osteoblasts into osteocytes.^Citation48 Reduces the expression of Runx2, collagen 1A2, and osteocalcin.^Citation47 Increases the mRNA expressions of RANKL and OPG.^Citation49
IL-15	Increased in joint fluids is increased in early-stage OA.^Citation51 Increases the levels of MMP-1 and MMP-3.^Citation51 Associated with the development of neuropathic pain-like symptoms.^Citation51
IL-17	IL-17 levels are elevated and positively correlated with OA severity.^Citation52 Stimulates the production of IL-1β, IL-6 and TNF-α.^Citation52
IL-18	Downregulated the mRNA expressions of Collagen II, Sox9 and Aggrecan.^Citation53 Promotes the proapoptotic effect of chondrocytes.^Citation53
MMPs	Mediates the degradation of collagen proteins.^Citation34
PGE2	Stimulate the expression of MMP-13 and ADAMTS-5.^Citation35 Upregulates the expression of IL-6 mRNA.^Citation36
ADAMTS	Cleave the aggregated proteins.^Citation36
NO	Promote chondrocytes MMP expression, increase the sensitivity to oxidants.^Citation42 Promoting the production of TNF-α in synovial cells.^Citation42

Abbreviations: MMPs, matrix metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; iNOS, Inducible nitric oxide synthase; JSN, joint space narrow; IL-1, interleukin 1; RANKL, receptor activator of NF-κB ligand; OPG, osteoprotegerin; TNF, tumor necrosis factor; PGE_2, prostaglandin E2.

Figure 3 Fatty acids subtype.

Table 2 FAs Involved in the Pathophysiology of OA

FAs		Activities in OA
SFA	FA, PA, SA, OL, LA and AA	Increases in OA chondrocytes.^Citation13,Citation57
	PA and SA	Increases the levels of IL-1β, IL-6, MMP-13, and ADAMTS and reduced the expression of the IL-10.^Citation58–60 Cartilage degeneration and OA-like changes appear.^Citation61 Promotes chondrocytes autophagy.^Citation58
	MA, PA and SA	Enhances expression of the hypertrophic markers ADAMTS4, ADAMTS5 and MMP-13. Declines the expression of ACAN, COL2, and SOX9.^Citation61
	PA	Induces CHOP expression.^Citation62 Causes chondrocyte mitochondrial dysfunction and changes in glycolytic metabolism.^Citation64
	SA	Induces the expression of IL-1β, IL-6 and TNF-α.^Citation63
	SFA	Decreases joint space width.^Citation65
MUFAs	OL	Reduces the expression of COX-2 and MMP-1.^Citation66
	OL and PA	Stimulates the production of ROS and RNS such as , H2O2, NO, IL-6 and IL-8.^Citation67
N-6 PUFAs	N-6 PUFAs	Positively correlated with the severity of osteoarthritis and synovitis.^Citation69 Positively correlated with joint effusion, knee joint structural damage,^Citation13 osteophyte formation, synovitis.^Citation70
	LA	The production of PGE2, IL-6 and NO increased.^Citation14,Citation66,Citation71
	AA	Upregulate the expression of PEG, ADAMTS^Citation72 and COX-2.^Citation73
n-3 PUFAs	n-3 PUFAs	Inversely correlated with the levels of inflammatory mediators and pain tolerance.^Citation74 Reduces the expression levels of ADAMTS-4, ADAMTS-5, MMP3, MMP-13, TNF-α, IL1-β, IL-6, and COX-2.^Citation76–78 Reduces the expression of Col-X and Runx2.^Citation79
	EPA + DHA	Negatively associated with the serum d-ROMs.^Citation80

Abbreviations: MMPs, matrix metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; IL-1, interleukin 1; TNF: tumor necrosis factor; ACAN, aggrecan; COL2, collagen type II; SOX9, SRY-related HMG box-containing 9; CHOP, a protein marker for ER stress; COX-2, cyclooxygenase-2; ROS, reactive oxygen species; RNS, reactive nitrogen species; PGE_2, prostaglandin E2; Col-X, type X collagen; Runx2, Runt-related transcription factor 2.

Table 3 Adiponectin and FAs

	Author	Activities on FAs
Liver	Berg AH, Fruebis J and Yamauchi T	Adiponectin can reduce plasma free FA levels after meals.^Citation115 Increases plasma lipid clearance,^Citation116 and promotes FA oxidation in the liver and muscle.^Citation117
	Xu A and Yamauchi T	Increases the activity of carnitine palmityl transferase I and Reduces the activities of ACC and FAS.^Citation118,Citation119
	Schindler M	Adiponectin upregulates the mRNA levels of the FA transporters.^Citation121
	Xu A	Decreases the expression of FA genes.^Citation118
	Awazawa M	Adiponectin inhibits the expression of SREBP1c.^Citation123
	Pawlak M and Ishtiaq SM	Promotes triglyceride decomposition, intracellular FA transport, and mitochondrial FA β -oxidation.^Citation127,Citation128
	Yamauchi T	Blocking AdipoR1 and R2 leads to increased tissue triglyceride content, inflammation and oxidative stress.^Citation18
Muscle	Fruebis J and Yamauchi T	Adiponectin promotes the oxidation of skeletal muscle FAs.^Citation116,Citation117
	Yamauchi T	Adiponectin increases the phosphorylation levels of FA oxidation, AMPK and ACC.^Citation119
	Yoon MJ	Adiponectin promotes FA oxidation by activating AMPK, p38 MAPK and PPAR-α.^Citation125
	Yoon MJ, Shabani P and Nakamura MT	Adiponectin can increase PPAR-α target genes such as ACO, CPT1 and FABP3.^Citation125,Citation129,Citation130
	Lopez-Yus M	Adiponectin can upregulate the expression of genes involved in intracellular mitochondrial FA transport (LPL, CD36, CPT1B) and lipolysis (HSL, ATGL).^Citation20

Abbreviations: FA, fatty acids; ACC, acetyl CoA carboxylase; FAS, fatty acid synthase; SREBP1c, sterol regulatory element-binding protein 1c; AMPK, AMP-activated protein kinase; PPAR-α, peroxisome proliferator activated receptor alpha; ACO, acetyl CoA carboxylase oxidase; CPT1, carnitine palmitoyl transferase 1; FABP3, fatty acid binding protein 3; LPL, lipoprotein lipase; CPT1B, carnitine palmitoyl transferase 1B; HSL, hormone-sensitive lipase; ATGL, adipose triglyceride lipase.

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