Osteoarthritis, inflammation and obesity : Current Opinion in Rheumatology

Secondary Logo

Journal Logo

OSTEOARTHRITIS: Edited by Steven B. Abramson

Osteoarthritis, inflammation and obesity

Berenbaum, Francisa,b; Eymard, Florenta; Houard, Xaviera

Author Information
Current Opinion in Rheumatology 25(1):p 114-118, January 2013. | DOI: 10.1097/BOR.0b013e32835a9414
  • Free



Obesity is a well known risk factor for the initiation and perpetuation of knee osteoarthritis [1]. This association is obvious because any overload on a weight-bearing joint would provoke tear and wear at the surface of cartilage. In recent years, this simplistic view of the pathophysiologic features of osteoarthritis has been greatly transformed, thanks to the discovery of a central role of inflammation in osteoarthritis [2]. Inflammatory mediators such as cytokines, lipid derivatives, reactive oxygen species or advanced-glycation end products can be produced and activate cells from joint tissues (mainly synovium, cartilage and subchondral bone), thus leading to the release of matrix metalloproteinases (MMPs) into the joint cavity and eventually cartilage degradation [3]. More recently, strong epidemiological data have shown that the risk of hand osteoarthritis is about two-fold in people with obesity as compared with normal-weight people [4]. Thus, the role of obesity in osteoarthritis is much more complex than previously thought because overload cannot completely explain the risk [5,6]. Systemic factors must be involved, which led to the hypothesis that adipokines, cytokines mainly produced by the adipose tissue, could play a role, at least in osteoarthritis of the hand but potentially other locations [7]. More recently, studies have demonstrated increased risk of osteoarthritis in obese patients with metabolic syndrome (MetS) compared with obese patients without MetS [8]. The discovery of a new phenotype linking osteoarthritis and low-grade inflammation related to obesity is a great excitement in the field because it opens a new area of research in the fields of pathophysiology, diagnosis, prognosis, treatments and prevention [9▪▪]. This review summarizes original published results related to osteoarthritis, obesity and inflammation.


MEDLINE was searched via PubMed for English-language original articles published between January 2011 and July 2012 with the search terms ‘osteoarthritis and inflammation’, ‘osteoarthritis and obesity’. Relevant references from selected publications and relevant articles published before January 2011 were identified.

Box 1:
no caption available


The increased mechanical load is an essential component in obesity-associated osteoarthritis of weight-bearing joints. Moreover, numerous studies focused on the importance of the mechanical stimulus in joint physiology. Interestingly, recent data link mechanical stress to inflammation in osteoarthritis by the presence of mechanoreceptors at the surface of chondrocytes [10], which may explain why in a recent study [11], compressive stress on cartilage explants induced the expression of IL-8/Kc. Synovial membrane and subchondral bone are also submitted to mechanical stress. Mechanical stretch enhances the expression of COX-2 and IL-1β and the amount of PGE2 synthesis in fibroblast-like synoviocytes [12]. It further increases the production of MMP-2 induced by inflammatory stimuli in fibroblasts [13]. Subchondral bone sclerosis is an important feature of osteoarthritis. Osteoblasts from the sclerotic areas of osteoarthritis subchondral bone show an altered phenotype with higher expression of inflammatory mediators as compared with osteoblasts from nonsclerotic areas [14]. Interestingly, Sanchez et al.[15▪▪] recently showed that this peculiar phenotype can be mimicked by mechanical loading of osteoblasts from nonsclerotic areas of osteoarthritis subchondral bone. Compression indeed increased expression of genes coding for IL-6, cyclooxygenase 2, RANKL, FGF-2, and IL-8, as well as MMP-3, MMP-9, and MMP-13 but reduced expression of osteoprotegerin [15▪▪].


Several studies have used high-fat fed animals to investigate the aggravating role of obesity in knee osteoarthritis independently of overweight status. In vitro, knee cartilage from rabbits fed a high-fat diet showed lower glycosaminoglycan content and aggrecanase-1 expression than cartilage from rabbits fed a normal-fat diet, independently of animal weight [16]. In a posttrauma osteoarthritis model (closed intra-articular fracture of one knee at week 16), mice fed a high-fat diet from 4 weeks of age showed higher osteoarthritis cartilage degeneration at 8 weeks postfracture than those fed a normal diet [17]. Interestingly, in another posttrauma mouse model (destabilization of the medial meniscus with transection of the medial collateral ligament), Mooney et al.[18] demonstrated that the accelerated osteoarthritis progression seen in animals on high-fat diet was not correlated with weight gain. Whereas there was a significant weight gain between a short and a long-term high-fat diet, histological osteoarthritis parameters were comparably accelerated relative to those of lean controls. Such a result was strengthened by Gierman's study [19] showing lack of correlation between osteoarthritis severity and body weight in an original experimental model of mice transgenic for human C-reactive protein (CRP) on a high-fat diet. Use of this model revealed a positive correlation between the induction of CRP evoked by the high-fat diet on day 3 and osteoarthritis grade at endpoint. Moreover, addition of treatment with anti-inflammatory properties (Rosuvastatin and Rosiglitazone) to high-fat diet induced an inhibition of osteoarthritis histologic lesions in male mice. These data suggest that obesity-induced low-grade inflammation is critical for inducting osteoarthritis. Indeed, a very high-fat diet in mice causes, in parallel, osteoarthritis and systemic inflammation such as increased levels of leptin, adiponectin, Kc/IL-8, CXCL9 and IL-1RA [20▪▪]. Surprisingly, when animals are placed on a wheel-running exercise plan, progression of knee osteoarthritis is reduced, without reducing body fat, which suggests that increased aerobic exercise may act independently of weight loss in promoting joint health.

Adipokines are cytokines mainly produced by adipose tissue and released into the blood [21]. One of their principal roles is to modulate the metabolism, satiety and their dysfunctions have been implicated in some forms of obesity [22].

The main adipokines with a demonstrated role in osteoarthritis, at least in vitro, are leptin, adiponectin, resistin, nicotinamide phosphoribosyltransferase (NAMPT)/visfatin, lipocalin-2 and SAA3 [23,24] (Fig. 1). Chemerin is a recently described chemokine but also an adipokine that regulates adipocyte development and metabolic function, as well as glucose metabolism in liver and skeletal muscle tissues [25,26]. Chemerin is detected in osteoarthritis synovial fluid with levels linked to disease severity [27]. In joints, chemerin can be expressed by chondrocytes [28] and fibroblast-like synoviocytes [29]. Moreover, chemerin significantly increases Toll-like receptor 4 mRNA and synthesis of CCL2 in osteoarthritis fibroblast-like synoviocytes [29], whereas it stimulates proinflammatory cytokines and matrix metalloproteinase release in chondrocytes [28].

The dual source of adipokines in knee osteoarthritis (OA). Obesity-derived adipose tissue is the main source of adipokines, released into the blood. These adipokines can act far from their source up to the joints. Another source could come locally from joint cells, including chondrocytes, bone cells, synovium and cells from the infrapatellar fat pad (IFP).

The effect of adipokines on the osteoarthritis process is in general controversial. For leptin, its role is mainly catabolic although the pioneer study [30] showed anabolic effect. Leptin, alone or in synergy with IL-1, induced collagen release from bovine cartilage explants and upregulated MMP-1 and MMP-13 expression in bovine chondrocytes [31]. However, NAMPT/visfatin is generally considered an inflammatory and pro-degradative adipokine [32,33]. A new study [34] showed that NAMPT/visfatin may inhibit matrix synthesis by articular chondrocytes and counteract IGF-1 function in chondrocytes by activating the erk/MAPK pathway independently of the IGF-1 receptor. Moreover, visfatin, but not leptin, increased MMP activity, nitric oxide (NO) production and proteoglycan release in porcine cartilage explants [35]. Interestingly, these results were reproduced in meniscus explants.

The discrepancy in the literature as to the effect of adipokines may be explained by differential expression of adipokines and their receptors depending on the differentiation state of chondrocytes. Monolayer culture downregulated adiponectin and leptin but upregulated their receptors [36▪]. Interestingly, neutralization of leptin induced a loss of chondrocyte phenotype, which suggests that adipokines themselves can modulate chondrocyte differentiation [36▪].


Being able to provide diagnostis or prognosis of osteoarthritis at an early stage is a great challenge for the future of therapy and prevention [37]. Adipokine concentration testing has been recently assessed for this aim in hand and knee osteoarthritis. In hand osteoarthritis, serum levels of adiponectin, but not leptin or resistin, were associated with disease progression in assessing baseline and 6-year radiographs of joint space narrowing in 164 patients [38]. However, Choe et al.[39] showed higher serum levels of resistin, but not adiponectin, in radiographic subchondral erosion than in non-radiographic hand osteoarthritis with no difference in joint space narrowing. An absence of a relationship between leptin concentration and hand osteoarthritis has been confirmed in a cross-sectional study [24] from a NHANES III sample.

In knee osteoarthritis, baseline serum level of leptin receptor but not leptin was associated with reduced levels of the cartilage formation biomarker PIIANP, increased cartilage defect score and increased cartilage volume loss assessed by MRI in 117 patients over 2 years [40]. In contrast, a baseline serum level of leptin was associated with bone formation biomarkers (osteocalcine and N-terminal propeptide of human procollagen type I) [40]. Plasma adiponectin levels were higher in patients undergoing total knee replacement surgery, when preoperative radiographs showed the most severe lesions, than in patients with less severe disease [41]. However, the literature is somewhat confusing in such a population: de Boer et al.[42] assessed adipokine concentration in a similargroup of 172 patients and did not find any association of adiponectin and resistin serum level with cartilage damage, only with synovial inflammation.


White adipose tissue is the most common, known source of adipokines, but joint tissues are also a source. For example, osteoarthritis cartilage can release adiponectin [41] and, as described above, chemerin can be produced by chondrocytes and fibroblast-like synoviocytes [28,29]. Another recent source of adipokines has been recently described as the infrapatellar fat pad (IFP). IFP, also known as Hoffa's fat pad, is a piece of fat situated within the knee, under the patella, behind patellar tendon and joint capsule and in front of femoral condyles and tibial plateau. It is described as intracapsular but extra synovial, the synovial membrane lining its posterior surface.

Because of its close relationship with joint tissues, this adipose tissue may play a role by releasing inflammatory mediators reaching the synovium and cartilage [43]. Indeed, as compared with subcutaneous adipose tissue (ScAT) from the same osteoarthritis patients, IFP secretes high amounts of IL-6, TNF-α, adipsin, adiponectin and visfatin [44▪]. This may result primarily from the increased stromal vascular fraction (SVF) found in IFP. Cell composition of SVF only shows an increased proportion of mast cells in IFP as compared with ScAT, whereas the proportion of T-cells decreases without any difference in their phenotype [44▪]. A microarray analysis comparing the expression of multiple genes in IFP from end-stage and early-stage osteoarthritis tissue showed increased expression of genes of adipogenesis in end-stage tissue, but results for inflammatory cytokines were too heterogeneous for definitive conclusions [45]. Interestingly, IFP cytokine production was increased by IL-1β and decreased by a PPARα agonist [46]. Conditioned media from cultured IFP from osteoarthritis patients modulated matrix component release and MMP expression in chondrocytes but controversial results were reported. Indeed, Hui et al.[31] showed that conditioned media from osteoarthritis IFP induced the production of collagenase (MMP-1, MMP-13) by human chondrocytes in culture, whereas Bastiaansen-Jenniskens et al.[47] showed a decrease in the catabolic profile of bovine cartilage after stimulation by osteoarthritis IFP conditioned media (decreased release of NO and glycosaminoglycans and decreased expression of MMP-1).


The link between osteoarthritis, inflammation and obesity is now well established. However, whether targeting inflammation-induced obesity in humans is an appropriate treatment remains unknown. Patients who lose a lot of weight show an association of pain and function improvements, with decreased low-grade inflammation [48▪]. However, the association does not imply causality. Preclinical studies targeting adipokines are expected to bring new hope for patients, especially those with MetS.



Conflicts of interest

The authors declare no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 154).


1. Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 2010; 18:24–33.
2. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol 2011; 23:471–478.
3. Kapoor M, Martel-Pelletier J, Lajeunesse D, et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 2011; 7:33–42.
4. Yusuf E, Nelissen RG, Ioan-Facsinay A, et al. Association between weight or body mass index and hand osteoarthritis: a systematic review. Ann Rheum Dis 2010; 69:761–765.
5. Aspden RM. Obesity punches above its weight in osteoarthritis. Nat Rev Rheumatol 2011; 7:65–68.
6. Pottie P, Presle N, Terlain B, et al. Obesity and osteoarthritis: more complex than predicted!. Ann Rheum Dis 2006; 65:1403–1405.
7. Gomez R, Conde J, Scotece M, et al. What's new in our understanding of the role of adipokines in rheumatic diseases? Nat Rev Rheumatol 2011; 7:528–536.
8. Sowers M, Karvonen-Gutierrez CA, Palmieri-Smith R, et al. Knee osteoarthritis in obese women with cardiometabolic clustering. Arthritis Rheum 2009; 61:1328–1336.
9▪▪. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet 2011; 377:2115–2126.

A comprehensive review of osteoarthritis, from pathophysiology to treatment. It points out the importance of deciphering the phenotypes of osteoarthritis.

10. Guilak F. Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol 2011; 25:815–823.
11. Chauffier K, Laiguillon MC, Bougault C, et al. Induction of the chemokine IL-8/Kc by the articular cartilage: possible influence on osteoarthritis. Joint Bone Spine 2012 (in press).
12. Takao M, Okinaga T, Ariyoshi W, et al. Role of heme oxygenase-1 in inflammatory response induced by mechanical stretch in synovial cells. Inflamm Res 2011; 60:861–867.
13. Wang Y, Tang Z, Xue R, et al. Combined effects of TNF-alpha, IL-1beta, and HIF-1alpha on MMP-2 production in ACL fibroblasts under mechanical stretch: an in vitro study. J Orthop Res 2011; 29:1008–1014.
14. Sanchez C, Deberg MA, Bellahcene A, et al. Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthritis Rheum 2008; 58:442–455.
15▪▪. Sanchez C, Pesesse L, Gabay O, et al. Regulation of subchondral bone osteoblast metabolism by cyclic compression. Arthritis Rheum 2012; 64:1193–1203.

The first study looking at the inflammatory role of compression on osteoblasts derived from subchondral osteoarthritis bone. This highlights the critical role of mechanical load in the remodelling of the subchondral bone and strongly suggests the involvement mechanical stressed subchondral bone cells in osteoarthritis via the release of inflammatory mediators.

16. Brunner AM, Henn CM, Drewniak EI, et al. High dietary fat and the development of osteoarthritis in a rabbit model. Osteoarthritis Cartilage 2012; 20:584–592.
17. Louer CR, Furman BD, Huebner JL, et al. Diet-induced obesity significantly increases the severity of posttraumatic arthritis in mice. Arthritis Rheum 2012; 64:3220–3230.
18. Mooney RA, Sampson ER, Lerea J, et al. High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury. Arthritis Res Ther 2011; 13:R198.
19. Gierman LM, van der Ham F, Koudijs A, et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum 2012; 64:1172–1181.
20▪▪. Griffin TM, Huebner JL, Kraus VB, et al. Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum 2012; 64:443–453.

This is an important study showing the beneficial effect of exercise on knee osteoarthritis structure.

21. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 2012; 18:363–374.
22. Conde J, Scotece M, Gomez R, et al. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis 2011; 2011:203901.
23. Gabay O, Berenbaum F. Adipokines in arthritis: new kids on the block. Curr Rheumatol Rev 2009; 5:226–232.
24. Massengale M, Reichmann WM, Losina E, et al. The relationship between hand osteoarthritis and serum leptin concentration in participants of the Third National Health and Nutrition Examination Survey. Arthritis Res Ther 2012; 14:R132.
25. Ernst MC, Sinal CJ. Chemerin: at the crossroads of inflammation and obesity. Trends Endocrinol Metab 2010; 21:660–667.
26. Iannone F, Lapadula G. Chemerin/ChemR23 pathway: a system beyond chemokines. Arthritis Res Ther 2011; 13:104.
27. Huang K, Du G, Li L, et al. Association of chemerin levels in synovial fluid with the severity of knee osteoarthritis. Biomarkers 2012; 17:16–20.
28. Berg V, Sveinbjornsson B, Bendiksen S, et al. Human articular chondrocytes express ChemR23 and chemerin; ChemR23 promotes inflammatory signalling upon binding the ligand chemerin(21-157). Arthritis Res Ther 2010; 12:R228.
29. Eisinger K, Bauer S, Schaffler A, et al. Chemerin induces CCL2 and TLR4 in synovial fibroblasts of patients with rheumatoid arthritis and osteoarthritis. Exp Mol Pathol 2012; 92:90–96.
30. Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003; 48:3118–3129.
31. Hui W, Litherland GJ, Elias MS, et al. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Ann Rheum Dis 2012; 71:455–462.
32. Gosset M, Berenbaum F, Salvat C, et al. Crucial role of visfatin/pre-B cell colony-enhancing factor in matrix degradation and prostaglandin E2 synthesis in chondrocytes: possible influence on osteoarthritis. Arthritis Rheum 2008; 58:1399–1409.
33. Jacques C, Holzenberger M, Mladenovic Z, et al. Proinflammatory actions of visfatin/nicotinamide phosphoribosyltransferase (Nampt) involve regulation of insulin signaling pathway and Nampt enzymatic activity. J Biol Chem 2012; 287:15100–15108.
34. Yammani RR, Loeser RF. Extracellular nicotinamide phosphoribosyltransferase (NAMPT/visfatin) inhibits insulin-like growth factor-1 signaling and proteoglycan synthesis in human articular chondrocytes. Arthritis Res Ther 2012; 14:R23.
35. McNulty AL, Miller MR, O’Connor SK, Guilak F. The effects of adipokines on cartilage and meniscus catabolism. Connect Tissue Res 2011; 52:523–533.
36▪. Francin PJ, Guillaume C, Humbert AC, et al. Association between the chondrocyte phenotype and the expression of adipokines and their receptors: evidence for a role of leptin but not adiponectin in the expression of cartilage-specific markers. J Cell Physiol 2011; 226:2790–2797.

This is an interesting study looking at the interactions between chondrocyte differentiation and adipokines.

37. Patra D, Sandell LJ. Recent advances in biomarkers in osteoarthritis. Curr Opin Rheumatol 2011; 23:465–470.
38. Yusuf E, Ioan-Facsinay A, Bijsterbosch J, et al. Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis. Ann Rheum Dis 2011; 70:1282–1284.
39. Choe JY, Bae J, Jung HY, et al. Serum resistin level is associated with radiographic changes in hand osteoarthritis: cross-sectional study. Joint Bone Spine 2012; 79:160–165.
40. Berry PA, Jones SW, Cicuttini FM, et al. Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis. Arthritis Rheum 2011; 63:700–707.
41. Koskinen A, Juslin S, Nieminen R, et al. Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways. Arthritis Res Ther 2011; 13:R184.
42. de Boer TN, van Spil WE, Huisman AM, et al. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis Cartilage 2012; 20:846–853.
43. Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Osteoarthritis Cartilage 2010; 18:876–882.
44▪. Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens YM, et al. The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype. Ann Rheum Dis 2011; 70:851–857.

This study compares the inflammatory phenotype of two adipose tissues, IFP and subcutaneous adipose tissue from the same osteoarthritis patients and supports a role of IFP in osteoarthritis.

45. Gandhi R, Takahashi M, Virtanen C, et al. Microarray analysis of the infrapatellar fat pad in knee osteoarthritis: relationship with joint inflammation. J Rheumatol 2011; 38:1966–1972.
46. Clockaerts S, Bastiaansen-Jenniskens YM, Feijt C, et al. Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1beta and inhibited by peroxisome proliferator activated receptor alpha agonist. Ann Rheum Dis 2012; 71:1012–1018.
47. Bastiaansen-Jenniskens YM, Clockaerts S, Feijt C, et al. Infrapatellar fat pad of patients with end-stage osteoarthritis inhibits catabolic mediators in cartilage. Ann Rheum Dis 2011; 71:288–294.
48▪. Richette P, Poitou C, Garnero P, et al. Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis. Ann Rheum Dis 2011; 70:139–144.

A large study showing a beneficial effect of dramatic weight loss on the concentration of systemic inflammatory cytokines in parallel with improved knee osteoarthritis symptoms.


adipokines; inflammation; metabolic syndrome; obesity; osteoarthritis

© 2013 Lippincott Williams & Wilkins, Inc.