ARTHRITIS & RHEUMATISM Vol. 48, No. 11, November 2003, pp 3009–3012 DOI 10.1002/art.11315 © 2003, American College of Rheumatology
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Systemic and Local Regulation of Articular Cartilage Metabolism: Where Does Leptin Fit in the Puzzle? Richard F. Loeser that comprise the cartilage matrix are present for many years (up to a lifetime). For example, the half-life of aggrecan, the major proteoglycan in cartilage, is close to 25 years (5), while the half-life of type II collagen has been calculated to be ⬎100 years (6). Adult articular cartilage, however, is not a completely inert tissue. Chondrocytes respond to mechanical stimulation with increased synthetic activity, and labeling studies have shown that chondrocytes are metabolically active (7,8). There is evidence for active turnover of some components of the matrix, in particular the pericellular matrix. A number of growth factors and cytokines have been shown to regulate the metabolic activity of chondrocytes (Table 1). In nondiseased tissue, anabolic activity mediated by growth factors such as IGF-1, osteogenic protein 1 (bone morphogenetic protein 7 [BMP-7]), TGF, and perhaps fibroblast growth factors and cartilage-derived morphogenetic proteins appears to be predominant, with little or no activity of cytokines. Where might leptin fit in this mix? Leptin is classified as a cytokine-like hormone, which activates a receptor that signals through the janus-activated kinase/ signal transducer and activator of transcription (JAK/ STAT) pathway as well as through insulin receptor substrate 1 and extracellular signal–regulated kinase (9). Figenschau et al (4) provided evidence that functional leptin receptors are present on human articular chondrocytes and demonstrated phosphorylation of STAT-1 and STAT-5 in chondrocytes treated with recombinant human leptin. In their study, leptin concentrations of 10–100 ng/ml stimulated chondrocyte proliferation, while lower concentrations of 0.1–1 ng/ml stimulated proteoglycan and collagen synthesis. Whether these levels of leptin might be present in vivo is not known. The concentration of leptin in normal cartilage has not been determined. Dumond et al (3) detected leptin in SF from subjects with OA, at average concentrations of 8–13 ng/ml, but normal SF was not tested. Unlike the highly positive immunostaining for leptin seen in osteoarthritic cartilage, few cells staining
Leptin is a small, 16-kd protein produced and secreted primarily by adipocytes found in white adipose tissue. Initially discovered as a central regulator of appetite and energy expenditure, leptin may also be involved in the regulation of metabolic activity in the growth plate (1) and bone (2). In this issue of Arthritis & Rheumatism, Dumond et al (3) report that leptin can be detected in synovial fluid (SF) obtained from patients with osteoarthritis (OA), and that it can be produced locally by articular chondrocytes as well as by cells in osteophytic tissue. When injected into rat joints, leptin stimulated expression of 2 cartilage growth factors, insulin-like growth factor 1 (IGF-1) and transforming growth factor  (TGF), and this expression was accompanied by an increase in proteoglycan synthesis. In a previous study by Figenschau et al (4), functional leptin receptors were detected on human adult articular chondrocytes, and treatment of isolated cells in vitro was shown to stimulate cell proliferation as well as matrix synthesis. These findings raise a number of intriguing questions. Could leptin act centrally or locally to influence articular cartilage metabolism in the adult? Does leptin play a role in the altered metabolism observed in osteoarthritic cartilage? And, perhaps most importantly, could leptin provide a metabolic link between obesity and OA? The articular cartilage in adults is maintained by the activity of its resident cell, the chondrocyte. Under normal conditions, the metabolic activity of the chondrocyte appears quite low. Cell division is a rare event, and extensive matrix synthesis is not required for maintenance of the tissue, because the majority of molecules Supported by NIH grants AG-16697 and AR-49003. Richard F. Loeser, MD: Rush Medical College, Chicago, Illinois. Address correspondence and reprint requests to Richard F. Loeser, MD, Rheumatology, Rush–Presbyterian–St. Luke’s Medical Center, 1725 West Harrison, Suite 1017, Chicago, IL 60612. E-mail:
[email protected]. Submitted for publication May 16, 2003; accepted in revised form July 8, 2003. 3009
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Table 1.
Growth factors and cytokines that can regulate adult articular chondrocyte metabolism Protein
Insulin-like growth factor 1 Osteogenic protein 1 Transforming growth factor  Fibroblast growth factor 2 Fibroblast growth factor 18 Cartilage-derived morphogenetic protein Bone morphogenetic protein 2 Leptin Interleukin-1 Tumor necrosis factor ␣ Interleukin-4 Interleukin-6 Monocyte chemoattractant protein 1 RANTES
Action(s) Promotes matrix synthesis, cell survival; anticatabolic Potent stimulator of matrix production Promotes matrix production and osteophyte formation Mitogenic; stimulates matrix synthesis and matrix metalloproteinase production Stimulates matrix production Stimulates matrix production Stimulates matrix production Stimulates proliferation and matrix production Stimulates catabolic activity; antianabolic Promotes catabolic activity Inhibits antianabolic effects of interleukin-1 Promotes catabolic activity; antianabolic Promotes catabolic activity; may be antianabolic Promotes catabolic activity
positively for leptin were observed in normal cartilage. The latter finding does not exclude a role for leptin in normal cartilage homeostasis. As Dumond et al and others have shown, there was little or no immunostaining for other growth factors thought to be important in cartilage, including IGF-1 and TGF. A possible explanation for a lack of growth factor immunostaining in normal cartilage is that, under normal homeostatic conditions, there may be little or no new synthesis of growth factors required for tissue maintenance. The cells may be responding to growth factors bound to and stored in the matrix, where they are less accessible to detection by antibodies because of interference from matrix proteins. When growth factor expression is activated in osteoarthritic tissue, cellular staining then becomes evident. Similar to results from the in vitro studies, proteoglycan synthesis was stimulated by intraarticular injection of leptin into rat knee joints. In the study by Dumond et al (3), this effect was associated with increased immunostaining for TGF and IGF-1, as well as for leptin itself, in the chondrocytes from the injected joints. Therefore, the results demonstrating the presence of functional leptin receptors on human articular chondrocytes and leptin stimulation of chondrocyte synthetic and proliferative activity suggest that leptin could have growth factor activity in articular cartilage. It is not clear, however, whether this is a direct action of leptin or whether it is possibly indirect, through leptin stimulation of IGF-1 and TGF production. The question of whether or not leptin might have any cytokine-like activity in cartilage through stimulation of the JAK/ STAT pathway has not been investigated.
Unlike the low level of chondrocyte metabolic activity noted in normal articular cartilage, chondrocytes in osteoarthritic tissue are highly active. At different stages in the disease process, both anabolic and catabolic activity are increased (10). In addition to the increased production and activity of cytokines that stimulate cartilage catabolism, many growth factors (including IGF-1, TGF, and BMP-2) are up-regulated in what may be an attempt by the chondrocyte to activate repair pathways in response to matrix damage. As shown by Dumond et al (3), leptin (along with IGF-1 and TGF) appears to be up-regulated in osteoarthritic tissue. In the absence of knowledge of the function of leptin in cartilage, it is not clear whether increased production of leptin would be good or bad. If leptin is an anabolic factor, either directly or through its effect on IGF-1 and TGF production, then the increased production of leptin may be part of the attempted repair response. Conversely, another recent study demonstrated that costimulation of chondrocytes with leptin and interferon-␥ resulted in increased production of nitric oxide (NO) in association with increased expression of inducible NO synthase (11). Because NO is believed to play a role in the development of OA, this finding could suggest a detrimental effect of leptin. However, leptin by itself did not increase NO production, and it is not known whether leptin works in concert with other cytokines that may be more relevant to OA, such as interleukin-1. Although the development of OA has not been characterized in leptin-deficient mice, these animals have been studied in an antigen-induced model of inflammatory arthritis (12). Leptin receptors have been
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noted on CD4⫹ and CD8⫹ T cells, suggesting that leptin could play a role in regulating humoral and cellular immune responses. Compared with wild-type controls, the leptin-deficient (ob/ob) mice were observed to have less synovial inflammation, although there was no difference in the amount of cartilage destruction. Because in this model reduced synovial inflammation might be expected to be accompanied by less cartilage destruction, it is possible that the leptin deficiency had negative consequences for cartilage metabolism. Obesity is a potent risk factor for the development of knee OA (13) as well as hip OA (14) and perhaps hand OA (15). For knee and hip OA, it has been hypothesized that obesity would increase the risk of OA because of increased joint loading, but this hypothesis would be more difficult to apply to hand OA. Thus, the possibility exists that in addition to having biomechanical effects, obesity could have a systemic metabolic effect that influences the development of OA. Leptin, which was derived from the Greek word leptos (meaning thin), was discovered by cloning the mutated gene present in a very obese strain of mice (16). Mice lacking production of functional leptin or lacking functional leptin receptors have a phenotype resembling that of humans with morbid obesity. Leptin appears to act centrally by stimulating receptors present in the hypothalamus to regulate food intake and energy expenditure. Plasma levels of leptin correlate very closely with fat mass, and levels fall after weight loss (16). Most obese humans have been shown to have high plasma levels of leptin and are thought to have reduced leptin sensitivity, akin to the high levels of insulin noted in persons with type II diabetes. Only ⬃5–10% of obese subjects appear to have reduced levels of functional leptin. In the study by Dumond et al (3), levels of leptin in SF obtained from subjects with knee OA ranged from 0.6 to 28.5 ng/ml and correlated positively with the body mass index. Plasma levels of leptin were not measured, but in a recent study of older obese adults with knee OA, our group observed an average plasma level of 34 ng/ml (Miller GD, et al: unpublished observations), indicating that leptin may move passively from plasma to SF but is not more concentrated in SF. As a low molecular weight protein, leptin should be accessible to the chondrocytes by diffusion from the SF, in addition to the local production. The finding of leptin in osteophytic tissue and the ability of leptin to increase production of TGF, a known stimulator of osteophyte formation (17), suggest that leptin could promote osteophyte formation in OA.
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Obesity is associated with higher bone mass, which may contribute to the development of OA, but the role of leptin in the control of bone mass in the adult is not clear (2). Therefore, more information about leptin function in bone and cartilage is needed before any conclusions can be made about its possible connection to the development of OA. If obesity is associated with reduced leptin sensitivity in joint tissues, as has been observed in the hypothalamus, then leptin could be important in the development of OA if its growth factor activity helps maintain cartilage and/or bone integrity. Alternatively, if there is a normal response to leptin stimulation in the cartilage of obese subjects with elevated levels of leptin, then leptin could play a role in the development of OA if its activity is found to be detrimental, for example by stimulating osteophyte formation, NO production, or cytokine activity. Clearly, further studies on the function of leptin in cartilage may provide novel information about the metabolic regulation of cartilage metabolism and the pathogenesis of OA. REFERENCES 1. Maor G, Rochwerger M, Segev Y, Phillip M. Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. J Bone Miner Res 2002;17:1034–43. 2. Thomas T, Burguera B. Is leptin the link between fat and bone mass? J Bone Miner Res 2002;17:1563–9. 3. Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003;48:3118–29. 4. Figenschau Y, Knutsen G, Shahazeydi S, Johansen O, Sveinbjornsson B. Human articular chondrocytes express functional leptin receptors. Biochem Biophys Res Commun 2001;287:190–7. 5. Maroudas A, Bayliss MT, Uchitel-Kaushansky N, Schneiderman R, Gilav E. Aggrecan turnover in human articular cartilage: use of aspartic acid racemization as a marker of molecular age. Arch Biochem Biophys 1998;350:61–71. 6. Verzijl N, DeGroot J, Thorpe SR, Bank RA, Shaw JN, Lyons TJ, et al. Effect of collagen turnover on the accumulation of advanced glycation endproducts. J Biol Chem 2000;275:39027–31. 7. Sandy JD, Adams ME, Billingham ME, Plaas A, Muir H. In vivo and in vitro stimulation of chondrocyte biosynthetic activity in early experimental osteoarthritis. Arthritis Rheum 1984;27: 388–97. 8. Muir H. The chondrocyte, architect of cartilage: biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. Bioessays 1995;17:1039–48. 9. Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 1997;272:32686–95. 10. Goldring MB. The role of the chondrocyte in osteoarthritis. Arthritis Rheum 2000;43:1916–26. 11. Otero M, Gomez Reino JJ, Gualillo O. Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-␥ in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum 2003;48:404–9. 12. Busso N, So A, Chobaz-Peclat V, Morard C, Martinez-Soria E,
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15. Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM. Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee. Epidemiology 1999;10:161–6. 16. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–70. 17. Scharstuhl A, Glansbeek HL, van Beuningen HM, Vitters EL, van Der Kraan PM, van Den Berg WB. Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol 2002;169: 507–14.
