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Adipokines in osteoarthritis: friends or foes of cartilage homeostasis?
Available online at
www.sciencedirect.com Joint Bone Spine 75 (2008) 669e671
Research lectures
Adipokines in osteoarthritis: friends or foes of cartilage homeostasis? Pascale Pottie Gegout*, Pierre-Jean Francin, Didier Mainard, Nathalie Presle UMR 7561 CNRS Nancy Universite´, Physiopathologie et Pharmacologie articulaires, Faculte´ de Me´decine, avenue de la foret de Haye, 54505 Vandoeuvre les Nancy, France Accepted 26 July 2008 Available online 25 November 2008
Keywords: Adipokines; Osteoarthitis; Leptin; Obesity
Overweight and obesity are increasingly prevalent and constitute major risk factors for osteoarthritis. The deleterious role for obesity in osteoarthritis is well established, and a prevailing hypothesis is that increased loads on joint surfaces related to high body weight lead to cartilage wear. The knee is the joint where the link between osteoarthritis and obesity is the strongest. Nevertheless, obesity is also associated with finger osteoarthritis [1,2], suggesting that metabolic factors exerting systemic effects may contribute to the high prevalence of osteoarthritis among obese individuals. Leptin, a 16-Kda adipokine encoded by the Ob gene, is among the systemic factors implicated in obesity. Obese individuals produce abnormally large amounts of leptin. Leptin has been identified in osteoarthritic joints. Reduced appetite and increased energy expenditure are the best known effects of leptin. The effects of leptin are mediated by areas of the hypothalamus that contain leptin receptors. Of the six leptinereceptor isoforms identified to date, only the intracytoplasmic long isoform ObRb seems functional. Several leptin-signaling pathways have been identified. The main pathway may involve activation of the JAKeSTAT system (STATs 1, 3, and 5). Phosphorylated STATs can upregulate or downregulate specific genes [3]. Abnormalities in leptin secretion or signaling have been identified in ob/ob mice that carry a mutation in the leptin gene and in db/db mice and fa/fa rats characterized by a mutation in the ObRb receptor. These mutations are associated with severe obesity. They are rare in humans, however. Leptin is produced in
* Corresponding author. E-mail address: [email protected] (P. Pottie Gegout). 1297-319X/$ - see front matter Ó 2008 Published by Elsevier Masson SAS. doi:10.1016/j.jbspin.2008.07.008
proportion to fat mass. Both central and peripheral effects of leptin have been identified. To exert central effects, leptin must cross the bloodebrain barrier. Abnormal truncated leptin receptors may impair the ability of leptin to cross the bloodebrain barrier. This mechanism is among the hypotheses put forward to explain the leptin resistance seen in obese patients. We identified leptin in joint fluid specimens from patients with osteoarthritis, and we showed that leptin concentrations correlated closely with BMI. Table 1 reports the concentrations of leptin, adiponectin, resistin, and soluble leptin receptor (sOB-R) in joint fluid from patients with osteoarthritis. Only leptin concentrations differed significantly between males and females, in both joint fluid and serum specimens [4]. We investigated the production of leptin and adiponectin in cartilage, osteophytes, infrapatellar fat pad, synovial membrane, and meniscus taken from the knees of patients with osteoarthritis (Fig. 1). Leptin was identified in all these tissues (Fig. 1a), with the highest concentrations being found in the osteophytes, synovial membrane, and infrapatellar fat pad. Findings were similar for adiponectin, although production by osteophytes was lower (Fig. 1b). The leptin/adiponectin ratio was extremely high in osteophytes (Fig. 1c), indicating a high level of leptin production. These findings corroborate the results of immunohistological studies showing marked leptin expression in osteophytes [5]. All three adipokines had different levels in joint fluid and serum (Fig. 2, Table 2). Serum resistin and adiponectin levels were consistently higher than the levels in the matched joint fluid specimens. In females, leptin levels were higher in joint fluid than in serum, whereas no significant difference was
P.P. Gegout et al. / Joint Bone Spine 75 (2008) 669e671
670
Table 1 Concentrations of adipokines (leptin, adiponectin, and resistin) and of the soluble leptin receptor (sOB-R) in joint fluid specimens from patients with osteoarthritis
n Age (yrs) BMI (kg/m2) Leptin (ng/ml) Adiponectin (mg/ml) Resistin (ng/ml) sOB-R (ng/ml)
Females
Males
20 71.05 28.20 20.77 2.34 8.47 7.33
15 65.80 30.13 9.49 2.31 5.73 4.85
(7.41) (4.28) (3.61) (0.37) (1.75) (1.15)
(7.74) (5.09) (2.14)* (0.47) (1.58) (1.00)
BMI, body mass index. Males and females were compared using the Manne Whitney U-test. P values less than 0.05 were considered significant (*).
found in males. These data suggest local dysregulation of adipokine production in the osteoarthritic joint, so that circulating levels do not reflect joint levels. Furthermore, we obtained the first evidence that sOB-R is present in joint fluid from osteoarthritic joints. Joint fluid levels were lower than serum levels. Leptin was present in larger amounts in the joint compartment than in the systemic compartment. In contrast, its soluble receptor, which plays a key role in modulating the biological effects of leptin, was found in only small amounts in joint fluid. Therefore, concentrations of free leptin were considerably higher in the joint than in the bloodstream. This difference was more marked in women than in men. We found that intraarticular adiponectin concentrations in patients with osteoarthritis were considerably lower than leptin concentrations, compared to the corresponding serum concentrations, replicating the leptin/adiponectin imbalance seen in the serum of obese individuals. In addition, the free fraction of leptin, which is the biologically active fraction, was greater in joint fluid from female patients with osteoarthritis than from their male counterparts. This finding suggests a mechanism for the links between knee osteoarthritis and both female gender and obesity. Taken in concert, these data suggest that adipokines may play a pathophysiological role in the initiation or progression of osteoarthritis and may constitute one of the main links between obesityrelated metabolic disorders and joint cartilage destruction [6e8]. The identification in humans of adipose-derived mediators that may act upstream from initiating events or later on as perpetuators of joint degeneration can be expected to suggest new pharmacological strategies for slowing or preventing
Fig. 1. Concentrations of leptin (a) and adiponectin (b), and leptin/adiponectin ratio (c), in various tissues from joints with osteoarthritis. Explants of synovial membrane (S), infrapatellar fat pad (FP), meniscus (M), osteophytes (O), cartilage (C), and bone (B) were cultured in serum-free medium for 48 h.
cartilage destruction. Studies in humans with knee osteoarthritis have shed light on the mechanisms of action of leptin and on the contributions of other adipokines to the pathophysiology of this degenerative disease.
Table 2 Concentrations of adipokines (leptin, adiponectin, and resistin) and of the soluble leptin receptor (sOB-R) in matched specimens of joint fluid (JF) and serum from patients with osteoarthritis Females (n ¼ 14)
Leptin (ng/ml) Adiponectin (mg/ml) Resistin (ng/ml) sOB-R (ng/ml)
Males (n ¼ 11)
Serum
JF
14.39 11.04 10.09 17.38
17.57 1.59 5.51 7.81
(2.71) (1.62) (0.98) (3.79)
(2.75)# (0.25)# (1.45)# (1.11)#
Correlations between joint fluid and serum values. NS, non significant.
r
Serum
JF
0.789 (P ¼ 0.004) 0.559 (P ¼ 0.04) 0.077 (NS) 0.483 (NS)
8.56 8.68 14.01 14.47
9.73 2.23 3.67 4.34
(2.66)* (1.44) (1.69) (4.43)
r (2.87)* (0.60)# (0.59)# (1.27)#
0.936 0.924 0.816 0.750
(P ¼ 0.003) (P ¼ 0.005) (P ¼ 0.009) (P ¼ 0.03)
P.P. Gegout et al. / Joint Bone Spine 75 (2008) 669e671
671
References
Fig. 2. Concentrations of free leptin in joint fluid and serum specimens from patients with osteoarthritis. The molar ratio of leptin over its soluble receptor sOB-R is taken as the level of free leptin. The Wilcoxon test was used to evaluate differences in free leptin concentrations between matched serum and joint fluid specimens (#). The ManneWhitney U-test was chosen to look for significant differences between males and females regarding concentrations in joint fluid and serum (*). P values less than 0.05 were considered significant.
[1] Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthritis of the hand and knee in women: a twin study. J Rheumatol 1996;23:1221e6. [2] Reijman M, Pols HA, Bergink AP, et al. Body mass index associated with onset and progression of osteoarthritis of the knee but not of the hip: the Rotterdam Study. Ann Rheum Dis 2007;66:158e62. [3] Presle N, Pottie P, Mainard D, et al. Adipokines in osteoarthritis. In: Sharma L, Berenbaum F, editors. Osteoarthritis: a companion to rheumatology. Philadelphia: Mosby; 2007. p. 85e103. [4] Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003;48:3118e29. [5] Pottie P, Presle N, Terlain B, et al. Obesity and osteoarthritis: more complex than predicted!. Ann Rheum Dis 2006;65:1403e5. [6] Simopoulou T, Malizos KN, Iliopoulos D, et al. Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage 2007;15: 872e83. [7] Presle N, Pottie P, Dumond H, et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage 2006;14:690e5. [8] Chen TH, Chen L, Hsieh MS, et al. Evidence for a protective role for adiponectin in osteoarthritis. Biochim Biophys Acta 2006;1762:711e8.
www.sciencedirect.com Joint Bone Spine 75 (2008) 669e671
Research lectures
Adipokines in osteoarthritis: friends or foes of cartilage homeostasis? Pascale Pottie Gegout*, Pierre-Jean Francin, Didier Mainard, Nathalie Presle UMR 7561 CNRS Nancy Universite´, Physiopathologie et Pharmacologie articulaires, Faculte´ de Me´decine, avenue de la foret de Haye, 54505 Vandoeuvre les Nancy, France Accepted 26 July 2008 Available online 25 November 2008
Keywords: Adipokines; Osteoarthitis; Leptin; Obesity
Overweight and obesity are increasingly prevalent and constitute major risk factors for osteoarthritis. The deleterious role for obesity in osteoarthritis is well established, and a prevailing hypothesis is that increased loads on joint surfaces related to high body weight lead to cartilage wear. The knee is the joint where the link between osteoarthritis and obesity is the strongest. Nevertheless, obesity is also associated with finger osteoarthritis [1,2], suggesting that metabolic factors exerting systemic effects may contribute to the high prevalence of osteoarthritis among obese individuals. Leptin, a 16-Kda adipokine encoded by the Ob gene, is among the systemic factors implicated in obesity. Obese individuals produce abnormally large amounts of leptin. Leptin has been identified in osteoarthritic joints. Reduced appetite and increased energy expenditure are the best known effects of leptin. The effects of leptin are mediated by areas of the hypothalamus that contain leptin receptors. Of the six leptinereceptor isoforms identified to date, only the intracytoplasmic long isoform ObRb seems functional. Several leptin-signaling pathways have been identified. The main pathway may involve activation of the JAKeSTAT system (STATs 1, 3, and 5). Phosphorylated STATs can upregulate or downregulate specific genes [3]. Abnormalities in leptin secretion or signaling have been identified in ob/ob mice that carry a mutation in the leptin gene and in db/db mice and fa/fa rats characterized by a mutation in the ObRb receptor. These mutations are associated with severe obesity. They are rare in humans, however. Leptin is produced in
* Corresponding author. E-mail address: [email protected] (P. Pottie Gegout). 1297-319X/$ - see front matter Ó 2008 Published by Elsevier Masson SAS. doi:10.1016/j.jbspin.2008.07.008
proportion to fat mass. Both central and peripheral effects of leptin have been identified. To exert central effects, leptin must cross the bloodebrain barrier. Abnormal truncated leptin receptors may impair the ability of leptin to cross the bloodebrain barrier. This mechanism is among the hypotheses put forward to explain the leptin resistance seen in obese patients. We identified leptin in joint fluid specimens from patients with osteoarthritis, and we showed that leptin concentrations correlated closely with BMI. Table 1 reports the concentrations of leptin, adiponectin, resistin, and soluble leptin receptor (sOB-R) in joint fluid from patients with osteoarthritis. Only leptin concentrations differed significantly between males and females, in both joint fluid and serum specimens [4]. We investigated the production of leptin and adiponectin in cartilage, osteophytes, infrapatellar fat pad, synovial membrane, and meniscus taken from the knees of patients with osteoarthritis (Fig. 1). Leptin was identified in all these tissues (Fig. 1a), with the highest concentrations being found in the osteophytes, synovial membrane, and infrapatellar fat pad. Findings were similar for adiponectin, although production by osteophytes was lower (Fig. 1b). The leptin/adiponectin ratio was extremely high in osteophytes (Fig. 1c), indicating a high level of leptin production. These findings corroborate the results of immunohistological studies showing marked leptin expression in osteophytes [5]. All three adipokines had different levels in joint fluid and serum (Fig. 2, Table 2). Serum resistin and adiponectin levels were consistently higher than the levels in the matched joint fluid specimens. In females, leptin levels were higher in joint fluid than in serum, whereas no significant difference was
P.P. Gegout et al. / Joint Bone Spine 75 (2008) 669e671
670
Table 1 Concentrations of adipokines (leptin, adiponectin, and resistin) and of the soluble leptin receptor (sOB-R) in joint fluid specimens from patients with osteoarthritis
n Age (yrs) BMI (kg/m2) Leptin (ng/ml) Adiponectin (mg/ml) Resistin (ng/ml) sOB-R (ng/ml)
Females
Males
20 71.05 28.20 20.77 2.34 8.47 7.33
15 65.80 30.13 9.49 2.31 5.73 4.85
(7.41) (4.28) (3.61) (0.37) (1.75) (1.15)
(7.74) (5.09) (2.14)* (0.47) (1.58) (1.00)
BMI, body mass index. Males and females were compared using the Manne Whitney U-test. P values less than 0.05 were considered significant (*).
found in males. These data suggest local dysregulation of adipokine production in the osteoarthritic joint, so that circulating levels do not reflect joint levels. Furthermore, we obtained the first evidence that sOB-R is present in joint fluid from osteoarthritic joints. Joint fluid levels were lower than serum levels. Leptin was present in larger amounts in the joint compartment than in the systemic compartment. In contrast, its soluble receptor, which plays a key role in modulating the biological effects of leptin, was found in only small amounts in joint fluid. Therefore, concentrations of free leptin were considerably higher in the joint than in the bloodstream. This difference was more marked in women than in men. We found that intraarticular adiponectin concentrations in patients with osteoarthritis were considerably lower than leptin concentrations, compared to the corresponding serum concentrations, replicating the leptin/adiponectin imbalance seen in the serum of obese individuals. In addition, the free fraction of leptin, which is the biologically active fraction, was greater in joint fluid from female patients with osteoarthritis than from their male counterparts. This finding suggests a mechanism for the links between knee osteoarthritis and both female gender and obesity. Taken in concert, these data suggest that adipokines may play a pathophysiological role in the initiation or progression of osteoarthritis and may constitute one of the main links between obesityrelated metabolic disorders and joint cartilage destruction [6e8]. The identification in humans of adipose-derived mediators that may act upstream from initiating events or later on as perpetuators of joint degeneration can be expected to suggest new pharmacological strategies for slowing or preventing
Fig. 1. Concentrations of leptin (a) and adiponectin (b), and leptin/adiponectin ratio (c), in various tissues from joints with osteoarthritis. Explants of synovial membrane (S), infrapatellar fat pad (FP), meniscus (M), osteophytes (O), cartilage (C), and bone (B) were cultured in serum-free medium for 48 h.
cartilage destruction. Studies in humans with knee osteoarthritis have shed light on the mechanisms of action of leptin and on the contributions of other adipokines to the pathophysiology of this degenerative disease.
Table 2 Concentrations of adipokines (leptin, adiponectin, and resistin) and of the soluble leptin receptor (sOB-R) in matched specimens of joint fluid (JF) and serum from patients with osteoarthritis Females (n ¼ 14)
Leptin (ng/ml) Adiponectin (mg/ml) Resistin (ng/ml) sOB-R (ng/ml)
Males (n ¼ 11)
Serum
JF
14.39 11.04 10.09 17.38
17.57 1.59 5.51 7.81
(2.71) (1.62) (0.98) (3.79)
(2.75)# (0.25)# (1.45)# (1.11)#
Correlations between joint fluid and serum values. NS, non significant.
r
Serum
JF
0.789 (P ¼ 0.004) 0.559 (P ¼ 0.04) 0.077 (NS) 0.483 (NS)
8.56 8.68 14.01 14.47
9.73 2.23 3.67 4.34
(2.66)* (1.44) (1.69) (4.43)
r (2.87)* (0.60)# (0.59)# (1.27)#
0.936 0.924 0.816 0.750
(P ¼ 0.003) (P ¼ 0.005) (P ¼ 0.009) (P ¼ 0.03)
P.P. Gegout et al. / Joint Bone Spine 75 (2008) 669e671
671
References
Fig. 2. Concentrations of free leptin in joint fluid and serum specimens from patients with osteoarthritis. The molar ratio of leptin over its soluble receptor sOB-R is taken as the level of free leptin. The Wilcoxon test was used to evaluate differences in free leptin concentrations between matched serum and joint fluid specimens (#). The ManneWhitney U-test was chosen to look for significant differences between males and females regarding concentrations in joint fluid and serum (*). P values less than 0.05 were considered significant.
[1] Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthritis of the hand and knee in women: a twin study. J Rheumatol 1996;23:1221e6. [2] Reijman M, Pols HA, Bergink AP, et al. Body mass index associated with onset and progression of osteoarthritis of the knee but not of the hip: the Rotterdam Study. Ann Rheum Dis 2007;66:158e62. [3] Presle N, Pottie P, Mainard D, et al. Adipokines in osteoarthritis. In: Sharma L, Berenbaum F, editors. Osteoarthritis: a companion to rheumatology. Philadelphia: Mosby; 2007. p. 85e103. [4] Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003;48:3118e29. [5] Pottie P, Presle N, Terlain B, et al. Obesity and osteoarthritis: more complex than predicted!. Ann Rheum Dis 2006;65:1403e5. [6] Simopoulou T, Malizos KN, Iliopoulos D, et al. Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage 2007;15: 872e83. [7] Presle N, Pottie P, Dumond H, et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage 2006;14:690e5. [8] Chen TH, Chen L, Hsieh MS, et al. Evidence for a protective role for adiponectin in osteoarthritis. Biochim Biophys Acta 2006;1762:711e8.