Increased adiponectin levels are associated with higher radiographic scores in the knee joint, but not in the hand joint

Several studies have evaluated the association between serum adiponectin levels and knee and hand osteoarthritis (OA); mixed results have been reported. We investigated the relationship between OA and serum adiponectin levels according to the radiographic features of knee and hand OA. A total of 2402 subjects was recruited from the Dong-gu Study. Baseline characteristics were collected via a questionnaire, and X-rays of knee and hand joints were scored using a semi-quantitative grading system. The relationship between serum adiponectin levels and radiographic severity was evaluated by linear and logistic regression analysis. Subjects in the higher serum adiponectin levels tertiles were older and had a lower body mass index (BMI) than those in the lower tertiles. Regarding knee joint scores, serum adiponectin levels was positively associated with the total (P < 0.001), osteophyte (P = 0.003), and joint space narrowing (JSN) scores (P < 0.001) after adjustment for age, sex, BMI, smoking, alcohol consumption, education, and physical activity. In terms of hand joint scores, no association was found between serum adiponectin levels and the total, osteophyte, JSN, subchondral cyst, sclerosis, erosion, or malalignment score after the above-mentioned adjustments. Similarly, subjects with serum adiponectin levels above the median had higher total radiographic scores in the knee joints, but not in the hand joints, after adjustment. An increased serum adiponectin levels was associated with a higher radiographic score in the knee joint, but not in the hand joint, suggesting the involvement of different pathophysiologic mechanisms in the development of OA between those joints.


Scientific Reports
| (2021) 11:1842 | https://doi.org/10.1038/s41598-021-81513-z www.nature.com/scientificreports/ roles in the initiation and progression of OA, and exerts pro-or anti-inflammatory effects depending on the tissue and cell types 5 . Although the circulating adiponectin level was reported be elevated in patients with OA compared to healthy controls in two recent meta-analyses 6,7 , the role of adiponectin in the pathogenesis of OA is controversial. Several studies have evaluated the association between plasma and synovial fluid adiponectin levels and the severity of OA in the knee and hand based on radiographic findings. Studies examining the correlation of the adiponectin level with the severity of knee joint OA based on the Kellgren-Lawrence grade have yielded inconsistent results (positive associations in two studies 8,9 , negative associations in two others 10,11 , and no association in three studies [12][13][14] . Similarly, two studies found an inverse association between the adiponectin level and radiographic hand OA 15,16 , but two others found no such association 17,18 . These varying results may be attributable to the small numbers of subjects and use of a low-accuracy radiographic grading method, such as the Kellgren-Lawrence grade. To overcome these limitations of previous studies, we took advantage of the availability of a large, population-based cohort to evaluate the relationship between the adiponectin level and radiographic severity of knee and hand OA using a novel, semi-quantitative grading system 19 . The aim of this study was to investigate the association of serum adiponectin levels with the radiographic features of knee and hand OA.

Methods
Population and study design. The  Covariates. We collected information on the subjects' baseline characteristics-including smoking, alcohol drinking, education and physical activity-by means of questionnaires. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Smoking status was categorized as never smoker (< 100 lifetime cigarettes and not smoking currently), ex-smoker (> 100 lifetime cigarettes and not smoking currently), or current smoker (> 100 lifetime cigarettes and smoking now). Alcohol consumption in the past 12 months was used as the criterion to distinguish current alcohol drinkers from non-drinkers. Educational attainment was classified as high school or above high school. Physical activity was classified as regular or irregular according to the frequency of engagement in physical training/leisure activities during a typical week.

Statistical analysis.
The general characteristics of the subjects are presented as means and standard deviation (SD) for continuous variables and as number (%) for categorical variables. Continuous variables were compared by one-way analysis of variance, and categorical variables by chi-squared test. Linear regression analysis was performed to assess the relationship between serum adiponectin levels and radiographic scores of the knee and hand joints after adjusting for age, sex, BMI, smoking, alcohol consumption, education, and physical activ-

Results
Baseline characteristics stratified by serum adiponectin levels. The baseline characteristics and radiographic features of the knee and hand joints according to serum adiponectin levels tertile are presented in Table 1. Among the 2402 subjects, the mean age was 64 years (SD, 8.2 years) and the mean BMI was 24.4 kg/m 2 (SD, 2.9 kg/m 2 ); 1042 subjects (43.4%) were male. Subjects in the higher serum adiponectin tertiles were older (mean age, 64.9 years) and had a lower BMI (mean, 23.8 kg/m 2 ) than those in the lower tertiles. In addition, the proportions of subjects who were male (24.3%), current smokers (8.1%), current alcohol drinkers (40.1%), had an educational level of above high school (26.0%), and partook in regular physical activity (13.9%) were lower in subjects in the higher serum adiponectin tertiles than in those in the lower tertiles.
Regarding the radiographic scores of the knee joints, subjects in the higher serum adiponectin tertiles had a significantly higher total score (P < 0.001), osteophyte score (P < 0.001), JSN score (P < 0.001) and sclerosis score (P = 0.010) than those in the lower tertiles. However, the tibial attrition score did not differ among serum adiponectin tertiles (P = 0.136). Regarding the hand joint scores, subjects in the higher serum adiponectin tertiles had a significantly higher total score, JSN score, and subchondral cyst score than those in the lower tertiles (all P < 0.001). However, the osteophyte, sclerosis, erosion, and malalignment scores did not differ among serum adiponectin tertiles.
Association between the tertiles of serum adiponectin levels and knee and hand OA. Table 2 shows the relationships between serum adiponectin levels and total and individual radiographic scores of the knee and hand joints. In multiple linear regression analyses adjusted for age, sex, BMI, smoking, alcohol consumption, education level, and physical activity, serum adiponectin levels were positively associated with the total (P < 0.001), osteophyte (P = 0.003), and JSN (P < 0.001) scores in knee joints. However, in multiple linear regression analyses, there was no significant difference in the score for any hand joint parameter among the serum adiponectin tertiles after adjusting for age, sex, BMI, smoking, alcohol consumption, education level, and physical activity. www.nature.com/scientificreports/ Associations of serum adiponectin levels above and below the median with knee and hand OA. Table 3 shows the relationships of serum adiponectin levels above and below the median with the total radiographic scores of the knee and hand joints based on the median radiographic scores. In multivariate logistic regression analysis adjusted for age, sex, BMI, smoking, alcohol consumption, education level, and physical activity, subjects with serum adiponectin levels above the median had higher total radiographic scores in the knee joints (P = 0.049), but not in the hand joints. Regarding the individual radiographic scores (Supplementary Table S1), adiponectin levels above the median were associated with the osteophyte (P = 0.018) and JSN (P = 0.022) scores in knee joints, and erosion (P = 0.026) and malalignment (P = 0.046) scores in hand joints, after adjustment.

Discussion
In this cross-sectional study, serum adiponectin levels were positively associated with the radiographic severity of OA in the knee joints, but not in the hand joints. Among the knee OA parameters, the adiponectin level was associated with the osteophyte, JSN, and total scores. To our knowledge, this is the largest study to investigate the relationship between serum adiponectin levels and radiographic severity of OA using a semi-quantitative grading system. In this study, serum adiponectin levels were positively associated with the radiographic severity of OA of the knee joints, and particularly with the osteophyte and JSN scores. Prior studies of the association between the blood adiponectin level and radiographic severity of knee OA produced conflicting results. In a Finish study of 35 male patients with knee OA, the plasma adiponectin level was significantly higher in patients with radiographically severe OA than in those with mild OA 8 . In a Turkish study of 60 patients with knee OA, serum adiponectin levels were positively correlated with the Kellgren-Lawrence grade 9 . However, in a Thai study 10 and the Anhui OA study 11 , the circulating adiponectin level was negatively associated with disease severity, as measured by the Kellgren-Lawrence grade, suggesting a protective role for adiponectin against knee OA. Interestingly, no association was found between the blood adiponectin level and severity of knee OA in the Framingham Offspring cohort study 14 , nor in Greek 12 , and Dutch studies 13 . These conflicting results may be attributable to small numbers of OA patients, use of radiographic grading systems with low accuracy (such as the Kellgren-Lawrence grade), inadequate control for confounding variables in the statistical analysis, and the use of different methods to measure isoforms of adiponectin. In comparison with previous studies, we recruited a large number (2402) of subjects from the Dong-gu study, obtained detailed information on the radiographic features of OA using a semi-quantitative grading system, and adjusted for relevant confounding variables in the statistical analysis. Although our finding of a positive association of adiponectin with the radiographic severity of knee OA requires confirmation in a prospective study, it provides insight into the role of adiponectin in the initiation and progression of knee OA.
Serum adiponectin levels were not associated with the radiographic severity of OA of the hand joints. A longitudinal study of 164 patients with hand OA reported that a higher level of adiponectin was associated with a lower risk of radiographic progression 15 . Another longitudinal study of 224 patients with hand OA investigated the associations between total and high-molecular-weight (HMW) adiponectin levels with the radiographic severity of hand OA 16 . The total adiponectin level was inversely associated with radiographic progression, but the HMW adiponectin level was not associated with progression. In contrast, in two cross-sectional studies 17,18 , serum adiponectin levels were not associated with the radiographic severity of hand OA. Our findings are in accordance with the results of cross-sectional studies, but not with those of longitudinal studies; this suggests that the differences are attributable to period and cohort effects 23 . Further studies are needed to determine if there is a causal relationship between serum adiponectin levels and radiographic severity of OA of the hand.
In this study, serum adiponectin levels were associated with the radiographic severity of OA in the knee joints, but not in the hand joints. Two hypotheses can be formulated that may explain the difference. First, obesity has a greater effect on knee OA than on hand OA 24 . In our previous study of the Dong-gu cohort, body weight was significantly associated with the radiographic severity of knee, but not hand, OA 25 . Because adiponectin originates predominantly from adipose tissue, it can be postulated that weight-bearing knee joints are more closely associated with the adiponectin level than are non-weight-bearing hand joints. Second, the expression level of adiponectin receptors differs among the joints. Adiponectin acts via two receptors: AdipoR1, predominantly found in skeletal muscle; and AdipoR2, mainly present in the liver 26 . The skeletal muscle mass of knee joints is greater than that of hand joints, so the role of adiponectin may differ among joints.
The strengths of our study included its inclusion of a large population-based cohort, detailed radiographic grading, and simultaneous evaluation of knee and hand joints. However, the study also had several limitations. First, the design was cross-sectional rather than longitudinal; therefore, the results are correlational and causality cannot be determined. Second, although many potential confounding factors were adjusted for, residual confounding effects of unmeasured variables may have introduced bias. Third, the adiponectin level was measured systemically, so may not reflect the intraarticular adiponectin level.

Conclusion
In this population-based study, serum adiponectin levels were positively associated with the radiographic severity of OA in knee joints, but not in hand joints. Our findings indicate that different pathophysiologic mechanisms underlie the initiation and progression of OA of the knee and hand joints.

Data availability
Full original protocol and dataset can be accessed upon request for academic researchers by contacting Professor Shin-Seok Lee (shinseok@chonnam.ac.kr). License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.