Why is obesity associated with osteoarthritis? Insights from mouse models of obesity

Abstract

Obesity is one of the most significant, and potentially most preventable, risk factors for the development of osteoarthritis, and numerous studies have shown a strong association between body mass index and osteoarthritis of the hip, knee, foot and hand. However, the mechanism(s) by which obesity contributes to the onset and progression of osteoarthritis are not fully understood. The strong association between body mass index, altered limb alignment, and osteoarthritis of the knee--and the protective effects of weight loss--support the classic hypothesis that the effects of obesity on the joint are due to increased biomechanical loading and associated alterations in gait. However, obesity is now considered to be a low-grade systemic inflammatory disease, and recent studies suggest that metabolic factors associated with obesity alter systemic levels of pro-inflammatory cytokines that are also associated with osteoarthritis. Thus, the ultimate influence of obesity on osteoarthritis may involve a complex interaction of genetic, metabolic, and biomechanical factors. In this respect, mouse models of obesity can provide excellent systems in which to examine causal relationships among these factors. In recent years, there have been surprisingly few reports examining the effects of obesity on osteoarthritis using mouse models. In this paper, we review studies on mice and other animal models that provide both direct and indirect evidence on the role of obesity and altered diet in the development of osteoarthritis. We also examine the use of different body mass indices for characterizing "obesity" in mice by comparing these indices to typical adiposity levels observed in obese humans. Taken together, evidence from studies using mice suggest that a complex interaction of environmental and genetic factors associated with obesity contribute to the incidence and severity of osteoarthritis. The ability to control these factors, together with the development of methods to conduct more intricate measures of local biomechanical factors, make mouse models an excellent system to study obesity and osteoarthritis.

Figures

Figure 1

Research on obese mouse models of OA remains flat despite a dramatic increase in research on obesity and OA and mouse models of OA. The main graph shows the number of research articles retrieved by a Web of Science® (ISI Web of KnowledgeSM, v.4.0) search for the following sets of terms: osteoarthritis=“osteoarthritis OR osteoarthrosis OR ‘degenerative joint disease’”, obesity=“obesity OR fat OR lard”, and mice=“mouse OR mice OR murine”. The inset graph displays the number of research articles retrieved for the previously described osteoarthritis search terms compared to the osteoarthritis plus obesity search terms. These data show that research in OA has taken off dramatically since 1990. Databases=Science Citation Index Expanded (SCI-EXPANDED); Social Sciences Citation Index (SSCI); Arts & Humanities Citation Index (A&HCI). Search conducted in September 2007 by TMG.

Figure 2

Research utilizing obese mouse models is much less common in the field of OA compared to other chronic diseases. The graphs show the number of articles retrieved by the Web of Science® (ISI Web of KnowledgeSM, v.4.0) using the following search terms: “Alzheimer’s”, “Cancer”, “Cardiovascular disease OR CVD”, “Diabetes”, “Osteoporosis”, and “Osteoarthritis.” These disease search terms were also combined with the search terms for “obesity” and “mouse” described in the legend for Figure 1. Search databases and search dates were the same as reported in Figure 1. Note: the Y-axis is a log-scale.

Figure 3

Feeding male C57BL mice a high-fat diet increases the incidence of knee OA. The similar slopes of OA incidence versus age between the high-fat and normal chow fed mice indicate that a high-fat diet accelerates the onset, but not the progression, of OA. The age at which ~50% of the mice developed OA was shifted earlier by about 8 months in the high-fat fed mice. Data shown are from papers by the Silberbergs [–66]. OA was defined as a histological grade of either a 2 or 3 on a 0–3 scale. A grade of 2 indicates “advanced age changes with marked degeneration and liquefaction of cartilage cells and matrix and roughening of the surface of the joint” [65]. A grade of 3 indicates “proliferation and hypertrophy of the articular tissues, ulceration of the cartilage and eburnation of the bone at the floor of such ulcers, fibrosis and cyst formation in the bone marrow with involvement of ligaments and synovialis” [65].

Figure 4

Percent body fat versus four different body mass indices in female C57BL/6J and leptin impaired mice that were 44–54 wks old. A. Percent body fat (%Fb) versus body mass (Mb). B. Percent body fat versus body mass divided by femur length (Lf). C. Percent body fat versus body mass divided by femur length squared. D. Percent body fat versus body mass divided by femur length cubed. The horizontal dashed lines are the percent body fat estimated for a 50 year old Caucasian woman with a BMI of 30. The vertical dashed lines indicate the index value for this percent body fat. Solid lines are least squares regressions, and statistics were calculated using JMP (v. 6.0).