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The infrapatellar fat pad (IFP) secretes inflammatory mediators in osteoarthritic knees, but the effect of aging on IFP inflammation is unknown. We tested the hypothesis that aging increases basal and interleukin-1β (IL-1β)-stimulated IFP inflammation in 10-, 20-, and 30-month-old male F344BN F1-hybrid rats. IFPs were cultured ex vivo for 24 hours and treated ±1ng/mL IL-1β to simulate injury-induced inflammation. IFP inflammation was evaluated by measuring secreted cytokine concentrations and by quantitative expression of immunoregulatory and pro- and anti-adipogenic genes. With age, osteoarthritis pathology increased and IFP mass decreased. Although adipocyte size did not change with age, variation in adipocyte size was positively associated with synovial thickness independent of age whereas associations with cartilage damage were age dependent. In the absence of IL-1β, aging was associated with a significant increase in IFP secretion of tumor necrosis factor α by 67% and IL-13 by 35% and a reduction in the expression of immunoregulatory M2 macrophage genes. However, following an IL-1β challenge, adipogenesis markers decreased and pro- and anti-inflammatory cytokines increased independent of age. The lone exception was leptin, which decreased >70% with age. Thus, although aging promotes osteoarthritis risk by increasing basal inflammation, our findings also revealed a potentially protective effect of aging by decreasing IL-1β-stimulated leptin production. [ABSTRACT FROM AUTHOR]

The chemokine receptor CXCR4 is expressed on adipocytes and macrophages in adipose tissue, but its role in this tissue remains unknown. We evaluated whether deficiency in either adipocyte or myeloid leukocyte CXCR4 affects body weight (BW) and adiposity in a mouse model of high-fat-diet (HFD)-induced obesity. We found that ablation of adipocyte, but not myeloid leukocyte, CXCR4 exacerbated obesity. The HFD-fed adipocyte-specific CXCR4-knockout (AdCXCR4ko) mice, compared to wild-type C57BL/6 control mice, had increased BW (average: 52.0 g vs. 35.5 g), adiposity (average: 49.3 vs. 21.0% of total BW), and inflammatory leukocyte content in white adipose tissue (WAT), despite comparable food intake. As previously reported, HFD feeding increased uncoupling protein 1 (UCP1) expression (fold increase: 3.5) in brown adipose tissue (BAT) of the C57BL/6 control mice. However, no HFD-induced increase in UCP1 expression was observed in the AdCXCR4ko mice, which were cold sensitive. Thus, our study suggests that adipocyte CXCR4 limits development of obesity by preventing excessive inflammatory cell recruitment into WAT and by supporting thermogenic activity of BAT. Since CXCR4 is conserved between mouse and human, the newfound role of CXCR4 in mouse adipose tissue may parallel the role of this chemokine receptor in human adipose tissue. [ABSTRACT FROM AUTHOR]

Objective To test the hypotheses that: (1) the transient receptor potential vanilloid 4 (TRPV4) ion channel is protective in the obesity model of osteoarthritis (OA), resulting in more severe obesity-induced OA in Trpv4 knockout (Trpv4-/-) mice; and (2) loss of TRPV4 alters mesodermal stem cell differentiation. Methods Male Trpv4-/- and wild-type (Trpv4+/+) mice were fed a control or high-fat diet (10% kcal and 60% kcal from fat, respectively) for 22 weeks, at which time spontaneous cage activity and severity of knee OA were evaluated. In addition, the adipogenic, osteogenic and chondrogenic potential of bone marrow-derived (MSC) and adipose-derived (ASC) stem cells from Trpv4-/- and Trpv4+/+ mice were compared. Results A high-fat diet significantly increased knee OA scores and reduced spontaneous cage activity in Trpv4-/- mice, while also increasing weight gain and adiposity. MSCs from Trpv4-/- mice had decreased adipogenic and osteogenic differentiation potential versus Trpv4+/+ MSCs. ASCs from Trpv4-/- mice had increased adipogenic and osteogenic and reduced chondrogenic differentiation potential versus Trpv4+/+ ASCs. Conclusions Pan-Trpv4-/- mice develop more severe OA with high-fat feeding, potentially due to more severe diet-induced obesity. The altered differentiation potential of Trpv4-/- progenitor cells may reflect the importance of this ion channel in the maintenance and turnover of mesodermally-derived tissues. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aging and female sex are the strongest risk factors for nontraumatic osteoarthritis (OA); whereas obesity is a modifiable risk factor accelerating OA. Prior studies indicate that the innate immune receptor toll‐like receptor 4 (TLR4) mediates obesity‐induced metabolic inflammation and cartilage catabolism via recognition of damage‐associated molecular patterns and is increased with aging in OA joints. TLR4 responses are limited by innate immunoreceptor adapter protein DNAX‐activating protein of 12kDA (DAP12). We undertook this study to test the hypothesis that TLR4 promotes, whereas DAP12 limits, obesity‐accelerated OA in aged female mice. We fed 13‐ to 15‐month‐old female WT, TLR4 KO, and DAP12 KO mice a high‐fat diet (HFD) or a control diet for 12 weeks, and changes in body composition, glucose tolerance, serum cytokines, and insulin levels were compared. Knee OA was evaluated by histopathology and μCT. Infrapatellar fat pads (IFPs) were analyzed by histomorphometry and F4/80+ crown‐like structures were quantified. IFPs and synovium gene expression were analyzed using a targeted insulin resistance and inflammation array. All HFD‐treated mice became obese, but only WT and TLR4 KO mice developed glucose intolerance. HFD induced cartilage catabolism in WT and DAP12 KO female mice, but not in TLR4 KO mice. Gene‐expression analysis of IFPs and synovium showed significant differences in insulin signaling, adipokines, and inflammation between genotypes and diets. Unlike young mice, systemic inflammation was not induced by HFD in the older female mice independent of genotype. Our findings support the conclusion that TLR4 promotes and DAP12 limits HFD‐induced cartilage catabolism in middle‐aged female mice. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The author reflects on the problems when the approach of quantifying the efficiency of locomotion applied to legged locomotion such as walking and running. He stresses that this approach is problematic because during these activities muscles are also active as brakes and isometric struts. In addition, the author emphasizes that it would be impossible to begin to understand the relative mechanical and metabolic roles of muscles designed for producing work.

Id1, a helix-loop-helix (HLH) protein that inhibits the function of basic HLH E protein transcription factors in lymphoid cells, has been implicated in diet- and age-induced obesity by unknown mechanisms. Here we show that Id1-deficient mice are resistant to a high fat diet- and age-induced obesity, as revealed by reduced weight gain and body fat, increased lipid oxidation, attenuated hepatosteatosis, lower levels of lipid droplets in brown adipose tissue, and smaller white adipocytes after a high fat diet feeding or in aged animals. Id1 deficiency improves glucose tolerance, lowers serum insulin levels, and reduces TNFα gene expression in white adipose tissue. Id1 deficiency also increased expression of Sirtuin 1 and peroxisome proliferator- activated receptor γ coactivator 1α, regulators of mitochondrial biogenesis and energy expenditure, in the white adipose tissue. This effect was accompanied by the elevation of several genes encoding proteins involved in oxidative phosphorylation and fatty acid oxidation, such as cytochrome c, medium-chain acyl-CoA dehydrogenase, and adipocyte protein 2. Moreover, the phenotype for Id1 deficiency was similar to that of mice expressing an E protein dominant-positive construct, ET2, suggesting that the balance between Id and E proteins plays a role in regulating lipid metabolism and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Although osteoarthritis (OA) was historically referred to as the non-inflammatory arthritis, it is now considered a condition involving persistent low-grade inflammation and activation of innate inflammatory pathways. Synovitis increases the risk of OA onset and progression and involves the recruitment of monocytes, lymphocytes, and other leukocytes. In particular, macrophages are important mediators of synovial inflammatory activity and pathologic cartilage and bone responses that are characteristic of OA. Advances in understanding how damage-associated molecular patterns (DAMPs) trigger monocyte/macrophage recruitment and activation in joints provide opportunities for disease-modifying therapies. However, the complexity and plasticity of macrophage phenotypes that exist in vivo have thus far prevented the successful development of macrophage-targeted treatments. Current studies show that synovial macrophages are derived from distinct cellular lineages, which correspond to unique functional roles for maintaining joint homeostasis. An improved understanding of the aetiology of synovial inflammation in specific OA-subtypes, such as with obesity or genetic risk, is a potential strategy for developing patient selection criteria for future precision therapies.

The infrapatellar fat pad (IFP) secretes inflammatory mediators in osteoarthritic knees, but the effect of aging on IFP inflammation is unknown. We tested the hypothesis that aging increases basal and interleukin-1β (IL-1β)-stimulated IFP inflammation in 10-, 20-, and 30-month-old male F344BN F1-hybrid rats. IFPs were cultured ex vivo for 24 hours and treated ±1ng/mL IL-1β to simulate injury-induced inflammation. IFP inflammation was evaluated by measuring secreted cytokine concentrations and by quantitative expression of immunoregulatory and pro- and anti-adipogenic genes. With age, osteoarthritis pathology increased and IFP mass decreased. Although adipocyte size did not change with age, variation in adipocyte size was positively associated with synovial thickness independent of age whereas associations with cartilage damage were age dependent. In the absence of IL-1β, aging was associated with a significant increase in IFP secretion of tumor necrosis factor α by 67% and IL-13 by 35% and a reduction in the expression of immunoregulatory M2 macrophage genes. However, following an IL-1β challenge, adipogenesis markers decreased and pro- and anti-inflammatory cytokines increased independent of age. The lone exception was leptin, which decreased >70% with age. Thus, although aging promotes osteoarthritis risk by increasing basal inflammation, our findings also revealed a potentially protective effect of aging by decreasing IL-1β-stimulated leptin production., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity is a significant risk factor for developing osteoarthritis in weight-bearing and non-weight-bearing joints. Although the pathogenesis of obesity-associated osteoarthritis is not completely understood, recent studies indicate that pro-inflammatory metabolic factors contribute to an increase in osteoarthritis risk. Adipose tissue, and in particular infrapatellar fat, is a local source of pro-inflammatory mediators that are increased with obesity and have been shown to increase cartilage degradation in cell and tissue culture models. One adipokine in particular, leptin, may be a critical mediator of obesity-associated osteoarthritis via synergistic actions with other inflammatory cytokines. Biomechanical factors may also increase the risk of osteoarthritis by activating cellular inflammation and promoting oxidative stress. However, some types of biomechanical stimulation, such as physiologic cyclic loading, inhibit inflammation and protect against cartilage degradation. A high percentage of obese individuals with knee osteoarthritis are sedentary, suggesting that a lack of physical activity may increase the susceptibility to inflammation. A more comprehensive approach to understanding how obesity alters daily biomechanical exposures within joint tissues may provide new insight into the protective and damaging effects of biomechanical factors on inflammation in osteoarthritis.