Timothy M. Griffin

The role of mechanical loading in the onset and progression of osteoarthritis.

Osteoarthritis is a progressive joint disease characterized by an imbalance of articular cartilage biosynthesis and degradation attributed to both inflammatory and biomechanical factors. Whereas moderate mechanical loading appears necessary for maintaining healthy cartilage, abnormal joint loading increases the risk of osteoarthritis. Obesity-induced osteoarthritis and the benefits of physical activity may be mediated by systemic levels of proinflammatory mediators as well as local biomechanical factors in the joint.

Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis

OBJECTIVE To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology. METHODS Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x-ray absorptiometry. RESULTS Adiposity was increased by approximately 10-fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine-induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin-8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis. CONCLUSION Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems.

Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice

IntroductionObesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet.MethodsFemale C57BL/6J mice were fed either a 10% kcal fat or a 45% kcal fat diet from 9 to 54 weeks of age. Longitudinal changes in musculoskeletal function and inflammation were compared with endpoint neurobehavioral and osteoarthritic disease states. Bivariate and multivariate analyses were conducted to determine independent associations with diet, percentage body fat, and knee osteoarthritis severity. We also examined healthy porcine cartilage explants treated with physiologic doses of leptin, alone or in combination with IL-1α and palmitic and oleic fatty acids, to determine the effects of leptin on cartilage extracellular matrix homeostasis.ResultsHigh susceptibility to dietary obesity was associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of osteoarthritis, including hyperalgesia and anxiety-like behaviors. Controlling for the effects of diet and percentage body fat with a multivariate model revealed a significant association between knee osteoarthritis severity and serum levels of leptin, adiponectin, and IL-1α. Physiologic doses of leptin, in the presence or absence of IL-1α and fatty acids, did not substantially alter extracellular matrix homeostasis in healthy cartilage explants.ConclusionsThese results indicate that diet-induced obesity increases the risk of symptomatic features of osteoarthritis through changes in musculoskeletal function and pain-related behaviors. Furthermore, the independent association of systemic adipokine levels with knee osteoarthritis severity supports a role for adipose-associated inflammation in the molecular pathogenesis of obesity-induced osteoarthritis. Physiologic levels of leptin do not alter extracellular matrix homeostasis in healthy cartilage, suggesting that leptin may be a secondary mediator of osteoarthritis pathogenesis.

Induction of osteoarthritis and metabolic inflammation by a very high‐fat diet in mice: Effects of short‐term exercise

OBJECTIVE To test the hypotheses that obesity due to a very high-fat diet induces knee osteoarthritis (OA), and that short-term wheel-running exercise protects against obesity-induced knee OA by reducing systemic inflammation and metabolic dysregulation. METHODS Male C57BL/6J mice were fed either a control diet (13.5% kcal from fat) or a very high-fat diet (60% kcal from fat) from age 12 weeks to age 24 weeks. From 20 to 24 weeks of age, half of the mice were housed with running wheels. The severity of knee OA was determined by assessing histopathologic features, and serum cytokines were measured using a multiplex bead immunoassay and enzyme-linked immunosorbent assays. Body composition was quantified by dual-energy x-ray absorptiometry, and insulin resistance was assessed by glucose tolerance testing. RESULTS Feeding mice with a very high-fat diet increased knee OA scores and levels of serum leptin, adiponectin, KC (mouse analog of interleukin-8 [IL-8]), monokine induced by interferon-γ (CXCL9), and IL-1 receptor antagonist to an extent in proportion to the gain in body fat (3-fold increase in percent body fat compared to controls). Wheel-running exercise reduced progression of OA in the medial femur of obese mice. In addition, exercise disrupted the clustering of cytokine expression and improved glucose tolerance, without reducing body fat or cytokine levels. CONCLUSION Obesity induced by a very high-fat diet in mice causes OA and systemic inflammation in proportion to body fat. Increased joint loading is not sufficient to explain the increased incidence of knee OA with obesity, as wheel running is protective rather than damaging. Exercise improves glucose tolerance and disrupts the coexpression of proinflammatory cytokines, suggesting that increased aerobic exercise may act independently of weight loss in promoting joint health.

Biomechanics of quadrupedal walking: how do four-legged animals achieve inverted pendulum-like movements?

SUMMARY Walking involves a cyclic exchange of gravitational potential energy and kinetic energy of the center of mass. Our goal was to understand how the limbs of walking quadrupeds coordinate the vertical movements of the fore and hind quarters to produce these inverted pendulum-like movements. We collected kinematic and ground reaction force data from dogs walking over a range of speeds. We found that the fore and hind quarters of dogs behaved like two independent bipeds, each vaulting up and over its respective support limb. The center of mass moved up and down twice per stride, like a single walking biped, and up to 70% of the mechanical energy required to lift and accelerate the center of mass was recovered via the inverted pendulum mechanism. To understand how the limbs produce these center of mass movements, we created a simple model of two independent pendulums representing the movements of the fore and hind quarters. The model predicted that the fore and hind quarter movements would completely offset each other if the fore limb lagged the hind limb by 25% of the stride time and body mass was distributed equally between the fore and hind quarters. The primary reason that dogs did not walk with a flat trajectory of the center of mass was that each fore limb lagged its ipsilateral hind limb by only 15% of the stride time and thereby produced time periods when the fore and hind quarters moved up or down simultaneously. The secondary reason was that the fore limbs supported 63% of body mass. Consistent with these experimental results, the two-pendulum model predicts that the center of mass will undergo two fluctuations per stride cycle if limb phase is less than 25% and/or if the total mass is not distributed evenly between the fore or hind quarters.

Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation

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.

Penguin waddling is not wasteful.

Penguins use twice as much metabolic energy as other terrestrial animals of a similar mass to walk a given distance, which was thought to be because side-to-side waddling requires excessive work. Here we show that waddling actually conserves mechanical energy and suggest instead that walking is expensive for penguins because their short legs require them to generate muscular force rapidly.

Biomechanics: Penguin waddling is not wasteful

Penguins use twice as much metabolic energy as other terrestrial animals of a similar mass to walk a given distance, which was thought to be because side-to-side waddling requires excessive work. Here we show that waddling actually conserves mechanical energy and suggest instead that walking is expensive for penguins because their short legs require them to generate muscular force rapidly.

The Energetic Cost of Climbing in Primates

Primates are exceptional among mammals for their climbing abilities and arboreal lifestyles. Here we show that small primates (less than 0.5 kilogram) consume the same amount of mass-specific energy (COTTOT) whether climbing or walking a given distance. COTTOT decreases with increasing body size for walking but does not change for climbing. This divergence of COTTOT is likely due to fundamental differences in the biomechanical determinants of the costs of climbing versus walking. These results have important implications for understanding the origins of primates, suggesting that small early primates may have been able to move into a novel arboreal niche without increasing metabolic costs.

Increased susceptibility of Trpv4 -deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet

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.