Biology and pathology of rho GTPase, PI-3 kinase-Akt, and MAP kinase signaling pathways in chondrocytes

Chondrocytes provide the framework for the developing skeleton and regulate long-bone growth through the activity of the growth plate. Chondrocytes in the articular cartilage, found at the ends of bones in diarthroidial joints, are responsible for maintenance of the tissue through synthesis and degradation of the extracellular matrix. The processes of growth, differentiation, cell death and matrix remodeling are regulated by a network of cell signaling pathways in response to a variety of extracellular stimuli. These stimuli consist of soluble ligands, including growth factors and cytokines, extracellular matrix proteins, and mechanical factors that act in concert to regulate chondrocyte function through a variety of canonical and non-canonical signaling pathways. Key chondrocyte signaling pathways include, but are not limited to, the p38, JNK and ERK MAP kinases, the PI-3 kinase-Akt pathway, the Jak-STAT pathway, Rho GTPases and Wnt-β-catenin and Smad pathways. Modulation of the activity of any of these pathways has been associated with various pathological states in cartilage. This review focuses on the Rho GTPases, the PI-3 kinase-Akt pathway, and some selected aspects of MAP kinase signaling. Most studies to date have examined these pathways in isolation but it is becoming clear that there is significant cross-talk among the pathways and that the overall effects on chondrocyte function depend on the balance in activity of multiple signaling proteins. © 2010 Wiley-Liss, Inc

Integrins and chondrocyte–matrix interactions in articular cartilage

The integrin family of cell adhesion receptors plays a major role in mediating interactions between cells and the extracellular matrix. Normal adult articular chondrocytes express α1β1, α3β1, α5β1, α10β1, αVβ1, αVβ3, and αVβ5 integrins, while chondrocytes from osteoarthritic tissue also express α2β1, α4β1, α6β1. These integrins bind a host of cartilage extracellular matrix (ECM) proteins, most notably fibronectin and collagen types II and VI, which provide signals that regulate cell proliferation, survival, differentiation, and matrix remodeling. By initiating signals in response to mechanical forces, chondrocyte integrins also serve as mechanotransducers. When the cartilage matrix is damaged in osteoarthritis, fragments of fibronectin are generated that signal through the α5β1 integrin to activate a pro-inflammatory and pro-catabolic response which, if left unchecked, could contribute to progressive matrix degradation. The cell signaling pathways activated in response to excessive mechanical signals and to fibronectin fragments are being unraveled and may represent useful therapeutic targets for slowing or stopping progressive matrix destruction in arthritis

Ageing and the pathogenesis of osteoarthritis

Ageing-associated changes that affect articular tissues promote the development of osteoarthritis (OA). Although ageing and OA are closely linked, they are independent processes. Several potential mechanisms by which ageing contributes to OA have been elucidated. This Review focuses on the contributions of the following factors: age-related inflammation (also referred to as 'inflammaging'); cellular senescence (including the senescence-associated secretory phenotype (SASP)); mitochondrial dysfunction and oxidative stress; dysfunction in energy metabolism due to reduced activity of 5'-AMP-activated protein kinase (AMPK), which is associated with reduced autophagy; and alterations in cell signalling due to age-related changes in the extracellular matrix. These various processes contribute to the development of OA by promoting a proinflammatory, catabolic state accompanied by increased susceptibility to cell death that together lead to increased joint tissue destruction and defective repair of damaged matrix. The majority of studies to date have focused on articular cartilage, and it will be important to determine whether similar mechanisms occur in other joint tissues. Improved understanding of ageing-related mechanisms that promote OA could lead to the discovery of new targets for therapies that aim to slow or stop the progression of this chronic and disabling condition

An Exploratory Case-Control Study on the Associations of Bacterially-Derived Vitamin K Forms with the Intestinal Microbiome and Obesity-Related Osteoarthritis

Background: Evidence suggests that natural metabolites produced by intestinal microorganisms may have beneficial or harmful effects on osteoarthritis (OA). This could include menaquinones, which are bacterially-synthesized, biologically-active vitamin K forms abundant in the intestinal microbiome. Objectives: The overall goal of this study was to evaluate the association of intestinally-derived menaquinones with obesity-related OA. Methods: This case-control study used data and biospecimens derived from a subgroup of Johnston County Osteoarthritis Study participants. Fecal menaquinone concentrations and microbial composition were determined in 52 obese participants with hand and knee OA and 42 age- and sex-matched obese participants without OA. The inter-relationships among fecal menaquinones were evaluated using principal component analysis. The differences in alpha and beta diversities and microbial composition across menaquinone clusters were evaluated using ANOVA. Results: The samples were clustered into the following 3 groups: cluster 1 characterized by higher fecal menaquinone-9 and -10 concentrations, cluster 2 characterized by lower overall menaquinone concentrations, and cluster 3 characterized by higher menaquinone-12 and -13 concentrations. Overall, fecal menaquinone clusters did not differ between participants with or without OA (P = 0.707). Microbial diversity did not differ across the fecal menaquinone clusters (all F-test P > 0.12). However, the relative abundance of bacterial taxa differed among clusters, with higher abundance of Coprococcus, Prevotella, and Eggerthella in cluster 2 than in cluster 1; higher abundance of Oscillospira, Dorea, Eubacterium, and Bacteroides in cluster 3 than in cluster 1; and higher abundance of Prevotella, Sutterella, and Dorea in cluster 3 than in cluster 2 (all P < 0.001). Conclusion: Menaquinones were variable and abundant in the human gut, but the fecal menaquinone clusters did not differ with OA status. Although the relative abundance of specific bacterial taxa differed among fecal menaquinone clusters, the relevance of these differences with respect to vitamin K status and human health is uncertain

A mouse model for chronic pain-induced increase in ethanol consumption

Chronic pain conditions are often co-morbid with alcohol abuse. “Self-medication” with alcohol introduces a host of problems associated with the abuse of alcohol which over time has the potential of exacerbating the painful condition. Despite the prevalence of chronic pain being associated with alcohol abuse, rodent models which mimic the co-morbid conditions are lacking. In the present study, we model osteoarthritis (OA) in C57BL/6J mice by surgically destabilizing the medial meniscus (DMM). Sham operated mice served as controls. Thirteen weeks after surgery, DMM but not sham operated mice exhibited pronounced incapacitance of the surgically-manipulated hindlimb compared to the non-surgically manipulated hindlimb. At this time, the mice were exposed to the two-bottle ethanol choice, beginning with 2.5% with a gradual increasing to 20%. Compared to sham controls, DMM mice consumed more EtOH and preferred EtOH over water at the 20% EtOH concentration. Histological analysis verified that the DMM mice exhibited significant damage to the articular cartilage and osteophyte growth compared to sham controls and these measures of the severity of OA correlated with the amount of ethanol intake. Thus, the combination of the DMM model of OA with the enhanced two-bottle ethanol choice is a potential preclinical approach in mice by which the basis of the co-morbid association of alcohol abuse and chronic pain conditions can be explored

Relationship of Objectively-Measured Habitual Physical Activity to Chronic Inflammation and Fatigue in Middle-Aged and Older Adults

Habitual (non-exercise) physical activity (PA) declines with age, and aging-related increases in inflammation and fatigue may be important contributors to variability in PA

Vitamin K Status and Lower Extremity Function in Older Adults: The Health Aging and Body Composition Study

While low vitamin K status has been associated with several chronic diseases that can lead to lower extremity disability, it is not known if low vitamin K status is associated with worse lower extremity function

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1–3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism