1.
The burden of metabolic syndrome on osteoarthritic joints.
Dickson, BM, Roelofs, AJ, Rochford, JJ, Wilson, HM, De Bari, C
Arthritis research & therapy. 2019;(1):289
Abstract
BACKGROUND The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes. MAIN TEXT A skewing of macrophages towards a pro-inflammatory M1 phenotype within synovial and adipose tissues is thought to play a role in OA pathogenesis. The metabolic perturbations typical of MetS are important drivers of pro-inflammatory macrophage polarisation and activity. This is mediated via alterations in the levels and activities of the cellular nutrient sensors 5' adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1), intracellular accumulation of metabolic intermediates such as succinate and citrate, and increases in free fatty acids (FFAs) and hyperglycaemia-induced advanced glycation end-products (AGEs) that bind to receptors on the macrophage surface. Altered levels of adipokines, including leptin and adiponectin, further influence macrophage polarisation. The metabolic alterations in MetS also affect the cartilage through direct effects on chondrocytes by stimulating the production of pro-inflammatory and catabolic factors and possibly by suppressing autophagy and promoting cellular senescence. CONCLUSIONS The influence of MetS on OA pathogenesis involves a wide range of metabolic alterations that directly affect macrophages and chondrocytes. The relative burden of intra-articular versus systemic adipose tissue in the MetS-associated OA remains to be clarified. Understanding how altered metabolism interacts with joints affected by OA is crucial for the development of further strategies for treating this debilitating condition, such as supplementing existing therapies with metformin and utilising ω-3 fatty acid derivatives to restore imbalances in ω-3 and ω-6 fatty acids.
2.
Genetics of menopause-associated diseases.
Massart, F, Reginster, JY, Brandi, ML
Maturitas. 2001;(2):103-16
Abstract
Menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is estimated that perhaps 50 million women worldwide will go into menopause annually. Atherosclerotic cardiovascular disease, osteoporotic fractures and Alzheimer's dementia are common chronic disorders after menopause, representing major health problems in most developed countries. Apart from being influenced by environmental factors, these chronic disorders recognize a strong genetic component, and there are now considerable clinic evidences that these disorders are related to low hormonal milieu of postmenopausal women. Here, we review up-to-date available data suggesting that genetic variation may contribute to higher susceptibility to four sporadic chronic syndromes such as osteoporosis (OP), osteoarthritis (OA), Alzheimer's disease (AD) and coronary artery disease (CAD). For these four syndromes candidate genes that today appear as major loci in genetic susceptibility encode for proteins specific of a given system, as the vitamin D receptor (VDR) gene for the skeleton and, therefore, OP or angiotensin converting enzyme (ACE) for the cardiovascular system and, therefore, CAD. The investigation of gene polymorphisms in various pathological conditions typical of postmenopause offer an explanation not only of their genetic inheritance but also of their co-segregation in given individuals. In this view, it may be possible to identify a common set of genes whose variants contribute to a common genetic background for these different disorders. Ideal candidates appear genes of the estrogen response cascade [i.e. estrogen receptor (ERs), enzymes involved in estrogen metabolism or co-activators and co-inhibitors]. All together this information may represent the basis both for future recognition of individuals at risk and for the pharmacogenetic driving of drug responsiveness.