Leptin changes differentiation fate and induces senescence in chondrogenic progenitor cells

Abstract

Body weight is a component of the mechanical theory of OA (osteoarthritis) pathogenesis. Obesity was also found to be a risk factor for digital OA involving non-weight-bearing joints, which suggested that metabolism influences the occurrence and progression of OA. The metabolic origin of OA has been partially attributed to the involvement of adipokines, such as leptin, the levels of which are significantly and positively correlated with cartilage degeneration in OA patients. However, the mechanisms by which leptin-induced cartilage degeneration occurs are poorly understood. The discovery of chondrogenic progenitor cells (CPCs) opened up new opportunities for investigation. Investigating the effects of leptin on differentiation and proliferation in CPCs would increase our understanding of the roles played by leptin in the aetiology and development of OA. Here, CPCs were harvested using single-cell sorting from rat cartilage tissues to obtain mesenchymal stem-like cells, which possess clonogenicity, proliferation and stemness. High doses of leptin decreased the ability of the CPCs to migrate, inhibited their chondrogenic potential and increased their osteogenic potential, suggesting that leptin changes differentiation fates in CPCs. High doses of leptin induced cell cycle arrest and senescence in CPCs by activating the p53/p21 pathway and inhibiting the Sirt1 pathway. Inhibiting the Sirt1 pathway accelerated cartilage senescence in knockout (KO) mice. Activating the leptin pathway induced higher Ob-Rb expression and was significantly correlated with cartilage degeneration (lower levels of Coll-2) and tissue senescence (higher levels of p53/p21 and lower levels of Sirt1) in OA patients, suggesting that leptin-induced CPCs senescence contributes to the development of OA. Taken together, our results reveal new links between obesity and cartilage damage that are induced by leptin-mediated effects on cell behaviour and senescence.

Adipokines and inflammation: is it a question of weight?

“…Chondrogenic progenitor cells (CPCs) are cartilage seed cells crucial to maintain cartilage homeostasis and replace damaged tissue. Leptin reduces CPC migratory ability and their chondrogenic potential and induces CPC senescence and osteogenic transformation, thus changing the pattern of CPC differentiation (Zhao et al ., ). Leptin also regulates bone metabolism via induction of abnormal osteoblast function, which is associated with joint destruction in OA patients (Conde et al ., ).…”

Obesity, Fat Mass and Immune System: Role for Leptin

“…Chondrogenic progenitor cells as cartilage seed cells are crucial to maintain cartilage homeostasis and replace damaged tissue ( Seol et al, 2012 ). Leptin (50 ng/ml) can reduce CPCs migratory ability and their chondrogenic potential, and augment CPCs osteogenic transformation, hence changing CPC differentiation fate ( Zhao et al, 2016 ). CPC cell cycle arrest and senescence are also induced by leptin ( Zhao et al, 2016 ).…”

“…Leptin (50 ng/ml) can reduce CPCs migratory ability and their chondrogenic potential, and augment CPCs osteogenic transformation, hence changing CPC differentiation fate ( Zhao et al, 2016 ). CPC cell cycle arrest and senescence are also induced by leptin ( Zhao et al, 2016 ). Furthermore, leptin influenced the regulation of bone metabolism through induction of abnormal osteoblast function, which is associated to joint destruction in OA patients ( Findlay and Atkins, 2014 ; Conde et al, 2015 ).…”

Arterial ageing: from endothelial dysfunction to vascular calcification

“…The function and health of the vascular network are regulated by the vascular endothelium releasing molecules that act in an autocrine and paracrine manner . In addition to the redox balance , nitric oxide (NO) is the most important mediator of normal endothelial function, through its powerful vasodilator action. NO is synthesized by the endothelial NO synthase (eNOS or NOS III) via the action of different neurohumoral mediators such as acetylcholine and circulating hormones .…”