Oxidized lipids enhance RANKL production by T lymphocytes: Implications for lipid-induced bone loss

Abstract

Osteoporosis is a systemic disease that is associated with increased morbidity, mortality and health care costs. Whereas osteoclasts and osteoblasts are the main regulators of bone homeostasis, recent studies underscore a key role for the immune system, particularly via activation-induced T lymphocyte production of Receptor Activator of NFκB Ligand (RANKL). Well-documented as a mediator of T lymphocyte/dendritic cell interactions, RANKL also stimulates the maturation and activation of bone-resorbing osteoclasts. Given that lipid oxidation products mediate inflammatory and metabolic disorders such as osteoporosis and atherosclerosis, and since oxidized lipids affect several T lymphocyte functions, we hypothesized that RANKL production might also be subject to modulation by oxidized lipids. Here, we show that short term exposure of both unstimulated and activated human T lymphocytes to minimally oxidized low density lipoprotein (LDL), but not native LDL, significantly enhances RANKL production and promotes expression of the lectin-like oxidized LDL receptor-1 (LOX-1). The effect, which is also observed with 8-iso-Prostaglandin E2, an inflammatory isoprostane produced by lipid peroxidation, is mediated via the NFκB pathway, and involves increased RANKL mRNA expression. The link between oxidized lipids and T lymphocytes is further reinforced by analysis of hyperlipidemic mice, in which bone loss is associated with increased RANKL mRNA in T lymphocytes and elevated RANKL serum levels. Our results suggest a novel pathway by which T lymphocytes contribute to bone changes, namely, via oxidized lipid enhancement of RANKL production. These findings may help elucidate clinical associations between cardiovascular disease and decreased bone mass, and may also lead to new immune-based approaches to osteoporosis.

PKA-induced Receptor Activator of NF-κB Ligand (RANKL) Expression in Vascular Cells Mediates Osteoclastogenesis but Not Matrix Calcification

“…This RANKL induction appears to be modest but it suggests an additional source of RANKL in the vasculature. The findings are also consistent with our previous study that shows induction of RANKL in T lymphocytes by minimally modified lipoprotein particles (20), of which ox-PAPC is a biologically active, phospholipid component (31,32). These findings suggest that ox-PAPC is molecular component that is largely responsible for biological activities of minimally modified lipoproteins.…”

“…We previously found that RANKL expression is increased in calcified cartilaginous metaplasia in atherosclerotic lesions of hyperlipidemic mice (19). RANKL expression is also increased by minimally modified low-density lipoprotein in T lymphocytes (20). Kaden et al (21) have previously shown that treatment of human aortic valvular cells with soluble RANKL promotes osteoblastic differentiation and matrix calcification.…”

Atorvastatin Reduces Circulating Osteoprogenitor Cells and T‐Cell RANKL Expression in Osteoporotic Women: Implications for the Bone–Vascular Axis

“…Of interest, upregulation of RANKL was found in circulating T cells of patients with acute coronary syndrome (ACS) (unstable angina/myocardial infarction) as compared to subjects with stable coronary artery disease [9]. More recently, researches by Graham et al [15] demonstrated that exposure of T cells to oxidized lipids is accompanied by increased expression of RANKL in the cells. The same group also showed that RANKL was upregulated in the bone marrow and splenic T cells of mice that develop osteopenia when fed high-fat diet [16].…”

“…Nevertheless, a number of studies indicated that the accumulation of lipid oxidation products within the skeleton may contribute to pathological bone resorption, mainly through the inhibition of osteoblast differentiation and the induction of osteoclast maturation/activation [14]. Of interest, data are available showing that oxidized lipids can induce RANKL expression in T cells [15] and that RANKL is increased in bone marrow and splenic T cells of mice with hyperlipidemia-induced bone loss [16]. No data are available so far showing whether lipid-lowering strategies can modulate in vivo OPG/RANK/RANKL expression in immune cells.…”

Serum Lipids Effect on Bone Mineral Density: A Pilot Study in Apparently Healthy Syrians

“…Oxidized lipids were reported to inhibit osteoblasts differentiation [14,15], reduce their viability [13] and increase their apoptosis [16]. They were also found to affect bone resorption by increasing osteoclastogenesis cytokines production such as receptor activator of nuclear factor-κB (RANKL) and interleukin-6 from both T-lymphocytes and osteoblasts [17][18][19][20][21]. Furthermore, it has been reported that oxidized lipids down regulate parathyroid hormone receptor (PTH1R) in osteoblasts causing resistance to PTH [22][23][24][25][26].…”