Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro

Abstract

Although increased bone marrow fat in age-related bone loss has been associated with lower trabecular mass, the underlying mechanism responsible remains unknown. We suggested that marrow adipocytes exert a lipotoxic effect on osteoblast function and survival through the reversible biosynthesis of fatty acids (FA) into the bone marrow microenvironment. We have used a two-chamber system to co-culture normal human osteoblasts (NHOst) with differentiating pre-adipocytes in the absence or presence of an inhibitor of FA synthase (cerulenin) and separated by an insert that allowed unidirectional trafficking of soluble factors only and prevented direct cell–cell contact. Supernatants were assayed for the presence of FA using mass spectophotometry. After 3 weeks in co-culture, NHOst showed significantly lower levels of differentiation and function based on lower mineralization and expression of alkaline phosphatase, osterix, osteocalcin and Runx2. In addition, NHOst survival was affected by the presence of adipocytes as determined by MTS-formazan and TUNEL assays as well as higher activation of caspases 3/7. These toxic effects were inhibited by addition of cerulenin. Furthermore, culture of NHOst with either adipocyte-conditioned media alone in the absence of adipocytes themselves or with the addition of the most predominant FA (stearate or palmitate) produced similar toxic results. Finally, Runx2 nuclear binding was affected by addition of either adipocyte conditioned media or FA into the osteogenic media. We conclude that the presence of FA within the marrow milieu can contribute to the age-related changes in bone mass and can be prevented by the inhibition of FA synthase.

Pioglitazone increases bone marrow fat in type 2 diabetes: results from a randomized controlled trial

“…First, it is possible that increased marrow adiposity contributes to the increased skeletal fragility observed in clinical studies of TZDs. Co-culture experiments demonstrate that adipocytes induce osteoblast apoptosis via a paracrine mechanism (8) and inverse relationships between marrow fat and BMD have been reported in prospective studies on animals (9) and cross-sectional studies on humans (10). Decreased bone formation has been reported in both preclinical and clinical studies on TZDs (3).…”

“…First, it is plausible that increased bone marrow fat induced by TZDs might detrimentally affect BMD. Evidence from in vitro studies suggests that adipocytes adversely influence bone cell function in a paracrine manner (8), prospective studies on animals report a contemporaneous increase in marrow fat and decrease in BMD (9), and correlative studies in humans suggest an inverse relationship between bone marrow fat and BMD (10). Second, it has been suggested that changes in bone marrow fat might artifactually alter measurement of BMD by dualenergy X-ray absorptiometry (DXA) (11).…”

Decreased osteoclastogenesis, osteoblastogenesis and low bone mass in a mouse model of type 2 diabetes

“…Fat tissue is targeted by insulin and has a key role in insulin resistance. Adipocytes also secrete factors that inhibit the differentiation of osteoblasts (20), and a high-insulin …”

Enhanced antitumor activity of cucurbitacin B combined with cerulenin in osteosarcoma

“…It acts an inhibitor of fatty acid synthase (FASN) by reacting with the keto-acyl synthase domain of FASN. Various studies have been performed to investigate the anti-tumor activity of cerulenin against the malignant neoplasms (Elbaz et al, 2010;Wang et al, 2008). The present study demonstrates the effects of the combination of cucurbitacin B and cerulenin on the rate of osteosarcoma cell proliferation, suppression of SENP5 expression and induction of apoptosis.…”