Osteonecrosis of the Femoral Head: Lipotoxicity Exacerbation in MSC and Modifications of the Bone Marrow Fluid

Abstract

Osteonecrosis of the femoral head (ON) is a multifactorial bone disease that can evolve to a progressive destruction of the hip joint. Different pathogenic processes have been proposed, among them, an increase of bone marrow (BM) fat resulting from adipocyte accumulation. Marrow adipocytes are active BM residents that influence the microenvironment by releasing cytokines, adipokines, and free fatty acids (FA). We explored the impact of palmitate (Palm) and oleate on function and survival of BM-derived mesenchymal stromal cells (MSC) of osteonecrotic patients (ONMSC) and healthy volunteers. Moreover, we analyzed the FA profile of the serum and the BM supernatant fluid (BMSF). We demonstrated that exposure to the saturated FA Palm favored MSC differentiation through the adipogenic lineage at the expense of the osteoblastic phenotype. Moreover, adipogenesis was intensified in ONMSC. The susceptibility to Palm toxicity was aggravated in ONMSC concomitantly with a greater activation of the proapoptotic extracellular signal-regulated kinase pathway. Moreover, cellular mechanisms implicated in the protection against lipotoxicity, such as stearoyl-coenzyme A desaturase 1 and carnitine palmitoyl transferase 1 expression, were dysregulated in ONMSC. Palm-induced interleukin (IL)-6 and IL-8 secretion was also exacerbated in ONMSC. Our results established that, in the serum, the FA profiles were comparable in ON and healthy subjects. However, both the concentrations and the FA composition were modified in the BMSF of ON patients, highlighting a drastic change of the BM microenvironment in ON patients. Altogether, our work suggests that marrow adipocyte enlargement could affect the process of bone remodeling and, therefore, play a role in the pathogenesis of ON.

Efficacy and safety of stem cell therapy for the early-stage osteonecrosis of femoral head: a systematic review and meta-analysis of randomized controlled trials

“…However, the mechanisms behind stem cell therapy remained unclear and may be partly explained by the theory of biological characteristics [ 49 , 50 ]. Since stem cells have the capabilities of self-renew and proliferation, when injected into necrotic femoral head, they could differentiate into osteoblast, chondrocyte, and other tissues to repair dead bones [ 51 ].…”

Ganoderma lucidum Immune Modulator Protein rLZ-8 Could Prevent and Reverse Bone Loss in Glucocorticoids-Induced Osteoporosis Rat Model

“…Bone marrow mesenchymal stem cells (BMSCs) are the common precursor cell to adipocytes and osteoblast cells. Adipocytes accumulation or lipid toxicity is frequently reported in various diseases, including postmenopausal osteoporosis, aging osteoporosis and osteonecrosis (Gillet et al, 2017). Some investigators found that bone marrow adipocytes could suppress osteoblast differentiation through secreting factors like PPARg, adiponectin or fatty acids (Gillet et al, 2017).…”

“…Adipocytes accumulation or lipid toxicity is frequently reported in various diseases, including postmenopausal osteoporosis, aging osteoporosis and osteonecrosis (Gillet et al, 2017). Some investigators found that bone marrow adipocytes could suppress osteoblast differentiation through secreting factors like PPARg, adiponectin or fatty acids (Gillet et al, 2017). Besides analyzing the bone tissue directly, biomarkers of bone turnover in serum or urine are frequently used to investigate the metabolic status of bone in both bench and clinical (Takahashi et al, 2010;Wheater et al, 2013).…”

Mesenchymal stromal cells for osteonecrosis

“…These findings suggest that MSCs of patients with ON (ON MSCs) can proliferate and differentiate in the hypoxic area. Adipogenesis seems to be intensified in ON MSCs [ 22 ]. Cellular mechanisms of protection against lipotoxicity, such as stearyl-coenzyme A desaturase 1 and carnitine palmitoyl transferase 1 expression are dysregulated in ON MSC; moreover, palmitate-induced interleukin (IL)-6 and IL-8 secretion is higher in ON MSC [ 22 ].…”