RESUMEN
Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.
RESUMEN
PURPOSE: Laser therapy has been used for the prevention and management of medication-related ostenecrosis of the jaw (MRONJ). The aim of this paper was to investigate the action of laser therapy on extraction socket healing in rats in conditions at risk for MRONJ, evaluating the expression of markers of bone metabolism. METHODS: Thirty male Sprague-Dawley rats were divided in four groups: control group (C, n = 5), laser group (L, n = 5), treatment group (T, n = 10), and treatment plus laser group (T + L, n = 10). Rats of group T and T + L received zoledronate 0.1 mg/kg and dexamethasone 1 mg/kg every 2 days for 10 weeks. Rats of group C and L were infused with vehicle. After 9 weeks, the left maxillary molars were extracted in all rats. Rats of groups L and T + L received laser therapy (Nd:YAG, 1064 nm, 1.25 W, 15 Hz, 5 min, 14.37 J/cm(2)) in the socket area at days 0, 2, 4, and 6 after surgery. Western blot analysis was performed to evaluate the alveolar expression of osteopontin (OPN) and osteocalcin (OCN) 8 days after extraction. RESULTS: Rats of groups L and T + L showed a significant higher expression of OCN compared to rats of groups C and T (+348 and +400 %, respectively; P = 0.013 and P = 0.002, respectively). The expression of OPN did not show significant differences among the different groups. CONCLUSIONS: Our findings suggest that laser irradiation after tooth extraction can promote osteoblast differentiation, as demonstrated by the higher expression of OCN. Thus, laser irradiation could be considered a way to improve socket healing in conditions at risk for MRONJ development.