Extracellular glutamate alters mature osteoclast and osteoblast functions

Glutamatergic intercellular communication is involved in many aspects of metabolic homeostasis in normal bone. In bone metastasis, the balance between bone formation and degradation is disrupted. Although the responsible mechanisms are not clear, we have previously identified that cancer cell lines used in bone tumour models secrete glutamate, suggesting that tumour-derived glutamate may disrupt sensitive signalling systems in bone. This study examines the role of glutamate in mature osteoclastic bone resorption, osteoblast differentiation, and bone nodule formation. Glutamate was found to have no effect on the survival or activity of mature osteoclasts, although glutamate transporter inhibition and receptor blockade increased the number of bone resorption pits. Furthermore, transporter inhibition increased the area of resorbed bone while significantly decreasing the number of osteoclasts. Alkaline phosphatase activity and extracellular matrix mineralization were used as measurements of osteoblast differentiation. Glutamate significantly increased osteoblast differentiation and mineralization, but transport inhibitors had no effect. These studies support earlier findings suggesting that glutamate may be more important for osteoclastogenesis than for osteoclast proliferation or functions. Since glutamate is capable of changing the differentiation and activities of both osteoclast and osteoblast cell types in bone, it is reasonable to postulate that tumour-derived glutamate may impact bone homeostasis in bone metastasis. Key words: bone, cancer, glutamate, metastasis, osteoblast, osteoclast, transporter. La communication intercellulaire glutamatergique participe a de nombreux aspects de l'homeoslasie metabolique dans l'os normal. Dans la melastase osseuse, l'equilibre entre la formation et la degradation de l'os est rompu. Bien que les mecanismes a la base de ce desequilibre ne soient pas clairs, nous avons indique dans des travaux anterieurs que les lignees de cellules cancereuses utilisees dans les modeles de tumeurs osseuses secretent du glutamate, ce autorise a penser que le glutamate tumoral pourrait perturber les systemes de signalisation sensibles dans l'os. La presente etude examine le role du glutamate dans la resorption de l'osteoclaste mature, la differenciation osteoblastique et la formation de nodules osseux. Le glutamate n'a pas eu d'effet sur la survie ou l'activite des osteoclastes matures, quoique l'inhibition du transporteur de glutamate et le blocage du recepteur aient augmente les puits de resorption osseuse. De plus, l'inhibition du transporteur a augmente la surface de l'os resorbe tout en diminuant significativement le nombre d'osteoclastes. L'activite de la phosphatase alcaline et la mineralisation de la matrice extracellulaire ont servi de mesures de la differenciation osteoblastique. Le glutamate a augmente de maniere significative la differenciation et la mineralisation des osteoclastes, mais les inhibiteurs du transport n'ont eu aueira effet. Ces observations conforteni les resultats anterieurs suggerant que le glutamate pourrait etre plus important pour l'osteoclastogenese que les fonctions ou la proliferation des osteoclastes. Comme le glutamate est capable de modifier la differenciation et les activites des deux types de cellules dans l'os, il est raisonnable de postuler que le glutamate provenant des tumeurs pourrait avoir un impact sur l'homeostasie du tissu osseux dans la melastase osseuse. Mots-cles : os, cancer, glutamate, melastase, osteoblast, osteoclast, transporter. [Traduit par la Redaction]
Introduction A variety of factors participate in the highly coordinated balancing of osteoclast (Oc) and osteoblast (Ob) cell functions in bone remodelling. Recent evidence suggests that the neurotransmitter L-glutamate is [...]