Protein tyrosine phosphatases and connexin 43 are involved in alendronate signalling in bone cells

VIRGINIA LEZCANO; TERESITA BELLIDO; LILIAN I PLOTKIN; RICARDO BOLAND; SUSANA MORELLI

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

ELSEVIER SCIENCE BV

Año: 2012

0167-4889

Bisphosphonates (BPs) are potent inhibitors of bone resorption which inhibit osteoclasts. They have also been shown to act on osteocytes and osteoblasts preventing apoptosis via opening of connexin (Cx) 43 hemichannels and activation of the extracellular signal regulated kinases ERKs. We previously demonstrated the presence of a saturable, specific and high affinity binding site for alendronate (ALN) in osteoblastic cells which express Cx43. However, HeLa cells lacking Cx43 also bound BPs. Like BPs, the protein tyrosine phosphatase (PTP) inhibitor Na increased proliferation in cells expressing Cx43 or not. Altogether these results suggest dissociation of the proliferative and anti-apoptotic effects of BPs. Herein we show that bound [3H]-alendronate is displaced by phosphatase substrates. Moreover, similarly to Na, ALN inhibited the activity of transmembrane and cytoplasmic PTPs, pointing out the catalytic domain of phosphatases as a putative BP target. It was also demonstrated that the transmembrane receptor-like PTPs, RPTPµ and RPTPalpha, as well as the cytoplasmic PTP1B, are highly expressed in ROS 17/2.8, MLO-Y4 and HeLa cells. Furthermore, we evidenced that Cx43 interacts with RPTPµ in ROS 17/2.8 and MLO-Y4 cells. These results support the hypothesis that BPs bind and inhibit PTPs associated to Cx43, activating signaling pathways in osteoblasts/osteocytes.