Bisphosphonates and Connexin 43: A Critical Review of Evidence

Abstract

Bisphosphonates (BPs) are drugs commonly used in the treatment of various disease arising or affecting bone tissue. There is a standard use in bone neoplasia and metastasis, hormonal and developmental disorders as well as for compensation of adverse effects in several medical therapies. Many in-vivo and in-vitro studies have assessed the effi cacy of this drug and its function in cellular scale. In this concern, BPs are described to inhibit the resorptive function of osteoclasts and to prevent apoptosis of osteoblasts and osteocytes. They can preserve the osteocytic network, reduce fracture rate, and increase the bone mineral content, which is therapeutically used. Connexin 43 (Cx43) is a crucial molecule for basal regulation of bone homeostasis, development, and differentiation. It is described for signal transduction in many physiological and pathological stimuli and recently to be involved in BP action.

Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway

“…It is generally believed that the tumorigenic phenotype is widely associated with lack of Cx expression and GJIC, while restoring Cx expression and GJIC improved the sensitivity of cancer cells to chemotherapeutics and inhibited tumor growth 12 . Cx43 is the most widely studied isoform of Cxs due to its abundant expression in the heart, breast, brain and colorectal tissues 13 . It has been proven that Cx43 and its derived GJIC act as tumor suppressors to inhibit glioma and colorectal cancer growth 14 , 15 .…”

The anti-metastatic micro-environment of the bone: Importance of osteocyte Cx43 hemichannels

“…Physiologically, in osteocytes, Cx43 hemichannels are mechanosensitive and become activated by fluid flow and shear stress [13]. Therapeutically, part of the bone-protective actions of bisphosphonate drugs could be attributed to its ability to trigger Cx43-hemichannel opening, thereby promoting cell survival and suppressing apoptosis in osteoblasts and osteocytes (critically reviewed in [17]). The presence of functional Cx43 hemichannels in osteoblasts and osteocytes was critical for the activation of cell survival signaling pathways, like Src and ERK, in response to bisphosphonate drugs and to protect against in vivo bone loss induced by glucocorticoids [18][19][20].…”

“…The signaling pathways involved ought to be elucidated. Interestingly, it appears that the bisphosphonate drugs are selectively acting on Cx43 hemichannels present in osteocytes, since osteoblasts expressing Cx43 hemichannels do not release ATP upon bisphosphonate drug exposure, although other studies convincingly challenge this concept (reviewed in [17]). Thus, the difference between osteoblasts and osteocytes in responsiveness to bisphosphonate drugs will be an interesting avenue to explore.…”

ZO-1 expression shows prognostic value in chronic B cell leukemia

“…Gap junction formation and hemichannel expression and assembly is being precisely regulated, including cytokine regulation (Sáez et al, 2014;RibeiroRodrigues et al, 2015) and may be affected by pharmacological substances (Sadr-Eshkevari et al, 2014). At least 20 different human connexins have been identified (Oyamada et al, 2005), from which Cx43 is the major connexin in lymphocytes (Saez et al, 2003).…”