Abstract
Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Hypercalcemia is common in patients with ATL. These patients rarely develop metastatic calcification and acute pancreatitis. The underlying pathogenesis of this condition is osteoclast hyperactivity with associated overproduction of parathyroid hormone-related protein, which results in hypercalcemia in association with bone demineralization. The discovery of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL), its receptor RANK, and its decoy receptor osteoprotegerin (OPG), enhanced our understanding of the mechanisms of ATL-associated hypercalcemia. Macrophage inflammatory protein-1-α, tumor necrosis factor-α, interleukin-1, and interleukin-6 are important molecules that enhance the migration and differentiation of osteoclasts and the associated enhanced production of RANKL for osteoblast formation. In this paper, we focus on metastatic calcification and acute pancreatitis in ATL, highlighting recent advances in the understanding of the molecular role of the RANKL/RANK/OPG system including its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis for bone resorption in hypercalcemic ATL patients.
Highlights
Adult T-cell leukemia (ATL) was first reported as a new clinical entity in 1977 in Japan [1, 2]
16 to 20 million people are infected with human T-cell leukemia virus type 1 (HTLV-1) worldwide, and 1 to 5% of the infected individuals develop ATL during their lifetime [7] caused by the transformation of their CD4+ T cells [8]
The activity of osteoclasts is regulated by various cytokines and calciotropic hormones including macrophage inflammatory protein-1-alpha (MIP-1α), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL6, IL-11, macrophage-colony stimulating factors (M-CSF), PTH, parathyroid hormone-related protein (PTHrP), 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), and calcitonin [30,31,32]
Summary
Adult T-cell leukemia (ATL) was first reported as a new clinical entity in 1977 in Japan [1, 2]. A type C retrovirus was isolated from patients with cutaneous T-cell lymphoma by Poiesz and colleagues in 1980 [3] This virus was later renamed human T-cell leukemia virus type 1 (HTLV-1). In 1981, Hinuma et al [4] and Yoshida and colleagues [5] reported the isolation of a type C retrovirus named adult T-cell leukemia virus. The activity of osteoclasts is regulated by various cytokines and calciotropic hormones including macrophage inflammatory protein-1-alpha (MIP-1α), TNF-α, interleukin-1 (IL-1), IL6, IL-11, macrophage-colony stimulating factors (M-CSF), PTH, PTHrP, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), and calcitonin [30,31,32]. Members of the TNF and TNFreceptor (TNFR) superfamily, receptor activator of nuclear factor-κB ligand (RANKL), receptor activator of nuclear factor-κB (RANK), and osteoprotegerin (OPG) play a key role in the formation and activation of osteoclasts in conjunction with various cytokines and calciotropic hormones [30, 33, 34]
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