Abstract
Multiple myeloma (MM) is characterized by bone destruction due to increased bone resorption and decreased bone formation. Semaphorin 4D (CD100, Sema4D) is expressed by osteoclasts, binds to its receptor Plexin-B1, and acts as a mediator of osteoclast–osteoblast interaction that ultimately inhibits osteoblastic bone formation. Preclinical data suggest that Sema4D/Plexin-B1 pathway is implicated in MM-induced bone disease. However, there is no information on the role of Sema4D in MM patients. Thus, we evaluated Sema4D and Plexin-B1 in six myeloma cells lines in vitro; in the bone marrow plasma (BMP) and serum of 72 newly diagnosed symptomatic MM (NDMM) patients and in 25 healthy controls. Only one myeloma cell line produced high Sema4D. BMP and circulating Sema4D and Plexin-B1 levels were significantly higher in MM patients compared to controls (p < 0.01). Sema4D correlated with serum calcium levels (p < 0.001), increased bone resorption (as assessed by CTX; p < 0.01), and ISS (p < 0.001). There was a trend for higher Sema4D levels in patients with osteolysis (p = 0.07), while patients with diffuse MRI pattern had higher BMP Sema4D levels (p = 0.02). Our data suggest that Sema4D is elevated in MM patients and correlate with adverse myeloma features and increased bone resorption, providing a possible target for novel therapeutic approaches in MM.
Highlights
Multiple myeloma (MM) is the second most common hematologic malignancy and is characterized by the development of osteolytic bone disease due to disrupted bone remodeling; there is an upregulation of bone resorption due to increased number and activity of osteoclasts, whereas bone formation is suppressed due to reduced osteoblast number and activity[1,2]
Bisphosphonates are correlated with jaw osteonecrosis and renal impairment, while they have no effect on osteoblast function
Semaphorins are signaling molecules involved in the cell–cell communication between osteoclasts and osteoblasts[6,7] and especially Sema4D has a dominant effect by suppressing osteoblast differentiation and modulating osteoblast motility[13,14]
Summary
Multiple myeloma (MM) is the second most common hematologic malignancy and is characterized by the development of osteolytic bone disease due to disrupted bone remodeling; there is an upregulation of bone resorption due to increased number and activity of osteoclasts, whereas bone formation is suppressed due to reduced osteoblast number and activity[1,2]. Semaphorins were originally described as axonal guidance molecules. They are expressed outside the nervous system, in a wide variety of tissues, and are implicated in diverse biological procedures, including cell migration, Sema3A favors the angiogenic effect of Vascular Endothelial Growth Factor[165] and may be involved in the angiogenic transition from monoclonal gammopathy of undetermined significance to MM5. It has been suggested that semaphorins are involved in the cell–cell communication between osteoclasts and osteoblasts during bone remodeling[6,7]. Semaphorin 4D (CD100—Sema4D) is expressed by osteoclasts and acts as a mediator of osteoclast–osteoblast interaction that inhibits osteoblastic bone formation[8].
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