The Effects of CCL3 on Osteoblast Inhibition in Myeloma-Induced Bone Disease

Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow. A common manifestation of the disease is bone destruction that caused by increased osteoclastic bone resorption and decreased bone formation. Suppression of osteoblast activity appears to persist even in patients enjoying long-term complete remission that without any detectable MM tumor cells. CCL3, also known as MIP-1α, is a pro-inflammatory and chemoline. To investigate if CCL3, a recently described osteoclast stimulatory factor,was possibly involved in the inhibition of osteoblast in MM-induced bone disease,osteoblast from BM of MM patients and healthy donors were cultured in vitro. Our results showed the proliferation and osteogenic potential of osteoblasts from MM patients were suppressed. MM-derived OBs expressed higher levels of CCR1 compared with normal controls. It’s an indication that CCL3 is able to influence OBs in MM bone disease (MBD).We cultured MM-derived OBs in osteogenic media and then stimulated them with CCL3 in the absence or presence of neutralizing antibody against CCL3. Our data suggested that CCL3 impaired matrix mineralization and suppressed osteocalcin (OCN).Gene expression analysis of osteoblastic transcription factors in CCL3-treated OBs revealed a Runx2 and Osterix downregulation. CCL3 antibody at least partially restored OBs activity with an upregulation of OCN levels and Runx2 and Osterix expression. These results showed that CCL3 may contribute to OB/OC imbalance by inhiting OBs’ dedifferentiation and function in MBD.