Chondroitin synthase 1 is a key molecule in myeloma cell-osteoclast interactions.

There is a symbiotic relationship between continued growth and proliferation of myeloma cells and the bone destructive process. It has been shown in animal models that blocking bone destruction can result in decreased myeloma tumor burden. Osteoclasts are bone destroying cells found in the bone marrow, and their significance in myeloma is supported by recent findings that osteoclasts alone can support sustained survival and proliferation of purified primary myeloma cells in ex vivo co-cultures. However, molecular mechanisms associated with interactions between myeloma cells and osteoclasts remain unclear. Here, we show that when myeloma plasma cells are co-cultured with osteoclasts, chondroitin synthase 1 (CHSY1) is the most significantly altered soluble, secreted protein present in the conditioned medium. RNA interference experiments with CHSY1 small interfering RNA (siRNA) reduced the amount of CHSY1 in the co-culture conditioned medium, and this was associated with a 6.25-fold increase in apoptotic myeloma cells over control co-cultures. CHSY1 contains a Fringe domain, and Fringe is well known for its regulation of Notch signaling via its DDD motif. And interestingly, Fringe domain in CHSY1 has this DDD motif. Shortly after co-culture with osteoclasts, we found that the Notch2 receptor was activated in myeloma cells but Notch1 was not. Activation of Notch2 was down-regulated by CHSY1 siRNA treatment. Modulating Notch signaling by CHSY1 via its DDD motif provides new insight into mechanisms of the interactions between myeloma cells and their bone marrow microenvironment. Targeting this interaction could shed light on treatment of myeloma, which is currently incurable.