Research ArticleCancer

C-reactive protein promotes bone destruction in human myeloma through the CD32–p38 MAPK–Twist axis

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Sci. Signal.  12 Dec 2017:
Vol. 10, Issue 509, eaan6282
DOI: 10.1126/scisignal.aan6282

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Liver protein instructs bone loss in myeloma

Bone loss is common in patients with multiple myeloma (MM). MM cells activate osteoclasts, cells that degrade bone. The sera of MM patients typically have increased amounts of C-reactive protein (CRP), which is secreted by the liver in response to cytokines associated with tissue inflammation and physiological stress, including those secreted by MM. Using samples from patients, as well as human cell lines and mice bearing human bone grafts and MM cells, Yang et al. found that CRP is not merely a diagnostic marker for MM but that rather it feeds back on MM cells to stimulate the expression and secretion of osteoclast-activating cytokines from MM cells, thereby driving bone loss in patients. These findings suggest that targeting the cyclical CRP signaling axis may reduce or prevent MM-associated bone loss.


Bone destruction is a hallmark of myeloma and affects 80% of patients. Myeloma cells promote bone destruction by activating osteoclasts. In investigating the underlying mechanism, we found that C-reactive protein (CRP), a protein secreted in increased amounts by hepatocytes in response to myeloma-derived cytokines, activated myeloma cells to promote osteoclastogenesis and bone destruction in vivo. In mice bearing human bone grafts and injected with multiple myeloma cells, CRP bound to surface CD32 (also known as FcγRII) on myeloma cells, which activated a pathway mediated by the kinase p38 MAPK and the transcription factor Twist that enhanced the cells’ secretion of osteolytic cytokines. Furthermore, analysis of clinical samples from newly diagnosed myeloma patients revealed a positive correlation between the amount of serum CRP and the number of osteolytic bone lesions. These findings establish a mechanism by which myeloma cells are activated to promote bone destruction and suggest that CRP may be targeted to prevent or treat myeloma-associated bone disease in patients.

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