Bone disease in multiple myeloma (MM) is due to not only the activation of osteoclasts but also the impairment of osteoblast differentiation. Recent studies showed the overexpression of the Wnt signaling antagonists FRZB (secreted Frizzled-related protein 3, sFRP-3) and dickkopf1 (DKK1) is important in MM-related bone disease. Bone morphogenetic proteins (BMPs) and connective tissue growth factor (CTGF) are known to play essential roles in promoting the proliferation of early osteoprogenitor cells, specifically, differentiation from mesenchymal stem cells (MSC) to committed osteoprogenitor cells. Expression of CTGF is reported to be up-regulated by Wnt3A or BMPs stimulation. CTGF has four domains each of which participates in macromolecular interactions that are relevant to CTGF action as a modulating factor. In particular, Domain 2 is known to bind BMPs and thus block downstream signalling. The two N- and C-half domains are connected by a central hinge region which is protease sensitive. Some matrix metalloproteinases (MMP-2, 3, 7, 13) cleave this region. Study of clinical samples has shown that a major form of CTGF in the circulation is the N-half fragment. We analyzed the concentration of circulating CTGF in 39 patients with MM and 22 patients with malignant lymphoma (ML). Full length CTGF and N-half CTGF + full length CTGF in patient serum samples were detected and quantitated by separate sandwich ELISAs. The level of N-half CTGF was significantly higher in patients with MM compared to patients with ML (these subjects have normal BM) (p<0.001). Furthermore, serum content of N-half CTGF was significantly higher (p<0.001) in MM patients with bone disease compared to those without bone involvement. This may relate to BMP effects on bone physiology. Perhaps the CTGF N-half-fragment is a more effective BMP antagonist than intact CTGF. Alternatively, N-half CTGF may be less potent than intact CTGF for promoting osteoblast differentiation. First, we expected that cutting CTGF by MMP-13 produced by myeloma cells might be a cause of bone disease in MM. However, although the expression of MMP-13 was detected in myeloma cells by RT-PCR, cytoplasmic MMP-13 was positive only in MM patients with progressive disease (PD), and the level of serum MMP-13 was less than the sensitivity by ELISA. Furthermore, we analyzed the level of serum MMP-9 because it reportedly plays a role in the activation of osteoclasts. However, there was no significant difference between patients with MM and ML, and also no difference between MM patients with and without bone disease. We did not detect a significant difference of MMP9 expression between MM patients with and without bone disease by RQ-PCR. These results suggest that CTGF, N-half CTGF or both play a role in MM to promote bone involvement. In addition, evaluation of CTGF and CTGF fragments may serve as a useful approach to evaluate disease progression. The cause of high CTGF N-half-fragment in patients with MM should be clarified.

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