Untitled

Abstract

Matrix metalloproteinases (MMPs) play an important regulatory role in tissue morphogenesis, cell differentiation, tumor invasion and metastasis. Several authors have reported a direct correlation between the production of 72 kDa (MMP-2) and 92 kDa (MMP-9) type IV collagenases/gelatinases and the metastatic potential of cancer cells. Recently, we have identified the expression of both MMP-2 and MMP-9 in primary cultures of human giant cell tumor (GCT) of bone in vitro, and in tissue extracts in vivo. Interestingly, MMP-9 is not secreted by late-passaged GCT cells. It is possible that the production of MMP-9 is regulated by certain factor(s) secreted by the multinucleated giant cells in the primary culture. In order to test this hypothesis, the effect of primary-culture-conditioned medium on the expression of MMP-9 by late-passaged mononuclear stromal cells was examined. Adding conditioned medium from the primary GCT culture to the late-passaged stromal cells induced MMP-9, as evidenced by the presence of lytic bands at M(r) 92,000 and 72,000 on a gelatin zymogram. These enzyme activities were inhibited by EDTA, a well-known inhibitor of the MMPs. We confirmed these results by Western blotting using specific antibodies and RT-PCR for MMP-2 and MMP-9. Immunofluorescence studies with specific antibodies to MMP-9 further confirmed its expression by the passaged stromal cells cultured in the primary-culture-conditioned medium. The data indicate that MMP-2 and MMP-9 are produced by the mononuclear stromal cells when cultured in GCT primary-culture-conditioned medium. This suggests that multinucleated giant cells in primary cultures secrete a factor(s) that stimulates stromal cells to produce MMP-9, which, in turn, may contribute to the aggressive behavior of GCT.

Matrix Metalloproteinase Activity in the Stromal Cell of Giant Cell Tumor of Bone

“…Our results are consistent with other studies that demonstrated the stromal cells of GCT are stimulated by local cytokines such as tumor necrosis factor alpha (TNFα) and interleukin-1 (IL-1) to express and produce several angiogenic and proteolytic factors, including vascular endothelial growth factor (VEGF), MMP-3, and MMP-9 [39–43]. Rao et al showed that media from fresh GCT specimens activated MMP-9 in late-passaged stromal cells [31]. …”

Protein Expression Profiling of Giant Cell Tumors of Bone Treated with Denosumab

“…MMP-9 (matrix metalloproteinases-9) is one of the MMPs, a family of the prominent enzymes that degrade different components of the extracellular matrix [ 33 ]. Among the various MMPs, MMP-2 (gelatinase A) and MMP-9 (gelatinase B) may play a significant role in tumor progression and invasion in GCT [ 20 , 34 ]. Bone matrix destruction via type-I collagen degradation by osteoclasts leaves behind denatured type-I collagen (gelatin), which MMP-2 and MMP-9 degrade, leading to osteolysis [ 35 , 36 ].…”

“…The pathway analysis also identified several subpathways that were affected, to a statistically significant extent, in the GCTB patients—including the inhibition of the matrix metalloproteases pathway (data not shown). A number of studies have shown that MMPs are also synthesized in tumor cells to regulate tumor invasion and metastasis in malignant tumors [ 34 , 38 , 39 ]. MMP1 and a disintegrin-like metalloproteinase with thrombospondin motifs 1 (ADAMTS1), shed epidermal growth factor (EGF)-like ligands to suppress OPG, indirectly leading to osteoclastogenesis [ 40 ].…”

“…Moreover, MMP13 can activate MMP9 and TGFβ to increase the local expression of RANKL at the tumor-bone interface in breast cancer [ 41 , 42 ]. The MMPs have also been shown to be associated with the local aggressive behavior of GCTB [ 20 , 34 , 43 ]. MMP-9 was therefore presumed to play an important role in this subpathway in GCTB.…”

Differential Expression of ADAM23, CDKN2A (P16), MMP14 and VIM Associated with Giant Cell Tumor of Bone

“…Generally, MMPs at the metastastic sites are expressed at a higher level compared to corresponding primary tumors 73. MMP-9 is expressed in giant cell tumor of bone and because normal cells such as fibroblasts do not synthesize MMP-9, the production of MMP-9 may be important for the migration of cells into the blood stream, lymphatic vessels or adjacent normal tissues 74. MMP-13 has been reported to accelerate bone remodeling and promotes proliferation while inhibiting apoptosis in human osteoblast-like cells, and its expression is upregulated in giant cell tumor of bone 75-77.…”