Possible role of matrix metalloproteinases (MMPs) in hyperostosis of intracranial meningiomas.

OBJECT: Although bone invasion and hyperostosis are common phenomena in patients with intracranial meningiomas, the basic pathomechanism is not fully understood. Based on an immunohistochemical study of surgically resected samples with hyperostosis, we postulate a possible mechanism of hyperostosis in patients with intracranial meningiomas. MATERIALS AND METHODS: Forty-six meningiomas were evaluated in this study. Twenty-six meningiomas associated with hyperostosis specimens served as the study group, and 20 meningiomas without any bony changes served as controls. An immunohistochemical staining technique was used to detect the expression of matrix metalloproteinase (MMP)-2, -9, and -13, membrane type (MT)1-MMP, estrogen receptor (ER), and progesterone receptor (PR) in the main tumor and hyperostotic portions of the studied samples. RESULTS: In the non-hyperostosis group, expression of MMP-13, MT1-MMP, and ER was significantly less than in the main tumor portion of hyperostotic meningiomas, while there was no difference in the expression of MMP-2 and -9 and PR in the main tumor between the two groups. In the hyperostosis group, the immunoreactivity of MMP-2 in the hyperostotic portion revealed a higher pattern of expression than the main tumor (p < 0.002). The expression of MMP-9, MT1-MMP, ER, and PR had relatively positive immunoreactivity in the main tumor portion (P < 0.05). CONCLUSIONS: Increased expression of MMP-13 and MT1-MMP in the tumor portion of hyperostosis of meningiomas might contribute to the initiation of osteolysis. Activated MMP-2 in hyperostotic lesions may change the physiological metabolism of the skull bone, thus playing an important role in hyperostosis formation.

Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2.

More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. To begin to define the role COX-2 plays in driving bone cancer pain, we used an in vivo model where murine osteolytic 2472 sarcoma cells were injected and confined to the intramedullary space of the femur in male C3HHeJ mice. After tumor implantation, mice develop ongoing and movement-evoked bone cancer pain-related behaviors, extensive tumor-induced bone resorption, infiltration of the marrow space by tumor cells, and stereotypic neurochemical alterations in the spinal cord reflective of a persistent pain state. Thus, after injection of tumor cells, bone destruction is first evident at day 6, and pain-related behaviors are maximal at day 14. A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow [MF. tricyclic; 0.015%, p.o.] from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.

Proteolysis involving matrix metalloproteinase 13 (collagenase-3) is required for chondrocyte differentiation that is associated with matrix mineralization.

Collagenases are involved in cartilage matrix resorption. Using bovine fetal chondrocytes isolated from physeal cartilages and separated into a distinct prehypertrophic subpopulation, we show that in serum-free culture they elaborate an extracellular matrix and differentiate into hypertrophic chondrocytes. This is characterized by expression of type X collagen and the transcription factor Cbfal and increased incorporation of 45Ca2+ in the extracellular matrix, which is associated with matrix calcification. Collagenase activity, attributable only to matrix metalloproteinase (MMP) 13 (collagenase-3), is up-regulated on differentiation. A nontoxic carboxylate inhibitor of MMP-13 prevents this differentiation; it suppresses expression of type X collagen, Cbfal, and MMP-13 and inhibits increased calcium incorporation in addition to inhibiting degradation of type II collagen in the extracellular matrix. General synthesis of matrix proteins is unaffected. These results suggest that proteolysis involving MMP-13 is required for chondrocyte differentiation that occurs as part of growth plate development and which is associated with matrix mineralization.

Localized cranial hyperostosis of meningiomas: a result of neoplastic enzymatic activity?

Cranial hyperostosis is a common secondary manifestation of intracranial meningiomas. This may occur with or without neoplastic invasion, apart or even remote from the growth. Alkaline phosphatase (AP) is one of many enzymes produced by meningiomas and is known to possess indirect ossifying properties. Meningiomatous cranial hyperostosis could possibly be mediated by a humoral mechanism. This hypothesis was tested using chemical and histochemical determination of the occurrence of the enzyme in a series of hyperostosing and non-hyperostosing meningiomas. In the hyperostosing type the content of AP was in average more than three times as high as in the non-hyperostosing type. The results thus are in favour of the induction hypothesis.