Different roles of matrix metalloproteinase 2 in osteolysis of skeletal dysplasia and bone metastasis (Review)

Abstract

Matrix metalloproteinase 2 (MMP2) is a well-characterized protein that is indispensable for extracellular matrix remodeling and other pathological processes, such as tumor progression and skeletal dysplasia. Excessive activation of MMP2 promotes osteolytic metastasis and bone destruction in late-stage cancers, while its loss-of-function mutations result in the decreased bone mineralization and generalized osteolysis occurring progressively in skeletal developmental disorders, particularly in multicentric osteolysis, nodulosis and arthropathy (MONA). Either upregulation or downregulation of MMP2 activity can result in the same osteolytic effects. Thus, different functions of MMP2 have been recently identified that could explain this observation. While MMP2 can degrade bone matrix, facilitate osteoclastogenesis and amplify various signaling pathways that enhance osteolysis in bone metastasis, its role in maintaining the number of bone cells, supporting osteocytic canalicular network formation and suppressing leptin-mediated inhibition of bone formation has been implicated in osteolytic disorders caused by MMP2 deficiency. Furthermore, the proangiogenic activity of MMP2 is one of the potential mechanisms that are associated with both pathological situations. In the present article, the latest research on MMP2 in bone homeostasis is reviewed and the mechanisms underlying the role of this protein in skeletal metastasis and developmental osteolysis are discussed.

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

“…Conversely, in a bone MBC population unselected by molecular markers, dasatinib did not improve the progression-free survival (PFS), stressing the need for implementation of molecularly-defined patient cohorts (NCT00410813) [92]. Finally, TGFβ, CXCR4, and αvβ3 integrin are key mediators of breast cancer metastasis to bone (Table 2) [93][94][95][96]. Antagonists of these proteins are under investigation in preclinical models of metastatic breast cancer, showing accumulating positive data [97][98][99][100][101][102][103][104][105][106][107][108].…”

Multicentric Osteolysis, Nodulosis, and Arthropathy in two unrelated children with matrix metalloproteinase 2 variants: Genetic-skeletal correlations

“…Although defective MMP2 enzyme activity is closely linked to osteolysis and abnormal extracellular matrix and bone remodeling found in MONA syndrome, the exact mechanism by which these pathological changes are induced remains controversial. Correlating MMP2 enzyme activity with genotype-phenotype variability noticed in MONA syndrome may provide insights into the various suggested roles of MMP2 in health and disease, and may inspire future experimental animal research ( Li et al, 2021 ; Lieu et al, 2011 ).…”

Clinical Radiological and Molecular Profile of a Patient Affected With Multicentric Osteolysis Nodulosis and Arthropathy

“…Osteolysis is evident in advanced cases with narrowing and erosions of the interphalangeal joints, the collapse of the carpal rows, shortening and destruction of the tarsus [ 12 ]. Arthropathy may eventually extend to the hips, knees, elbows, spine and sacroiliac joints with similar changes of milder severity [ 4 ]. Long bones with thin cortices and associated osteopenia have also been reported.…”

“…The pathogenetic background of MONA is the MMP2 gene deficiency leading to complete loss of the MMP-2 activity, also known by the term gelatinase A or 72kDa type IV collagenase, the most widely expressed metalloproteinase [ 4 ]. It consists of four domains (Figure 9 ), with the catalytic domain being significant for its highly conserved region, both across species and different types of matrix metalloproteinases [ 18 ].…”

“…Therefore, the term “Winchester syndrome” is obsolete. MONA is characterized by excessive bone resorption (particularly of the carpal and tarsal bones), generalized osteoporosis, painless subcutaneous fibrocollagenous nodules on the palms and soles and progressive arthropathy manifested predominantly as joint swelling, pain, contractures and stiffness [ 4 ]. These phenotypic manifestations are caused by loss of function mutations within the MMP2 gene encoding matrix metalloproteinase-2 (MMP-2) [ 1 ].…”