MMP14 – multicentric osteolysis-nodulosis-arthropathy spectrum

MMP14 (HGNC:7160) encodes membrane-type 1 matrix metalloproteinase (MT1-MMP), a key collagenase in extracellular matrix remodeling. Although multicentric osteolysis-nodulosis-arthropathy spectrum (MONDO:0018298) is primarily caused by biallelic MMP2 mutations, MT1-MMP deficiency in Winchester syndrome exhibits overlapping osteolytic and arthropathic features, supporting a shared defective collagen-remodeling spectrum (DECORS) (PMID:31218820). To date, no patients with biallelic MMP14 variants present a pure MONA phenotype, limiting direct genetic evidence.

In vivo, Mmp14 knockout mice display progressive postnatal growth impairment, osteopenia, joint destruction, and reduced bone density—phenotypes that recapitulate key MONA features and underscore MT1-MMP’s indispensable collagenolytic activity (PMID:15137053). These models demonstrate that loss of MT1-MMP yields osteolytic and arthropathic pathology essentially ‘‘uncompensated’’ by other MMPs, mirroring the human MONA clinical spectrum.

Taken together, the clinical overlap and murine models indicate that MMP14 contributes to MONA-like pathology via shared mechanistic pathways, though further human genetic studies are needed to confirm MT1-MMP as a primary MONO gene. Key take-home: MT1-MMP disruption yields osteolysis and arthropathy akin to MONA, highlighting collagenolytic pathways as therapeutic targets.

References

• American journal of medical genetics. Part A • 2019 • Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling. PMID:31218820
• Journal of cellular physiology • 2004 • MT1-MMP: a tethered collagenase. PMID:15137053

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