MMP14-deficient extracellular matrix niche causes skeletal progenitor depletion and immune-mediated bone loss

Age-related bone loss, including osteopenia and osteoporosis, remains a major clinical challenge, with current therapeutic strategies largely limited to targeting bone resorption. New treatments are hindered by poor understanding of cell-intrinsic and microenvironmental drivers of age-related bone loss caused by impacting on the diverse cell populations within bone. We exploited the role of MMP14, a membrane bound metalloproteinase that serves as a key regulator of signaling pathways and the extracellular matrix (ECM) microenvironment. Using a conditional mouse model lacking MMP14 in chondrocyte-osteoblast lineage (Mmp14ΔHC), we found that young mice initially gained bone mass due to elevated PTH signaling from reduced PTH1R cleavage. Unexpectedly, this transitioned to severe osteopenia by adulthood. We identified two synergistic mechanisms: progressive depletion of skeletal progenitors, and aberrant crosstalk between mutant osteogenic cells and the immune system. Integrative multi-omics and functional assays revealed that MMP14 deficient osteoblasts aberrantly alter ephrin signalling, resulting in attraction of neutrophils causing elimination of osteoblasts. Collectively, these findings unveil a novel paradigm in which MMP14 functions in the ECM niche as a repellent of a neutrophil-driven program of osteoblast attrition to safeguard the osteogenic lineage from immune destruction. Our findings have direct implications for understanding inflammaging, age-related skeletal decline and the limitations of therapeutic PTH treatment for bone loss. Stabilizing the ECM or therapeutically disrupting neutrophil-osteoblast communication may offer promising strategies to preserve bone mass in aging and disease.