Mice with MMP14 switched off in bone-forming cells grow bone faster than normal early in life, but in adulthood immune cells begin killing the cells that build it
Mice with MMP14 switched off in bone-forming cells grow bone faster than normal early in life, but in adulthood immune cells begin killing the cells that build it
On 9 October 2026, a group from the University of Hong Kong and the Max Planck Institute of Biochemistry in Martinsried published a preprint on mice with the MMP14 gene switched off in osteoblasts, the cells that build bone. Bone mass increases in young mice but declines in adults, leaving their bones fragile. The authors identified the specific signal behind this reversal: an excess of two receptors on bone cells that attracts immune cells called neutrophils. They blocked this signal with inhibitors in experiments on human cells in vitro.
MMP14 encodes an enzyme that cleaves other proteins at the cell surface and remodels the extracellular matrix, the dense network of collagen and other molecules in which tissue cells live. The researchers switched it off specifically in osteoblasts because disabling it throughout the body causes the mouse’s entire skeleton to break down. The enzyme is best known in cancer research: it was first described in 1994 as a protein on the surface of invasive tumour cells, and increased activity is associated with faster spread of breast and bowel cancers. In people with an inherited mutation that completely disables MMP14, skeletal breakdown begins in childhood. This rare condition, Winchester syndrome, causes bones in the hands and feet to be resorbed and joints to lose mobility.
In a 2023 paper, the same laboratory showed that MMP14 cleaves the parathyroid hormone receptor in osteoblasts, dampening the signal from this hormone, which regulates bone remodelling. Without MMP14, the signal is stronger and young mice gain bone mass. That study did not examine what happened later. The new study followed mice of the same model into adulthood and found a reversal: by 2–6 months, trabecular bone, the spongy bone inside the skeleton, loses volume and strength, while the dense outer bone remains unchanged.
The pool of slowly dividing skeletal stem cells becomes depleted. A label that fades with each cell division showed that almost none of these cells remained in the mutant mice. Meanwhile, immature neutrophils, which normally attack bacteria, accumulated in the bone marrow. Spatial analysis of the tissue showed that they clustered next to osteoblasts rather than being evenly distributed.
To identify the signal, the authors switched off MMP14 in human osteoblasts and examined the proteins they released. Without MMP14, the cells released excessive amounts of two receptors, EPHA2 and EPHB4, proteins that MMP14 normally cleaves. These receptors normally keep neighbouring cells at a distance, but in excess they attract neutrophils, which engulfed the osteoblasts in vitro. Drugs targeting EPHA2 and EPHB4 stopped this attraction. The authors describe this as a “chemical beacon” for neutrophils and call MMP14 a “central coordinator and protector”: it regulates the strength of the hormonal signal, maintains the stem cell pool and keeps these receptors under control. Losing all three functions makes adult bone fragile.
The authors connect their findings to the chronic low-grade inflammation of ageing and to the limited long-term effectiveness of teriparatide, an approved osteoporosis drug that acts through the same hormonal pathway. Brief pulses of this signal build bone, while continuous signalling can increase bone loss. A review of how bone cell niches work linked the waning effects of such drugs to their failure to restore a depleted stem cell pool. This mechanism suggests two therapeutic approaches: stabilising the matrix around osteoblasts or blocking their interaction with neutrophils.