Cartilage remnants (purple) disrupt bones (pink) in MT1-MMP–deficient mice (right).

On page 661, Holmbeck et al. identify a new mechanism of cartilage remodeling. This quick remodeling system bypasses time-consuming steps to bone formation that are required in the previously known pathway.

In the well-known pathway to bone formation, a cartilage scaffold must be mineralized before it is degraded by osteoclasts and replaced with bone. But some bones seem to be formed without cartilage mineralization. Holmbeck et al. find that this process relies on the matrix metalloprotease MT1-MMP, which degrades unmineralized cartilage.

The authors examined bone formation in MT1-MMP–deficient mice, which have skulls that are misshapen by cartilage. They find that in wild-type mice this same cartilage is not mineralized, but rather expresses MT1-MMP before its removal and replacement with bone. Without the protease, the cartilage remains, and adult bone layers do not form correctly.

Cartilage leftovers were also found in joints and at bone–tendon interfaces. As the mice have a dwarf phenotype, the authors suggest that growth of limb bones (a mineralization-dependent process) must be accompanied by the remodeling of cartilage into ligaments and tendons. This could be done quickly by the MT1-MMP pathway, which avoids the mineralization step. Its speed is also well-suited to keeping up with the rapid growth of the skull that occurs after birth.

A few cells within the cartilage remnants expressed bone markers. Thus, some bone may be formed by differentiating cartilage cells rather than immigrating osteoblasts. If so, this hints at a mammalian version of metamorphosis—an MMP-dependent replacement of transient with definitive organs. ▪