Clinical issue

Bone formation, remodeling and repair are important for skeletal function. Bone remodeling relies on maintaining a balance between bone formation and resorption. The dynamic bone structure is regulated by many bone tissue components, including the vasculature, the cells that deposite bone (osteoblasts), and the cells that resorb bone (osteoclasts). Bone repair recapitulates many of the pathways involved in normal bone formation and remodeling.

Disruption of the careful balance between bone formation and deposition leads to disease. Abnormal bone formation can result in malformed bones or ectopic bone formation. Too much bone formation causes osteopetrosis and too much bone resorption results in osteoporosis. Understanding the factors that regulate these processes would shed light on disorders of bone development, maintenance and repair, and may provide therapeutic targets.

Results

Matrix metalloproteinases (MMPs), which degrade extracellular matrix (ECM) proteins, and a cytokine that induces blood vessel growth, vascular endothelial growth factor (VEGF), work together with osteoclasts in bone formation, remodeling and repair. However, the integration of these different factors during endochondral ossification, a main process in bone growth, is not known. In this study, the authors analyze mice that lack MMP-9 and that also contain osteopetrotic mutations in genes that affect osteoclast development. MMP-9 targets the cartilage ECM and reduces VEGF bioavailability.

Homeostasis of the osteoclast population at the growth plate depends on the level of both MMP-9 and VEGF. Osteoclasts are key regulators of growth plate dynamics because they express MMP-9 and other factors that are necessary for cartilage and bone resorption. These results elucidate some of the functional relationships among the components that regulate vascularization during endochondral ossification.

Implications and future directions

This study shows that cartilage vascularization and endochondral ossification depend on the integrated functions of MMP-9 and VEGF, together with osteoclasts, to regulate cartilage ECM remodeling and vascular growth. It is possible that disorders of bone formation involve dysregulation of these processes. This knowledge can also help build models of fracture repair, which utilize endochondral ossification to form new bone, to determine whether modulation of these factors promotes new bone formation and facilitates fracture repair with good functional restoration.