Harnessing the Wnt inhibitor Sfrp4 to understand cortical bone biology

What is it about?

Cortical bone size and thickness are critical determinants of bone strength in several species including humans. Reduction in these parameters decreases bone strength and leads to fragility fractures. Despite the enormous clinical importance of cortical bone, its biology remains elusive. The periosteum, which covers the outer surface of cortical bone, houses stem cells that contribute to cortical bone expansion during growth, cortical bone homeostasis in the adult, and are required for fracture repair and for response to anabolic (bone building) drugs. While studies to identify and characterize periosteal stem cells are on the rise, local factors involved in establishing, maintaining, and influencing their behavior are still poorly understood. We have reported that loss of function mutations in Secreted Frizzled Receptor Protein 4 (Sfrp4) cause Pyle disease, a rare skeletal disorder with limb deformity characterized by flaring of the metaphysis (end of the bone) and decreased diaphysis diameter and thickness of cortical bone, the outer layer of bone. As a result, the bones of individual with Pyle disease are fragile and fracture easily. Given that Sfrp4 influences cortical bone homeostasis, we explored whether it regulates the periosteal stem cell niche. Our study provides the first report of a secreted local factor, Sfrp4, involved in the regulation of a specific population of periosteal stem cells; Cathepsin K (Ctsk)-lineage periosteal stem cells which possess self-renewal ability and multipotency. We show a central role for Sfrp4 in the regulation of Ctsk-lineage periosteal stem cell function and their response to bone injury and anabolic treatment.

Featured Image

Photo by Matt Artz on Unsplash

Photo by Matt Artz on Unsplash

Why is it important?

Investigations into the role of paracrine and local factors regulating periosteal stem cell expansion, maintenance and function might be of considerable help to identify specific drug targets that can increase cortical bone strength. This would be important for the treatment of skeletal diseases, where cortical thickness is markedly impaired, or severe osteoporosis where cortical fragility is present. Aiming to the translational potential of these cells, exploring their regulation in bone repair is of significance for the pursuit of stem cell-based therapies.

Perspectives