Fight Aging!

Osteoporosis is the name given to the characteristic loss of bone mass and strength that occurs with age. In its later stages it becomes very dangerous, and bones can fracture even under normal load. Bone is a dynamic tissue, constantly restructured and rebuilt throughout life by the actions of osteoblasts responsible for creating the molecular structure of bone and osteoclasts responsible for breaking down that structure. At root, osteoporosis is an easy problem to visualize: the balance of activity slowly and systematically tips towards osteoclasts. The complexity of the problem lies in how and why that imbalance happens, and thus what might be the best strategy for the development of treatments. At present comparatively little can be done for patients, but that will hopefully change for the better in the years ahead.

Today's research materials discuss a new addition to existing potential approaches that might restore the balance between osteoblasts and osteoclasts, those that have been demonstrated in the laboratory in recent years. It is interesting in that the scientists involved don't yet know exactly why their basis for therapy works in animal models. That said, I think it fair to say that it probably falls into the category of increasing the activity of osteoblasts in order to restore the balance, while having all the appearance of a complex and indirect set of mechanisms that will take years to fully understand. Our biology is packed with complex and indirect mechanisms, which is one of the reasons why progress is always slower than we'd like.

Molecule Promoting Blood Vessel Growth in Bone Represents New Target for Osteoporosis Drugs

Researchers have shown that a substance, which is best known for spurring nerve growth, called SLIT3, both reversed the bone-weakening effects of osteoporosis and helped fractures heal when administered in mice. The research effort could fuel drug development efforts targeting the SLIT3 pathway in humans, enabling a new approach for blood vessel-directed therapy to treat bone loss, persistent fractures, and fragile bones. Existing drugs for osteoporosis work in one of two ways: Either they block the cells that destroy bone or they promote bone formation by cells called osteoblasts. "But only those promoting new bone formation will help you actually heal a bone fracture. Our findings have potentially demonstrated a third category: drugs that target blood vessel formation within bone, prompting new bone to form."

Researchers have investigation the cellular causes of osteoporosis in an effort to promote bone growth. Prior research using mice genetically engineered to lack an adaptor protein known as SHN3 showed that its absence conferred high bone mass. Building on that discovery, researchers decided to examine the resulting changes in bone blood vessels. They were surprised to find that osteoblasts secreted unchanged amounts of almost all known factors promoting blood vessel growth, but SLIT3 levels rose significantly. And when the mice were genetically altered to delete SLIT3, they exhibited low bone mass. "We next asked if we could use SLIT3 to treat mice with skeletal disease, especially osteoporosis and fracture healing. When we gave the rodents SLIT3, it reversed their osteoporosis and made their fractures heal faster and stronger. To my knowledge, this is the first example that we can develop a drug to treat bone disease in mice not by targeting the bone-forming cells, but instead by targeting special types of blood vessels that exist in bone."

Targeting skeletal endothelium to ameliorate bone loss

Recent studies have identified a specialized subset of CD31+ vascular endothelium that positively regulates bone formation. However, it remains unclear how endothelial tissue levels of these cells are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in the CD31+ subset of endothelial cells. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced the CD31+ subset population in the endothelium, resulted in low bone mass because of impaired bone formation, and partially reversed the high bone mass phenotype of Shn3-/- mice.

This coupling between osteoblasts and a subset of CD31+ endothelial cells is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.