A New Hybrid Molecule Directs Mesenchymal Stem Cells To Increase Bone Formation and Bone Strength


Osteoporosis is a disease that affects bone and results from aging or a lack of estrogen. Osteoporotic bone is less dense than normal bone, and the loss of bone density leads a tendency for bones to fracture easily. In particular, the bones of the wrist, hip, or back can fracture and fortunately, bone scans can help diagnose osteoporosis earlier and earlier.

Typically, osteoporosis is treated by prescribing a group of drugs collectively known as the “bisphosphonates.” These drugs have a common mode of action that includes one of the two cells involved in bone remodeling and healing. Cells called “osteoblasts” act as bone-building cells. Osteoblasts come from bone marrow (the squishy stuff inside your long bones), and they make new bone called “osteoid” that consists of a protein called “collagen” and a few other proteins. Then they deposit calcium and other minerals onto the protein matrix. After filling a cavity with bone, the osteoblasts flatten and line the cavity where they regulate the movement of calcium into and from the bone. Some of the osteoblasts become trapped in the bone while it is being deposited and they extend long extensions and become known as “osteocytes.” Osteocytes monitor the bone health and signal when there are breaks in the bone.

Osteoblasts

The second cell involved in bone remodeling is the osteoclast. Osteoclasts are large cells with many nuclei that dissolve existing bone. When a bone is broken, the osteocytes signal to each other and recruit osteoclasts to the site of the bone break. Osteoclasts dissolve the broken bone, and this gives room to the osteoblasts so that they can deposit new bone. The activities of both cell types are essential for bone healing and remodeling. The activities of these two cell types are also very carefully regulated.

When osteoblast activity is too high, a disease called “osteopetrosis” ensues, and this disease squeezes out the bone marrow and prevents the synthesis of enough blood cells. When osteoclast activity is too high, osteoporosis ensues, and bone density decreases so that fractures are a genuine possibility. Bisphosphonates bind to the surface of osteoclasts and prevent them from destroying bone. However, since both osteoclasts and osteoblasts are required for proper bone health, bisphosphonates essentially cause bone deposition to come to a stand-still. For this reason, some people experience increased fractures on bisphosphonates. What is needed is a treatment that can reverse the thinning of the bones and increase bone density.

A very interesting study led by scientists at the UC Davis Heath System examined a mouse model of osteoporosis to test the efficacy of a new treatment that can potentially increase bone density. If the results of this study are confirmed by further work, it could revolutionize osteoporosis treatments. The UC Davis team developed a novel technique to enhance bone growth by injecting a specific molecule into the bloodstream that guides mesenchymal stem cells to bone surfaces. Once there, these stem cells differentiate into osteoblasts, which promote bone growth.

Wei Yao, the principal investigator and lead author of the study said: “There are many stem cells, even in elderly people, but they do not readily migrate to bone. Finding a molecule that attaches to stem cells and guides them to the targets we need is a real breakthrough.”

Even though there is a great deal of research to develop stem cell-based treatments for many conditions and injuries that range from peripheral artery disease and macular degeneration to blood disorders, skin wounds and diseased organs, directing stem cells to travel and adhere to the surface of bone for bone formation has been among the elusive goals in regenerative medicine. To accomplish this, Yao and others used a unique hybrid molecule, LLP2A-alendronate that consists of two parts: the LLP2A part that attaches to mesenchymal stem cells in the bone marrow, and a second part that consists of the bone-homing bisphosphonate-class drug, alendronate (trade name – Fosamax). LLP2A-alendronate was injected into the bloodstream, and it bound to the cell surfaces of mesenchymal stem cells in the bone marrow and directed those cells to the surfaces of bone, where the stem cells carried out their natural bone-formation and repair functions.

The study shows that stem-cell-binding molecules can be exploited to direct stem cells to therapeutic sites inside an animal. One author even said. It represents a very important step in making this type of stem cell therapy a reality.

Twelve weeks after the LLP2A-alendronate was injected into mice, bone mass in the femur (thigh bone) and vertebrae (in the spine) increased and bone strength improved compared to control mice who did not receive LLP2A-alendronate. The treated mice were older mice that normally showed a particular degree of bone loss, but with this treatment, they had improved bone formation, as did those that were models for menopause.

Even though alendronate is commonly prescribed to women with osteoporosis to reduce the risk of fracture, it was used in this study because it goes directly to the bone surface, where it slows the rate of bone breakdown. The alendronate dose in this experiment was very low and was, therefore, unlikely to have inhibited LLP2A’s therapeutic effect.

Co-investigator on the study and director of the UC Davis Musculoskeletal Diseases of Aging Research Group, Nancy Lane, noted: “For the first time, we may have potentially found a way to direct a person’s own stem cells to the bone surface where they can regenerate bone. This technique could become a revolutionary new therapy for osteoporosis as well as for other conditions that require new bone formation.”

Mesenchymal stem cells from bone marrow induce new bone remodeling, which thicken and strengthen bone. The potential use of this stem cell therapy is not limited to treating osteoporosis, since it may prove invaluable for other disorders and conditions that could benefit from enhanced bone rebuilding, which includes bone fractures, bone infections or cancer treatments.

Jan Nolta, professor of internal medicine, an author of the study and director of the UC Davis Institute for Regenerative Cures opined, “These results are very promising for translating into human therapy. We have shown this potential therapy is effective in rodents, and our goal now is to move it into clinical trials.”

Paper citation: “Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass;” Min Guan, Wei Yao, Nancy E Lane et al.; Nature Medicine, 2012; DOI: 10.1038/nm.2665.