Why do some people with bone fractures heal quickly and others heal slowly? Of the 7 million fractures that occur in the United States every year, roughly 500,000 — or 7 percent — for unknown reasons don't heal in a timely manner. UCSF researchers are studying bone growth at the cellular and molecular levels in order to develop more effective clinical treatments and speed healing.
"It's not well understood why some patients heal faster than others," says Theodore Miclau, M.D., director of orthopaedic trauma and chief of Orthopaedic Surgery at San Francisco General Hospital (SFGH). "If we could just learn what makes infant bones heal so quickly and somehow bottle it, we likely could reduce healing times for everyone."
UCSF currently treats a high volume of bone fracture patients and has extensive experience in the repair of difficult fractures. "We have a very good understanding of osteobiologics and have a good handle on what works and what might not," Miclau says. "We are experts in internal fixation, so we know how to work with fractures that are difficult to stabilize properly."
Unlike other adult tissues, which heal by forming scar tissue, bone heals in one of two ways: stem cells from surrounding bone differentiate into cells that make new bone (intramembranous ossification), or stem cells first differentiate into a cartilage matrix, which is subsequently replaced by bone (endochondral ossification). This cartilage-to-bone process resembles the developmental process seen in fetal skeletogenesis, so researchers are studying how mesenchymal stem cells become cartilage and bone cells.
Miclau, along with UCSF principal investigators Celine Colnot, Ph.D., and Ralph Marcucio, Ph.D., is focusing on genes that regulate the development of cartilage and bone and how genetic mutations affect bone repair. Since there are known mutations that affect skeletal repair in mice, researchers can compare the healing process of tibial fractures among mice with various mutations. To better understand which stem cells create osteoblasts versus chondrocytes, researchers use genetic markers to track which stem cells from adjacent bones, bone marrow and surrounding soft tissue travel to the fracture callus.
"We are aiming to understand all stages of bone healing, particularly the early stages when stem cells are recruited to the fracture site to form bone and cartilage," says Colnot. "We want to better understand the normal healing process, so that we can understand how a genetic defect would affect the healing process."
Researchers are also studying other factors that affect the rate of skeletal healing: the severity of the fracture, the type of fracture (which bone and where in the bone), vascularization, inflammation, age, growth factors that regulate the recruitment of stem cells (such as bone morphogenetic protein, or BMP), and the differentiation process from stem cells to cartilage and bone cells.
Researchers recently published a study showing that one influence on cell differentiation is whether or not the fracture is stabilized. In a stabilized murine tibial fracture, stem cells differentiate directly into osteoblasts (bone). But when the fracture is unstable, stem cells differentiate into chondrocytes, creating a cartilage intermediate that is later replaced by bone. One hypothesis for this observation is that instability disrupts the formation of new blood vessels (angiogenesis), making it necessary to first create a cartilage scaffolding to provide the stability required for new blood vessels to grow.
Marcucio's work focuses on the effects of inflammation and age on fracture healing. Rather than the direct process of mesenchymal cell to cartilage to bone observed in fetal skeletogenesis, bone growth in adults requires an inflammatory response to jump-start the recapitulated embryological programs.
Using a technique called stereology, Marcucio assesses the rate of healing among mice of different ages. Not surprisingly, he found that younger mice healed more quickly than older mice. In one study, Marcucio replaced the bone marrow-derived stem cells in elderly mice with that of juvenile mice. The juvenile cells facilitated repair and rescued the delayed fracture healing seen in the elderly mouse.
Improving healing time has other positive ramifications. "The longer a person is in the hospital, the greater the chances of morbidity due to effects on the vascular and muscular systems and exposure to pathogens," says Marcucio. "If we can improve the healing rate in the elderly, we can decrease morbidity overall."
Since the orthopaedic clinic at San Francisco General Hospital is also a trauma center, many patients arrive with severe bone injuries that are accompanied by soft tissue injury and vascular damage. To study such damage, Marcucio developed a model to gauge the effect of ischemia on fracture healing in mice. He found that the model mimics observations seen in humans: ischemia leads to a decrease in cartilage and bone, an increase in adipose and fibrous tissue, and a dramatic decrease in the rate of healing. In severe cases, vascular injuries can lead to amputation.
"The goal is to have translational research capacity," says Miclau. "We want to go from the bench to bedside, and we have the opportunity to do this with patients who sustain traumatic injuries."
Looking toward the future, UCSF researchers are in the initial stages of developing human embryonic stem cells that produce bone and cartilage cells. They are aiming to recapitulate what occurs in embryonic stages of skeletal development in order to better understand how to stimulate fracture repair postnatally. A primary goal is to understand bone repair at the genetic level well enough to identify potential healing problems before they occur, and to tailor clinical treatment based on the genetic makeup of individual patients.
For more information, call Theodore Miclau at (415) 206-8812.
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