OREF-funded study indicates different processes are at work

Posttraumatic arthritis (PTA) can develop after acute joint injury, a meniscal or ligament tear, or an intra-articular fracture, even with optimal treatment. Despite its frequency—an estimated 10 per­cent to 15 percent of patients diagnosed as having osteoarthritis actually have PTA—this painful condition has not attracted much attention from researchers.

One investigator who is focused on PTA is Joseph Borrelli Jr., MD, a trauma surgeon and professor and chairman of orthopaedic surgery at the University of Texas Southwestern Medical Center in Dallas.

“Ten years ago, the issue of posttraumatic arthritis wasn’t really being addressed by anyone,” Dr. Borrelli said. “The mechanism by which it occurs still has not been fully delineated.”

Investigators widely believe that joint trauma results in primary cartilage damage, which is one factor that leads to irreversible tissue degeneration. It is unclear, however, whether these changes to the articular cartilage result directly from mechanical trauma or from a process in the cartilage such as cellular death.

With research funding from the Orthopaedic Research and Education Foundation (OREF), Dr. Borrelli developed an animal model of PTA so he could study in vivo cartilage changes after mechanical injury. His preliminary findings may elucidate the biochemical mechanism connecting joint injury and development of arthritis.

Finding the mechanism
“If you knew how PTA develops and could prevent it, you could make a huge impact on a very important segment of our population,” Dr. Borrelli said. “PTA generally occurs following trauma in people between 18 and 45 years, which is often one of the most productive parts of their lives.”

An OREF Career Development Award enabled Dr. Borrelli to study what happens to the articular cartilage using an open joint injury model in the rabbit. This model, he said, should apply to any site that has articular cartilage, including the knee, hip, ankle, wrist, elbow, shoulder, and facet joints of the spine.

In Dr. Borrelli’s model, a pendulum-type device strikes the rabbit’s right medial femoral condyle at either low impact (70 percent of the condyle’s fracture threshold) or high impact (90 percent of the fracture threshold). Intra-articular fractures are avoided to minimize the addition of confounding factors that cause arthritis. As a control, researchers opened the left leg of each rabbit, but did not strike the medial femoral condyle to ensure that the incision itself was not the cause of cartilage degeneration.

Histologic assessment, immunohistochemical assessment, and microcomputed tomography (micro-CT) was performed on bone and cartilage specimens shortly after the experiment, at 1 month, and at 6 months.

Within the first month after injury, thinning of the cartilage consistent with arthritis was found at both impact levels, especially at high impact, in the area of the injury. The thinning worsened over the 6 months of the study.

Micro-CT also found increased bone volume, which causes stiffening of the underlying bone, diminishing its shock absorption capacity and likely predisposing the injured cartilage to further degeneration. An additional experiment found that excessive new bone was forming directly beneath the injury site. No cartilage or bone changes were found in the lateral femoral condyle of the impacted leg, nor in the contralateral limb, proof that the changes seen were the direct result of the impact.

Unexpected finding
Surprisingly, chondrocytes in the animals’ impacted legs did not necessarily die but became metabolically inactive within the first month after injury. Production of several key substances—including bone morphogenetic protein (BMP)-2, type II collagen, and proteoglycan—needed to maintain normal structural integrity of the cartilage significantly decreased.

“Those of us studying PTA believe it has a different mechanism by which the cartilage deteriorates compared with osteoarthritis,” he said. “In the early stages of osteoarthritis, chondrocytes overproduce BMP-2 and the other compounds they need in an effort to maintain the cartilage. When the chondrocytes burn out, the cartilage starts to wear away. In our PTA model, the cells became inactive almost immediately after injury and stopped producing these compounds.”

Dr. Borrelli concluded, “Arthritis may develop either way, but how it develops appears to be different.”

Furthermore, the PTA model appears to show that a single impact—even without a fracture—can shut down the chondrocytes.

“This may explain why PTA sometimes develops very quickly in patients after an injury, regardless of how successful we were in fixing the fracture,” Dr. Borrelli said. “PTA can develop in just 6 months—unlike osteoarthritis, which may take up to 60 years to develop.”

Because PTA does not develop in every patient who sustains an injury, however, careful fracture repair and avoidance of postoperative complications are still important preventive steps.

Preventing PTA
The finding that chondrocytes are alive early after injury could mean that orthopaedic surgeons may one day be able to rescue the cartilage before PTA develops or to slow the progression of the disease.

This may be possible by stimulating the “sleeping” chondrocytes to produce vital substances, such as BMP-2, which is the next step in Dr. Borrelli’s research.

Animal research using a different injury model has shown that BMP-2 and osteogenic protein (OP)-1 (also called BMP-7) can stimulate chondrocytes following injury. Both proteins are commercially available, although neither has been extensively studied or is yet approved by the U.S. Food and Drug Administration for this use.

“We hope to be able to stimulate the chondrocytes, using either a local injection or a systemic delivery system, to repair the damage,” said Dr. Borrelli. “But first we need to more fully define the mechanism by which cartilage deteriorates after injury.”

Dr. Borrelli hopes that PTA research will eventually enable major advances in treatment, as have occurred in the past decade with research in rheumatoid arthritis.

With his OREF-funded research, Dr. Borrelli hopes to have a foundation for obtaining federal funding to apply his research on a larger scale.

The opportunity to do research also helps him in his clinical practice. “It enables me to think about things that I’m seeing in the operating room and certainly seeing afterward in my patients, and then try to make some sense of that through basic science research,” he said.

Kathleen Louden is a contributing writer for OREF and can be contacted at communications@oref.org