Study suggests link between gut microbiome and joint health in obese mice
By Brittany Wilson
The gastrointestinal microbiome is currently a hot topic of research concerning serious diseases affecting large portions of the world’s population. It has been implicated in a variety of conditions such as asthma, obesity, and now osteoarthritis (OA). Recent work presented at the Orthopaedic Research Society 2017 Annual Meeting by Eric Schott, Robert Mooney, Steve Gill, Michael Zuscik and colleagues at the Center for Musculoskeletal Research at the University of Rochester Medical Center have shown that prebiotic manipulation of the gut microbiome may lead to decelerated progression of OA. The work utilized a mouse model of high fat diet-induced obesity along with an injury to the medial meniscus to initiate degeneration in the knee. Specifically, mice that were fed a high fat diet along with the prebiotic supplement, oligofructose, demonstrated reduced systemic inflammation and decelerated cartilage degeneration after meniscal injury.
Prebiotic supplements are intended to nourish and support particular bacterial strains present in the gut. This is in contrast to probiotic supplements, often found and discussed in yogurt, which attempt to confer specific bacterial cultures directly to the gut. In the experiment reported by Schott et al, it is believed that an increased abundance of microbes from the genus Bifidobacterium, resulting from prebiotic supplementation, may be responsible for the reduction in systemic inflammation and deceleration of OA symptoms.
A link between altered gut microbiome and systemic inflammation in obesity has previously been established; however, the mechanisms by which the gut microbiome affect joint health are still largely unknown. Schott speculates that either the increased numbers of Bifidobacteria are crowding out other inflammation-inducing strains, or that these Bifidobacteria are producing a metabolic byproduct(s) that has positive effects on the host, including supporting healthy joints. Answers to these questions may provide the first evidence connecting the gut microbiome to joint health.
Future work in the Zuscik lab will further investigate the gut microbiome in OA, without obesity as a comorbid factor. They hope to determine if OA patients have an altered gut microbiome compared to healthy individuals. If the microbiome is altered in OA, perhaps correction of the abnormalities will protect against or even reverse OA symptoms. Additional clarification of the gut-joint connection may lead to novel therapeutic strategies involving the manipulation of the intestinal microbial community to treat or prevent OA. Results from this work may help to address a clinical problem of enormous scope for which no effective disease-modifying therapy has been established.
The Sport Professional Orthopaedic Research Tool (SPORT) group assesses long-term effects in recent study
By Brittany Wilson
Professional athletes are highly susceptible to orthopaedic injuries due to the inherent physical nature of their work. While types of orthopaedic procedures and their associated recovery times are well-documented, empirical evidence assessing athlete performance after returning to play is quite limited.
Wellington K. Hsu, the Clifford C. Raisbeck Distinguished Professor of Orthopaedic Surgery at Northwestern University in Chicago is working to change that. His research team, the Sport Professional Orthopaedic Research Tool (SPORT) group, has been compiling a database to elucidate how orthopaedic procedures affect professional athletes of four major athletic associations: National Basketball Association (NBA), National Football League (NFL), Major League Baseball, and National Hockey League (NHL).
In 2011, the SPORT group assessed the outcomes of professional athletes from these four professional athletic associations who underwent surgery to repair a herniated lumbar disc. While the return to play rate was over 80% for athletes diagnosed with lumbar disc herniation, surgical repair of a herniated lumbar disc led to different outcomes in athletes based upon sport and experience level at the time of diagnosis. The findings from the Professional Athlete Spine Initiative highlight the need for additional studies assessing orthopaedic procedures for other injuries in professional athletes. Hsu adds, “It is likely that different types of injuries will lead to different outcomes in an athlete depending on the relative demands of each sport.”
The SPORT group has published studies assessing post-injury outcomes in professional basketball and football players. It was found that NBA players who had treatment for a hand or wrist fracture had the greatest return to play rate (98.1%), while those who underwent Achilles tendon repair had the lowest rate (70.8%). Achilles tendon repair and arthroscopic knee surgery led to a greater decline in post-operative performance outcomes and shorter career lengths in NBA players than other orthopaedic procedures. Assessment of performance outcomes in NFL players undergoing various orthopaedic procedures revealed that anterior cruciate ligament repair, Achilles tendon repair, and patellar tendon repair have the greatest effect on an NFL career.
Continued research by the SPORT group will include the assessment of hockey and baseball players.
In the United States, there are hundreds of thousands of amputees caused by trauma alone, and this number is expected to steadily rise as the population continues to grow.
Although socket-type prostheses are the most common, an optimal fit is difficult to achieve, often resulting in painful sores and other complications. Socket prosthetic devices also lack stability due to their inefficient integration with the body. This has led to an increased interest in improving the methods of attaching prosthetic devices to amputees.
One approach gaining popularity is the integration of a prosthetic implant directly with the amputees’ residual bone. This implant penetrates the skin to connect to a prosthetic limb. This direct prosthesis-bone interface allows for a more stable connection to the skeleton enabling greater control of the prosthesis and heightened sensory feedback of the environment while eliminating pain and sores experienced with socket prosthetics.
Although this type of prostheses offers promise, it is not without issues. “Unfortunately, these implants face several challenges which prevent their approval by the FDA outside of clinical trials,” explains David Ruppert, a researcher at the University of North Carolina at Chapel Hill and North Carolina State University. “The implants need to conform to patients’ specific anatomy; the skin penetration of the implant is susceptible to infection; and a 12 month rehabilitation period is required to produce a stable bone-implant interface.” Ruppert, along with his collaborators, are currently conducting research focused on addressing the patients’ specific anatomy as well as reducing the lengthy rehabilitation period.
“Our findings showed that rough textured implants created though 3D printing exhibit stronger bone integration than machine threaded counterparts,” says Ruppert. “This highlights the superiority of using 3D printing to not only produce custom designs, but also custom surfaces that interface with amputees’ residual bones.”
In addition, the team of scientists found that vibrating the whole body at low-magnitude and high-frequency at a specific amplitude range can increase bone density around the implant. These results demonstrate that whole-body vibration can be used to minimize bone loss during rehabilitation.
Previous work investigating fracture healing has indicated that low intensity pulsed ultrasound (LIPUS) can be beneficial to bone healing through as yet undetermined mechanisms. It is also unclear if sufficient levels of the stimulus can reach the inner surfaces of the bone to stimulate bone healing. “In our future work we’ll investigate the effects of LIPUS on bone integration into an implant to see if further improvement on the rehabilitation period can be made,” Ruppert explains. “We will also investigate whether there is a cumulative effect of using LIPUS in conjunction with vibration. Finally, we aim to validate additional methods of 3D printing to the one used in our study to improve the level of detail in implant design. Ultimately, we hope to improve the quality of life for amputees.”
Ruppert’s work was presented at the 2016 Annual Meeting of the Orthopaedic Research Society.
As we get older, our ability to heal after breaking a bone declines. This leads to a prolonged healing time and, in some instances, the bone does not heal at all, resulting in significant mobility impairments. While it is not fully understood how aging alters our capacity for fracture repair, Linda Vi, along with a team of researchers at the University of Toronto has been studying mice in the hopes of gaining a better understanding of how bone ages. The team of scientists has recently shown that old mice retain the capacity for bone repair when they are exposed to a circulation of youthful blood.
“Bone is a remarkable organ in that it has the capacity to regenerate itself,” Vi explains. “It is a highly dynamic structure, laying down new bone and removing old bone, in response to changes on the forces applied to them.” However, when people age, there is a dysregulation of this process. Our bones become easier to injure and are more difficult to heal. While we do not fully understand how aging alters this bone healing process, aging is associated with a decline in the abundance and activity of osteoblasts, or our bone-forming cells, during fracture healing.
The group of researchers is interested in understanding how aging alters the recruitment and activation of these osteoblasts during repair. They wondered whether old cells can be stimulated to make bone. “In our study,” explains Vi, “we have identified that these improvements in fracture repair are derived from a type of immune cell, called macrophage. We show that different subtypes of macrophages are present within the healing bones of young and old mice, and that these young macrophages produce ‘youthful factors’, which are greatly diminished in the old macrophage population. When old mice were given just these young macrophages, the older animals showed remarkable improvements in both the pace and quality of fracture repair.”
What’s next for this group? Vi and her team are currently testing some of the ‘youthful factors’ identified in their study to learn more about their ability to promote fracture healing in old mice. “The long term goal of our work,” she explains, “is to be able to develop these ‘youthful factors’ into a potential therapy in the treatment of fracture healing for older individuals.”
Vi’s work was presented at the 2016 Annual Meeting of the Orthopaedic Research Society.
Osteoarthritis is a disease that affects millions of people. Osteoarthritis affects the entire joint, progressively destroying the articular cartilage, including damage to the bone. Patients suffering from osteoarthritis have decreased mobility as the disease progresses, eventually requiring a joint replacement since cartilage does not heal or regenerate. According to a 2010 Cleveland Clinic study, Osteoarthritis is the most prevalent form of arthritis in the United States, affecting more than 70% of adults between 55 and 78 years of age.
“My father was in major pain from his osteoarthritis,” explains Riccardo Gottardi, a scientist at the University of Pittsburgh supported by a Ri.MED Foundation fellowship. “He was in so much pain that he had to undergo a double hip replacement followed by a knee replacement soon afterwards. I could see the debilitating and disabling effects the disease had on him, as he was restricted in his mobility and never fully recovered even after surgery. This was very different from the person that I knew, who had always been active and never shied away from long hours of work in his life – he just could not do it anymore.”
For scientists like Gottardi, a key obstacle in understanding the mechanisms of osteoarthritis and finding drugs that could heal cartilage, is that cartilage does not exist separately from the rest of the body. Cartilage interacts with other tissues of the joint, especially with bone. Bone and cartilage strongly influence each other and this needs to be taken into account when developing new drugs and therapies.
Gottardi and a team of researchers at the Center for Cellular and Molecular Engineering, led by Dr. Rocky Tuan, have developed a new generation system to produce engineered cartilage, bone and vasculature, organized in the same manner as they are found in the human joint. This system is able to produce a high number of identical composite tissues starting from human cells. The team will use this system to study the interactions of cartilage with vascularized bone to identify potential treatments for osteoarthritis.
The team’s research has two main objectives: to help understand how cartilage interacts with the other joint tissues, especially bone; and to help develop new effective treatments that could stop or even reverse the disease. Their patent pending system is the first of its kind, and offers a number of advantages including the use of human cells that replicate native tissues. This system more closely matches the effects on humans than standard animal testing could achieve.
The team of scientists is further developing their system to produce tissues composed of more and different cell types that could better replicate the human joint. They have also started a number of collaborations with other research groups and companies that are interested in using the system to investigate other joint diseases and to test their product.
“After seeing what my father went through,” says Gottardi, “I decided that I did not want to just watch by working on diagnostics, but rather, I wanted to be able to do something about osteoarthritis and contribute to the improvement of current treatment options.”
Gottardi’s work was presented at the 2016 Annual Meeting of the Orthopaedic Research Society.