Seminar Series
Home → Seminar Series → Presentation

ICS import...
ICal Link

Friday October 20, 2017 -- Genetic Mouse Models of Knee Injury and Osteoarthritis: Integration with Human Studies

SMBB 2650, 11:45 am

speaker photo

Speaker: Linda Sandell, Mildred B Simon Professor, Washington University at St. Louis

Dr. Linda Sandell is the Mildred B. Simon Professor and Co Director of the

Musculoskeletal Research Center at Washington University in St. Louis. She

has been a leader in the field of orthopaedic research, pioneering the use of

molecular biologic techniques, large screening technologies, microscopy,

computational biology and genetics to study cell responses to cartilage cell

injury, the regulation of gene expression and osteoarthritis. Dr. Sandell was

President of the Orthopaedic Research Society and cofounder of the Women's

Leadership Forum. She was President of the Osteoarthritis Research Society

International (2010 2013), the Society for Matrix Biology and the Histochemistry Society. She has chaired three Gordon Conferences and founded

the Gordon Conference on Cartilage Biology and Pathology. Dr. Sandell has

been awarded the Kappa Delta Award for Basic Science Research by the American

Association for Orthopaedic Surgeons (1999), the Women's Leadership Forum

Award (2010) the Alfred R. Shands Jr, MD Award (2015), the Distinguished

Investigator Award (2016) by the Orthopaedic Research Society and the Lifetime

Achievement Award from the OARSI.

Presentation Abstract:

Osteoarthritis (OA) affects 50 million adults in the U.S.1 Far from being a wear and tear process primary OA is a chronic inflammatory disease that causes significant pain and suffering. There are limited treatment options and no disease modifying OA drugs (DMOADs). Hyaluronic acid and steroid injections are often used to treat pain and delay joint replacement; however, their efficacy is short lived, highly inconsistent, and without significant disease modifying effects. Joint injury is also a known predisposing factor for subsequent development of post traumatic OA (PTOA) and accounts for 12 of all OA; there is no treatment (including surgery) to prevent the development of PTOA. Several studies have documented a robust inflammatory response in the aftermath of joint injury that likely contributes to cartilage cell death and degeneration. Small animals provide a reproducible model system in which to test the effects of injury in the short term and the long term pathobiology of the development of osteoarthritis (OA). In addition, the effects of potential various treatments for events occurring during injury and OA can be tested. In this talk, I will focus on two models of osteoarthritis, (1) the destabilization of the medial tibial meniscal ligament (DMM) and (2) a non invasive impact injury. The DMM model has become the standard for many laboratories investigating the impact of specific gene mutations or knock out of specific molecules on the development and severity of OA. Many laboratories have used common inbred strains as OA models such as C57BL/6, DBA and MRL. We have taken an approach that allows us to inquire about the genetics of OA, through using recombinant inbred strains (RI) of mice and the advanced intercross (AI) of the strains LG/J and SM/J. The LG/J strain is a close relative of the MRL super healer mouse and heals its ear wounds well. The SM/J strain is a “non healer” mouse that does not heal ear wounds within a month. The RI and AI lines have members that are at the extremes of ear wound healing and span the range in between healing and non healing. Using these genetic models, we have demonstrated that healing of articular cartilage has a significant genetic component that is related to the ability to heal ear wounds in a positive manner (1). In contrast, the ability to heal cartilage is inversely related to the development of OA, thus individuals that heal poorly have a higher tendency to develop degenerative disease (2). These findings indicate that there are healing processes active in cartilage that likely to protect the cartilage from degeneration. In the model of non invasive cartilage injury in the mouse, we show early events that can be manipulated to potentially protect the joint from a degenerative response to the injury (3). Two important events are found to occur at these early times (1 to 14 days), apoptosis in the cartilage at the site of impact and a variable degree of proliferation in the synovium. We have also identified a different response in cells surrounding the direct impact zone. There is a significant difference in response of the synovium and cartilage if the impact forces are high enough to rupture the anterior cruciate ligament (ACL): the cartilage is damaged throughout the joint and ectopic calcifications form in the synovium. Recently, we have been able to abrogate the effects of injury by inhibiting inflammation and increasing autophagy by the inhibition of the transcription factor, NF kB (4).

These studies have been translated to humans where we have looked extensively for phenotypes in cartilage, ligament and meniscus in order to predict who will get OA after joint injury and identify targets for treatment (5, 6, 7).