Detecting Particle-Induced Osteolysis by Micro-CT Analysis Student: Bailey Lindenmaier Mentors: Dr. Russell Turner & Dr. Urszula Iwaniec Skeletal Biology Lab

Overview Relevance of particle-induced osteolysis Obesity and factors that contribute to increased risk of osteolysis Animal model for particle-induced osteolysis Aims Results and conclusions

Prosthetic Joint Replacement Approximately 600,000 joint (hip or knee) replacements are performed annually Conditions that lead to replacement surgery: Osteoarthritis Osteonecrosis Broken bone Bone tumor Joint replacement surgeries allow for an improved quality of life The new joint may loosen resulting in pain and require further operations

Particle-Induced Osteolysis Title: particle induced osteolysis

“Concerns Over ‘Metal on Metal’ Hip Implants” March 3, 2010 “Concerns Over ‘Metal on Metal’ Hip Implants” By BARRY MEIER May 10, 2011 “Hip Makers Told to Study More Data” By BARRY MEIER June 25, 2011 “In Medicine, New Isn’t Always Improved” By BARRY MEIER FDA has said that there is a major concern and that joint replacements need to be reevaluated August 22, 2011 “Hip Implant Complaints Surge, Even as the Dangers Are Studied” By BARRY MEIER and JANET ROBERTS

Obesity BMI > 30 kg/m2 Excess body fat Obesity is associated with: Increased joint replacement Increased failure rates Normal Overweight Obese Amenoric women and ob/ob mice with leptin = increase in osteocalcin which means bone formation

von Knoch Study Decrease in particle-induced osteolysis in obese (ob/ob) mice. von Knoch M, Jewison DE, Sibonga JD, Turner RT, Morrey BF, Loer F, Berry DJ, Scully SP. Biomaterials. 2004; 25(19):4675-4681. Studied particle-induced osteolysis in ob/ob mice, an animal model for obesity Surprisingly ob/ob is resistant to osteolysis Is leptin deficiency responsible? Adipokine Pleiotropic hormone vs. Amenoric women and ob/ob mice with leptin = increase in osteocalcin which means bone formation

Model of Obesity: ob/ob Mice Leptin Deficient Giving back leptin corrects for phenotypic abnormalities Hyperphagic Rapidly become obese by four weeks of age

Histological section of a mouse calvaria experiencing osteolysis Aim 1)Verify results obtained by von Knoch Leptin-deficient ob/ob mice are resistant to particle-induced osteolysis To Date: Only histological data has been collected Difficult to define a representative “region of interest” Leptin enhances production of bone and immune regulatory cytokines pathological bone resorption Histological section of a mouse calvaria experiencing osteolysis 2)Micro-computed tomography is a viable method to rapidly quantify particle- induced osteolysis in three dimensions

Study Design 4 week old ob/ob and WT mice Polyethylene particles (a major component of artificial joints), mean diameter 5 µm, were inserted directly over the calvarial periosteum of both parietal bones 2 week duration Fed ad libitum, 12hr light/dark cycle, singly housed Electron microscope of polyethylene particles

Group Treatment 1 WT 2 WT + Particle 3 ob/ob 4 ob/ob + Particle

µ-CT Analysis Micro - Computed Tomography Fires an x-ray beam at a rotating specimen X-ray attenuation is measured. Produces 3D images for structural measurements

Micro-CT Imaging of Parietal Bone 4 1 WT + Particles ob/ob + Particles WT ob/ob Group 1 Group 2 Group 3 Group 4

Osteolytic Score of Particle-Induced Osteolysis ob/ob WT (Severe) (None)) Two-way ANOVA Genotype (P = 0.028) Treatment (P < 0.001) Genotype x Treatment (P = 0.028) * * * P < 0.01 within genotype

Conclusions Micro-computed tomography is an effective method to identify and measure osteolysis ob/ob mice experience less particle-induced osteolysis than WT mice Lack of leptin signaling? Up regulated inflammatory cytokines?

On the Horizon Lab is in process of determining if leptin treatment will enhance particle-induced osteolysis in the ob/ob mice. To explore potential mechanisms through which leptin affects osteolysis. Dose-dependency Target therapies to reduce local leptin

Acknowledgements Howard Hughes Medical Institute Center of Healthy Aging Research, Oregon State University Skeletal Biology Lab Dr. Russell Turner Dr. Urszula Iwaniec Dawn Olson Kenneth Philbrick Kevin Ahern