Mechanisms of mechanically induced Osteoclastogenesis : in a novel in vitro model for bone implant loosening

Abstract

Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis.The majority of joint arthroplasties will last the whole lifetime. However, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. To avoid a revision, therefore, is the uttermost goal of modern orthopedics. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss.In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.The main goal of this thesis is to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?The first study focused on the creation and validation of a novel in vitro model for mechanical loading-induced bone degradation. This model simulates the mechanical (over)loading conditions around a loosening prosthesis, as observed in the clinics, and in animal models for mechanical induced osteolysis. Using the MLO-Y4 osteocyte-like cell line, we verified that osteocytes exposed to supraphysiological mechanical loading in our model induce differentiation of progenitor cells into osteoclasts by direct cell-to-cell communication and through the release of soluble factors. This was accompanied by the release of an increased concentration of nitric oxide and higher expression of membrane-bound RANKL, while the concentration of soluble RANKL was not altered. These findings confirm the successful translation of mechanical-induced bone loss to an in vitro model for bone implant loosening. Many people have supported me during my time as a Ph.D. student and I am deeply grateful. I want to highlight a few people specifically, as they contributed significantly to my success: Anna Fahlgren Thank you for giving me the opportunity to become part of your research team and guiding me to become a c...