Quantitative small‐animal surrogate to evaluate drug efficacy in preventing wear debris‐induced osteolysis

Abstract

Individuals who suffer from severe joint destruction caused by the various arthritidies often undergo total joint arthroplasty. A major limitation of this treatment is the development of aseptic loosening of the prosthesis in as many as 20% of patients. The current paradigm to explain aseptic loosening proposes that wear debris generated from the prosthesis initiates a macrophage-mediated inflammatory response by resident macrophages, leading to osteoclast activation and bone resorption at the implant interface. No therapeutic interventions have been proved to prevent or inhibit aseptic loosening. The development of therapeutic strategies is limited due to the absence of a quantitative surrogate in which drugs can be screened rapidly in large numbers of animals. We have previously described a model in which titanium particles implanted on mouse calvaria induce an inflammatory response with osteolysis similar to that observed in clinical aseptic loosening. Here, we present new methods by which the osteolysis in this model can be quantified. We determined that 6-8-week-old mice in normal health have a sagittal suture area of 50 (+/-6) microm2, which contains approximately five osteoclasts. As a result of the titanium-induced inflammation and osteolysis, the sagittal suture area increases to 197 (+/-27) microm2, with approximately 30 osteoclasts, after 10 days of treatment. The sagittal suture area and the number of osteoclasts in the calvaria of sham-treated mice remained unchanged during the 10 days. We also determined the effects of pentoxifylline, a drug that blocks the responses of tumor necrosis factor-alpha to wear debris, and the osteoclast inhibitor alendronate. We found that both drugs effectively block wear debris-induced osteolysis but not osteoclastogenesis. In conclusion, we found the measurements made with this model to be reproducible and to permit quantitative analysis of agents that are to be screened for their potential to prevent aseptic loosening.

Differences in the cytokine profiles associated with prostate cancer cell induced osteoblastic and osteolytic lesions in bone

“…It has been difficult to define the pathophysiology of metastatic prostate cancer in bone because of the inability to produce osteoblastic lesions in vivo [19,42,43]. We have established an intratibial injection model in SCID mice in which both osteolytic and osteoblastic lesions can be reliably produced with human prostate cancer cell lines.…”

“…Four tibias from each time point were analyzed in this manner. Statistical analysis was done by the KruskallLWallis nonparametric rank test method [43].…”

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

“…For instance, osteolysis is correlated with higher wear rates, 4,5 abundant wear particles are associated with periprosthetic tissues recovered during revision surgery, [6][7][8] and implantation of wear debris can trigger osteolysis in animal models. [9][10][11][12][13][14] A common theme which has emerged is that a critical initiating event in wear debris action is activation of pro-inflammatory cytokine signaling within periprosthetic macrophages, which in turn leads to an imbalance in the levels of the key osteoclastogenesis regulators RANKL and OPG. [15][16][17][18] However, the precise molecular and cellular pathogenesis whereby prosthetic wear debris leads to osteolytic bone loss remains unclear.…”

“…Evidence in favor of an important role for pro-inflammatory cytokines in osteolysis include the observations that wear particles can induce production of these cytokines in both cultured macrophage lineage cells 13,19 -21 and murine models of osteolysis, 9,10,12,13 and that blockade of pro-inflammatory signaling can ameliorate disease in these animal models. 13,22,23 However, the role of pro-inflammatory cytokines in human disease has been less well characterized.…”

Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease

“…To determine mean sagittal suture area, soft tissues in the suture area on the 3 H&E sections for each mouse were traced manually and quantified with the OsteoMeasure software (Osteometrics, Atlanta, GA). 35 The bone surface in each suture area was similarly traced and the suture perimeter averaged. The number of TRAP ϩ multinucleated cells apposed to bone surfaces in each suture area was then enumerated and expressed either as osteoclasts per millimeter of sutural bone perimeter or per square millimeter of suture area.…”