Mechanically Induced Periprosthetic Osteolysis: A Systematic Review.

BACKGROUND: Peri-prosthetic bone loss can result from chemical, biological, and mechanical factors. Mechanical stimulation via fluid pressure and flow at the bone-implant interface may be a significant cause. Evidence supporting mechanically induced osteolysis continues to grow, but there is no synthesis of published clinical and basic science data. QUESTIONS/PURPOSES: We sought to review the literature on two questions: (1) What published evidence supports the concept of mechanically induced osteolysis? (2) What is the proposed mechanism of mechanically induced osteolysis, and does it differ from that of particle-induced osteolysis? METHODS: A systematic review was performed of the PubMed and Web of Science databases. Additional relevant articles were recommended by the senior authors based on their expert opinion. Abstracts were reviewed and the manuscripts pertaining to the study questions were read in full. Studies showing support of mechanically induced osteolysis were quantified and findings summarized. RESULTS: We identified 49 articles of experimental design supporting the hypothesis that mechanical stimulation of peri-prosthetic bone from fluid pressure and flow can induce osteolysis. While the molecular mechanisms may overlap with those implicated in particle-induced osteolysis, mechanically induced osteolysis appears to be mediated by distinct and parallel pathways. CONCLUSIONS: The role of mechanical stimuli is increasingly recognized in the pathogenesis of peri-prosthetic osteolysis. Current research aims to elucidate the molecular mechanisms to better target therapeutic interventions.

A method for isolating high quality RNA from mouse cortical and cancellous bone.

The high incidence of fragility fractures in cortico-cancellous bone locations, plus the fact that individual skeletal sites exhibit different responsiveness to load and disease, emphasizes the need to document separately gene expression in cortical and cancellous bone. A further confounding factor is marrow contamination since its high cellularity may effect gene expression measurements. We isolated RNA from cortical and cancellous bone of intact mouse tibiae, and also after marrow removal by flushing or centrifugation. RNA isolated from cancellous bone by each method was sufficient for gene expression analysis. Centrifugation removed contaminating cells more efficiently than flushing, as indexed by histology and decreased expression of Icam4, a highly expressed erythroid gene. In contrast, centrifuged cortical bone had 12- and 13- fold higher expression of the bone-related genes Col1a1 and Bglap, while levels in marrow-free cancellous bone were 30- and 31-fold higher when compared to bone where marrow was left intact. Furthermore, cortical bone had higher expression of Col1a1 and Bglap than cancellous bone. Thus, RNA isolated by this novel approach can reveal site-specific changes in gene expression in cortical and cancellous bone sites.

Mechanisms of osteoclastic secretion.

A tight balance between bone resorption by osteoclasts and bone formation by osteoblasts is required for the maintenance of bone mass and integrity. A net increase in bone resorption over formation results in osteoporosis, a disease associated with significantly morbidity and mortality. Following attachment via the integrin alphavbeta3, osteoclasts degrade bone by generation of the ruffled border, the unique resorptive organelle of the cell. The adherent cell then secretes into the subcellular space protons and acidic proteases. We review here the concepts relating to the mechanisms of regulated secretion and provide preliminary data on the role of one protein important for secretion by osteoclasts.

Glucocorticoids and the osteoclast.

Glucocorticoid (GC)-induced bone loss is the most common cause of secondary osteoporosis but its pathogenesis is controversial. GCs clearly suppress bone formation in vivo but the means by which they impact osteoblasts is unclear. Because bone remodeling is characterized by tethering of the activities of the two cells, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To address this issue we compared the effects of dexamethasone on wild-type (WT) osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells and found that the bone-degrading capacity of GC-treated WT cells is suppressed. The inhibitory effect of dexamethasone on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF. Dexamethasone specifically arrests M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances, mice lacking the GC receptor in osteoclast lineage cells are spared the impact of dexamethasone on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of dexamethasone, GC receptor-deficient mice are protected from the steroid's inhibition of bone formation.