This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
Periprosthetic membranes are ﬁbrous granulomatous tissues composed of wear debris and numerous cell types, including ﬁbroblasts, macrophages, osteoclasts (OCs), osteoblasts (OBs), osteocytes (OSTs), mesenchymal stem cells (MSCs), synovial cells, endothelial cells, and, rarely, lymphocytes. Macrophages ingest wear debris, resulting in the production of proinﬂammatory factors such as tumor necrosis factor (TNF); interleukin (IL)-1, IL-6, IL-17; macrophage colony-stimulating factor (M-CSF); and reactive oxygen species. In addition, macrophages can differentiate into OCs, which can induce the fibroblast cytokines that contribute to bone resorption.
Autophagy is the basic catabolic mechanism that degrades/recycles unnecessary or dysfunctional cellular components through the action of lysosomes. The breakdown of cellular components promotes cellular survival during stress, such as starvation, by maintaining cellular energy levels. In most instances, autophagy does not lead to cell death. Although the products of autophagy are typically recycled intracellularly, they may also be secreted.
Autophagy is also important for the differentiation of OBs, OSTs, and OCs. In addition, autophagy is involved in OB mineralization, and autophagy proteins are required for OC bone resorption. Autophagy appears to be triggered by wear debris in OCs, OBs, and macrophages, where the process promotes the secretion of proinﬂammatory proteins associated with the development of aseptic loosening. Autophagy can also be involved in the secretion of proteins such as chemokine (C-C motif) ligand 2 (CCL2) and leukemia inhibitory factor (LIF), which were both overexpressed in aseptic loosening in a rat model.
Autophagy inhibition has been shown to decrease osteolysis severity in animal models. For example, 3-methyladenine inhibition of the autophagy response to TiAl6V4 particles improved bone microarchitecture in a murine calvaria resorption model. Although autophagy will probably not be the final answer for prosthetic loosening, it is an avenue that should prompt future research into new therapeutic approaches.
Camuzard O, Breuil V, Carle GF, Pierrefite-Carle V. Autophagy Involvement in Aseptic Loosening of Arthroplasty Components. J Bone Joint Surg Am. 2019 Mar 6;101(5):466-472. doi: 10.2106/JBJS.18.00479. PMID: 30845042