title: Evidence that osteocyte perilacunar remodelling contributes to polyethylene wear particle induced osteolysis.
abstract: Periprosthetic osteolysis (PO) leading to aseptic loosening, is the most common cause of failure of total hip replacement (THR) in the mid- to long-term. Polyethylene (PE) particulates from the wear of prosthesis liners are bioactive and are implicated in the initiation and or progression of osteolysis. Evidence exists that cells of the osteoblast/osteocyte lineage are affected by PE particles and contribute to the catabolic response by promoting osteoclastic bone resorption. In this study, we hypothesised that osteocytes contribute directly to PO by removing bone from their perilacunar matrix. Osteocyte responses to ultra-high molecular weight PE (UHMWPE) particles were examined in vitro in human primary osteocyte-like cultures, in vivo in the mouse calvarial osteolysis model, and in the acetabulum of patients undergoing revision total hip replacement (THR) surgery for PO. Osteocytes exposed to UHMWPE particles showed upregulated expression of catabolic markers, MMP-13, carbonic anhydrase 2 (CA2), cathepsin K (CTSK) and tartrate resistant acid phosphatase (TRAP), with no effect on cell viability, as assessed by Caspase 3 activity. Consistent with this catabolic activity causing perilacunar bone loss, histological analysis of calvarial sections from mice exposed to UHMWPE revealed a significant (p<0.001) increase in osteocyte lacunar area (Lac.Ar) compared to sham-operated animals. Furthermore, acetabular biopsies from patients with PO also showed significantly (p<0.001) increased osteocyte lacunar size in trabecular bone adjacent to PE particles, compared with osteocyte lacunar size in bone from primary THR patients. Together, these findings suggest a previously unrecognised action of UHMWPE wear particles on osteocytes, which directly results in a loss of osteocyte perilacunar bone. This action may exacerbate the indirect pro-osteoclastic action of UHMWPE-affected osteocytes, previously shown to contribute to aseptic loosening of orthopaedic implants.
  
  
  CONCLUSIONS
  This study addresses the clinical problem of periprosthetic osteolysis, bone loss in response to polyethylene wear particles derived from materials used in orthopaedic implants. Periprosthetic osteolysis has been thought to be due largely to wear particles stimulating the activity of bone resorbing osteoclasts. However, in this study we demonstrate for the first time that polyethylene particles stimulate another type of bone loss, mediated by the direct activity of bone mineral embedded osteocytes, termed osteocytic osteolysis or osteocyte perilacunar remodelling. This study provides new mechanistic insight into wear-particle mediated bone loss and represents a new paradigm for the way in which bone cells, namely osteocytes, the key controlling cell type in bone, react to biomaterials.
authors.affiliation: Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Renee T
authors.initials: RT
authors.lastname: Ormsby
authors.affiliation: Discipline of Anatomy and Pathology, University of Adelaide, Adelaide, SA 5005, Australia; Myeloma Research Laboratory, SAHMRI, North Terrace, Adelaide, SA 5000, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cantley
authors.affiliation: Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kogawa
authors.affiliation: Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: L Bogdan
authors.initials: LB
authors.lastname: Solomon
authors.affiliation: Discipline of Anatomy and Pathology, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Haynes
authors.affiliation: Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.affiliation: Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: gerald.atkins@adelaide.edu.au.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D023421:Models, Animal; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010014:Osteolysis / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D011095:Polyethylenes / Q000009:adverse effects*; D012886:Skull / Q000187:drug effects / Q000473:pathology
chemical_list: D011095:Polyethylenes; C111601:ultra-high molecular weight polyethylene
keywords: Aseptic loosening; Osteocyte; Osteocytic osteolysis; Periprosthetic; Polyethylene; UHMWPE