Genetic variation in inflammatory and bone turnover pathways and risk of osteolytic responses to prosthetic materials

Abstract

Wear particle-induced inflammatory bone loss (osteolysis) is the leading cause of total hip arthroplasty (THA) failure. Individual susceptibility to osteolysis is modulated by genetic variation. In this 2-stage case-control association study we examined whether variation within candidate genes in inflammatory and bone turnover signaling pathways associates with susceptibility to osteolysis and time to prosthesis failure. We examined two cohorts, comprising 758 (347 male) Caucasian subjects who had undergone THA with a metal on polyethylene bearing couple; 315 of whom had developed osteolysis. Key genes within inflammatory, bone resorption, and bone formation pathways were screened for common variants by pairwise-SNP tagging using a 2-stage association analysis approach. In the discovery cohort four SNPs within RANK, and one each within KREMEN2, OPG, SFRP1, and TIRAP (p < 0.05) were associated with osteolysis susceptibility. Two SNPs within LRP6, and one each within LRP5, NOD2, SOST, SQSTM1, TIRAP, and TRAM associated with time to implant failure (p < 0.05). Meta-analysis of the two cohorts identified four SNPs within RANK, and one each within KREMEN2, OPG, SFRP1, and TIRAP associated with osteolysis susceptibility (p < 0.05). Genetic variation within inflammatory signaling and bone turnover pathways may play a role in susceptibility to osteolysis. ß 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:193-198, 2015.Keywords: arthroplasty; genetics; hip; innate immunity; osteolysis A recent meta-analysis of worldwide joint replacement register data has shown that 12% of first (primary) THRs fail within 10 years of implantation, requiring revision surgery. 1 Adverse local tissue reactions to prosthesis materials characterized by periprosthetic osteolysis and resulting in prosthesis loosening accounts for 60% of these failures. 2 Osteolysis arises as a cell-mediated adverse inflammatory immune response to the wear debris materials shed from the implant surfaces. 3,4 Several investigators have shown that particulate debris from prosthetic materials initiate inflammatory signaling through pattern recognition receptors (PRR) including NOD-like and toll-like receptors (TLRs). [5][6][7][8][9] The NOD-like receptor NALP3 (NACHT-, LRR-, and pyrin domain-containing protein 3) is thought to play a central role in the inflammasome complex of proteins that sense and initiate pro-inflammatory responses to danger or pathogen-associated molecular patterns. 5,7 Furthermore, these PRRs are expressed in osteolytic membrane taken from patients with failing prostheses. 10,11 Bone turnover is closely regulated by the equilibrium between osteoblasts and osteoclasts that is regulated by the interplay between the Wnt and RANK signaling pathways. 12,13 P2 purinergic receptors are important regulators of both inflammation and bone remodeling. 14 Patients vary in their osteolytic response to particulate wear debris. 15 Macrophage responses to a particulate challenge in-vitro varies between indivi...

Gene Expression in Osteolysis: Review on the Identification of Altered Molecular Pathways in Preclinical and Clinical Studies

“…These studies used tissues and cells harvested from osteoarthritic patients as control group, given the difficulty in finding the material from healthy subjects. Half of the studies did not specify the material of which the prosthesis is made of [19,67,68] and in the other half the prostheses used were in PE [66,69,70]. Analyzing these studies, new genes emerged, different from those evaluated in the previous preclinical studies.…”

“…As outlined in Table 3, six studies analyzed human tissues and cells from patients affected by periprosthetic osteolysis and undergoing THR or TKR [19,66,67,68,69,70]. More precisely, synovial and pseudosynovial membranes [19,67,68], interfacial membranes [67], joint capsules [70], peripheral blood [66] and hPBMCs [69] were the retrieved tissues and cells.…”

“…More precisely, synovial and pseudosynovial membranes [19,67,68], interfacial membranes [67], joint capsules [70], peripheral blood [66] and hPBMCs [69] were the retrieved tissues and cells.…”

“…Among these six studies, three did not specify the materials of the prosthesis [19,67,68] and threee dealt with osteolysis due to prosthesis based on PE [66,69,70]. …”

“…None of the polymorphisms was associated with time to failure [66]. Saad et al analyzed tissue samples from patients undergoing revision surgeries for osteolysis and synovial samples from osteoarthritic patients undergoing primary surgeries.…”