Background/Purpose Total hip replacement (THR) is a highly successful treatment for degenerative arthritis, alleviating pain and restoring joint function in the vast majority of patients. However, inflammatory reactions to polyethylene wear debris resulting in destruction of bone (osteolysis) can lead to implant loosening and revision surgery.  To avoid the adverse effects of polyethylene wear products, metal-on-metal bearings were introduced. Recent studies, however, have revealed an alarming rate of early revision surgery related to the development of adverse local tissue reactions (ALTR) characterized by extensive and rapid necrosis of soft tissue surrounding implants with metal-on-metal (MoM) or dual modular neck (DMN) designs. We have used chemokine/cytokine profiling of synovial fluid and serum and gene expression analysis of peri-implant tissue to identify biomarkers for early detection and to gain insights into the pathogenesis of ALTR.

Methods Synovial fluid and serum was collected from ALTR and osteolysis patients at revision surgery, and cell-free aliquots were prepared and immediately frozen. Antibody arrays were used to identify selected chemokines and cytokines, and results confirmed by ELISA. For gene expression profiling, total RNA was prepared from peri-implant tissue using Trizol. RNA integrity was verified using an Agilent Bioanalyzer, and then subjected to microarray analysis (Affymetrix U133 2.0). Results were verified using real time PCR.

Results  Synovial fluid from ALTR patients demonstrated elevated levels of several chemokines and cytokines compared to those seen in osteolysis patients, including the interferon gamma inducible chemokines MIG/CXCL-9 and IP-10/CXCL10. Levels of these factors were generally higher in the DMN ALTR patients than the MoM ALTR patients. More modest elevations of these chemokines were found in ALTR serum samples. Microarray analysis revealed a unique ALTR gene expression profile that was absent in arrays prepared from peri-implant tissues from patients with osteolysis. Pathway analysis identified a unique chemokine/interferon signature that mirrored the protein profile of synovial fluid.

	Protein	Osteolysis	ALTR – DMN	p-value (DMN)	ALTR – MOM	p-value (MoM)
Synovial Fluid	MIG	1,320 (1,901)	178,442 (120,107)	8.46 E-6	68,609 (68,867)	2.52 E-3
	IP-10	1,880 (4,304)	100,137 (78,158)	9.32 E-5	32,829 (30,575)	2.00 E-3
	IL-6	497 (786)	28,583 (28,481)	1.53 E-3	16,102 (21,768)	2.10 E-2
	IL-8	8,621(12,820)	64,172 (58,125)	2.21 E-3	54,338 (41,930)	1.32 E-3
Serum	MIG	273 (163)	592 (315)	1.68 E-3	456 (279)	0.036
	IP-10	17.4 (9.8)	25.7 (29.5)	0.31	32.9 (31.0)	0.074

Table 1 Mean (Standard Deviation) levels of selected proteins in the synovial fluid and serum (in pg/ml). p-values are for comparison to the osteolysis group.

Conclusion Expression profiling of peri-implant tissues from ALTR patients reveals a unique chemokine/cytokine gene signature. The corresponding gene products are detectible in synovial fluid and serum, indicating their potential utility as biomarkers for early diagnosis and monitoring of patients at risk for ALTR. In addition, pathway analysis reveals up-regulation of genes involved in lymphocyte trafficking and activation, providing insights into disease pathogenesis and importantly identifies potential therapeutic targets to prevent this devastating complication.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-putative-biomarkers-and-molecular-mechanisms-associated-with-adverse-tissue-reactions-to-metal-on-metal-and-modular-neck-hip-implants/