title: Local delivery of mutant CCL2 protein-reduced orthopaedic implant wear particle-induced osteolysis and inflammation in vivo.
abstract: Total joint replacement (TJR) has been widely used as a standard treatment for late-stage arthritis. One challenge for long-term efficacy of TJR is the generation of ultra-high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle-induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle-induced osteolysis and the effects of 7ND treatment were evaluated using micro-CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle-induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle-induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.
authors.forename: Taishi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.
authors.forename: Michael
authors.initials: M
authors.lastname: Keeney
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.
authors.forename: Jukka
authors.initials: J
authors.lastname: Pajarinen
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.
authors.forename: Florence
authors.initials: F
authors.lastname: Loi
authors.affiliation: Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.|Department of Bioengineering, Stanford University, Stanford, California, 94305.
authors.forename: Stuart
authors.initials: S
authors.lastname: Goodman
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, California, 94305.|Department of Bioengineering, Stanford University, Stanford, California, 94305.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000008:administration & dosage* / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005549:Foreign-Body Reaction / Q000209:etiology / Q000517:prevention & control*; D007595:Joint Prosthesis / Q000009:adverse effects*; D008297:Male; D008810:Mice, Inbred C57BL; D010014:Osteolysis / Q000209:etiology / Q000517:prevention & control*; D011095:Polyethylenes / Q000009:adverse effects*; D055114:X-Ray Microtomography
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D011095:Polyethylenes; C111601:ultra-high molecular weight polyethylene
keywords: macrophage; mutant CCL2 protein (7ND); osteolysis; total joint replacement; wear particles