title: Suppression of osteogenic activity by regulation of WNT and BMP signaling during titanium particle induced osteolysis.
abstract: Periprosthetic osteolysis remains the leading obstacle for total joint replacements. Primarily, it was thought that aseptic loosening is mainly caused by macrophage mediated inflammatory process arising from production of wear debris. The role of osteoclasts and its sequential bone resorption ability has been extensively studied, but little is known about impaired osteogenesis during osteolysis. In the current study, we have tried to delineate the regulatory mechanism of osteogenic signals by Ti particles in osteoprogenitor cells as well its participatory role in wear debris induced osteolysis. Implantation of Ti particles on mice calvaria induced pro-inflammatory response, elevated expression of COX2 and reduced the expression of Osterix. Treatment of Ti particles to MC3T3 E-1 cells displayed decreased osteogenic activity including ALP activity, mineralization and mRNA levels several osteogenic genes. Moreover, the basal activity of WNT and BMP signaling pathways was suppressed in MC3T3 E-1 cells treated with Ti particles. As an early response to Ti particles, MC3T3 E-1 cells showed activation of ERK and JNK. Co-inhibition of ERK and JNK with their specific inhibitors resulted in partial recovery of WNT and BMP signaling activity as well as ALP activity and collagen synthesis. Finally, LiCl mediated activation of WNT signaling pathway demonstrated rescue of Ti particle facilitated suppression of Osterix expression in mice calvaria. Our results provide evidences that WNT signaling pathway is regulated by ERK, JNK, and BMP signaling pathway during wear debris induced inflammatory osteolysis and may be considered as suitable therapeutic targets for the treatment. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 912-926, 2017.
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Ju-Suk
authors.initials: JS
authors.lastname: Nam
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Ashish Ranjan
authors.initials: AR
authors.lastname: Sharma
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Supriya
authors.initials: S
authors.lastname: Jagga
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Garima
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Lich Thi
authors.initials: LT
authors.lastname: Nguyen
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Yeon Hee
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Jun-Dong
authors.initials: JD
authors.lastname: Chang
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.|Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, Greater Noida, 203201, India.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Chakraborty
authors.affiliation: Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Lee
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010014:Osteolysis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D014025:Titanium / Q000009:adverse effects* / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D019485:Bone Morphogenetic Proteins; D014025:Titanium
keywords: MAPK kinases; Ti particles; WNT signaling; osteolysis; osteoprogenitors; wear debris