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.

The Effects of Biomaterial Implant Wear Debris on Osteoblasts

“…Osteogenic differentiation and mineralization of osteoblasts are also impaired on exposure to wear particles. These effects are evidenced by the reduced gene expression of early boneformation-associated genes [e.g., ALP, runx 2, osterix (Dean et al, 1999a;Lohmann et al, 2000;Shen et al, 2014;Gu et al, 2017)] and late osteogenic markers (e.g., osteocalcin) (Nam et al, 2017), whilst simultaneously losing their capacity to synthesize type I collagen (Allen et al, 1997;Yao et al, 1997;Vermes et al, 2000Vermes et al, , 2001Lochner et al, 2011;Schulze et al, 2013) and mediate mineralization (Gu et al, 2017). Additionally, similar trends were observed in the expression of osteoblastogenesisrelated transcription factors such as osteopontin (OPN), TGF-β1, sp7, bgalp, Fra-2 (fos related antigen-2), Dlx5, and Dkk1 (dickkopf-related protein 1), even though some of these trends were not statistically significant (Chiu et al, 2010;Ma et al, 2010;Shen et al, 2014;Sun et al, 2015;Deng et al, 2017b;Gu et al, 2017).…”

“…In parallel, the expression of negative regulators of osteogenesis, such as BMP3, sclerostin (SOST), and Msx2, is found to be temporarily up-regulated during osteogenesis (Chiu et al, 2010;Ma et al, 2010). The particle-induced inhibition of osteogenic differentiation is mainly mediated by Wnt/β-catenin and BMP/smad signaling pathways, as both BMP and WNT signaling were suppressed in osteoprogenitor cells (Sun et al, 2015;Nam et al, 2017;Sun et al, 2019). Thus, these two signaling pathways could be used as a potential therapeutic target.…”

Stevioside Prevents Wear Particle-Induced Osteolysis by Inhibiting Osteoclastogenesis and Inflammatory Response via the Suppression of TAK1 Activation

“…Production of titanium (Ti), ultra-high molecular weight polyethylene (UHMWPE), or cement wear debris following TJA is deemed to play a critical role in the process of osteolysis ( Noordin and Masri, 2012 ). Considerable studies have shown that chronic inflammatory response and increased osteoclast-related bone resorption, which occur in response to implant-derived wear debris, might be responsible for osteolysis ( Masui et al, 2005 ; Holding et al, 2006 ; Abu-Amer et al, 2007 ; Nam et al, 2017 ).…”

Fibroblast-Like-Synoviocytes Mediate Secretion of Pro-Inflammatory Cytokines via ERK and JNK MAPKs in Ti-Particle-Induced Osteolysis

“…However, no activation of p38 MAPK was not observed in SW982 cells (Figure 3). Likewise, no activation of p38 by Ti particles has been reported in osteoblasts [36]. It appears that p38 signaling activation depends on the cell type, which might be essential for osteoclasts and macrophages, contributing to the inflammatory osteolysis.…”

“…Activation of MAPKs by wear particles is associated with induced inflammatory responses in various cell types [36][37][38]. Wear debris has been shown to stimulate intracellular signaling pathways such as MAPKs, leading to the secretion of pro-inflammatory cytokines.…”