Synovial Fluid Interleukin-16 Contributes to Osteoclast Activation and Bone Loss through the JNK/NFATc1 Signaling Cascade in Patients with Periprosthetic Joint Infection

Abstract

Because of lipopolysaccharide (LPS)-mediated effects on osteoclast differentiation and bone loss, periprosthetic joint infection (PJI) caused by Gram-negative bacteria increases the risk of aseptic loosening after reimplantation. Synovial fluid interleukin-16 (IL-16) expression was higher in patients with PJI than in patients without joint infection. Thus, we explored the effects of IL-16 on bone. We investigated whether IL-16 modulates osteoclast or osteoblast differentiation in vitro. An LPS-induced bone loss mice model was used to explore the possible advantages of IL-16 inhibition for the prevention of bone loss. IL-16 directly activated p38 and c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signaling and increased osteoclast activation markers, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, and nuclear factor of activated T cells 1 (NFATc1). IL-16 directly caused monocytes to differentiate into TRAP-positive osteoclast-like cells through NFATc1 activation dependent on JNK/MAPK signaling. Moreover, IL-16 did not alter alkaline phosphatase activity or calcium deposition during osteoblastic differentiation. Finally, IL-16 inhibition prevented LPS-induced trabecular bone loss and osteoclast activation in vivo. IL-16 directly increased osteoclast activation through the JNK/NFATc1 pathway. IL-16 inhibition could represent a new strategy for treating infection-associated bone loss.Int. J. Mol. Sci. 2020, 21, 2904 2 of 15 of differentiation 4 (CD4 + ) lymphocytes, monocytes, and eosinophils [11,12]. IL-16 is synthesized as a precursor protein (pro-IL-16) of approximately 68 kDa. Pro-IL-16 is cleaved by activated caspase-3 and then IL-16 generation [13]. CD4 serves as a signaling transducing receptor for IL-16 signaling. Increased intracytoplasmic calcium and inositol trisphosphate can be initiated when IL-16 interacts with CD4 receptors, and this subsequently activates stress-activated protein kinases (SAPKs) p46 and p54. Stimulation with IL-16 also activates members of the mitogen-activated protein kinase (MAPK) family, namely c-Jun N-terminal kinase (JNK) and p38 but does not activate extracellular signal-regulated kinase (ERK)-1 or ERK-2 [14]. IL-16 can activate monocytes and stimulate the secretion of inflammatory cytokines, chiefly tumor necrosis factor (TNF)-α, IL-1β, 15,16]. Currently, these cytokines are believed to promote the development of septic arthritis [17][18][19].PJI can result from Gram-positive (GP) or Gram-negative (GN) bacterial infections. Our previous retrospective study revealed that GN infections were associated with an increased risk of aseptic loosening as compared with GP infections [20]. The cell walls of GP bacteria contain lipoteichoic acid (LTA) components, whereas those of GN bacteria contain components of lipopolysaccharide (LPS). In studies of mice receiving intrafemoral injections of LPS or LTA, LPS reduced both the number of trabeculae and bone mineral density, whereas LTA did not have this effect [20]. In addition, disruption of the bal...

Hepcidin contributes to Swedish mutant APP-induced osteoclastogenesis and trabecular bone loss

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Lipoteichoic Acid Accelerates Bone Healing by Enhancing Osteoblast Differentiation and Inhibiting Osteoclast Activation in a Mouse Model of Femoral Defects

“…A Fast Violet B Salt capsule (catalog number 851-10 CAP, Sigma-Aldrich) was dissolved in naphthol AS-MX phosphate alkaline solution (catalog number 855, Sigma-Aldrich) and then used for ALP staining. Sigma 104 ® phosphatase substrate (catalog number 104105, Sigma-Aldrich) was used for ALP assays [ 37 ].…”

Ibudilast Mitigates Delayed Bone Healing Caused by Lipopolysaccharide by Altering Osteoblast and Osteoclast Activity

“…All procedures were approved by the Chang Gung Memorial Hospital review committee (IACUC approval number 2018121701). Ten-week-old male C57BL/6NCrlBltw mice were used for the femoral defect model [ 25 , 26 ].…”

“…A 3D image was constructed using CTVox software (version 3.3.0, SkyScan) for illustration purposes. For the detailed procedure, please refer to our previously published studies [ 25 , 26 ].…”