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

Yuhan Chang,Mei-Feng Chen,Cai-Yan Li,Steve W N Ueng,Chih-Chien Hu,Chih-Hsiang Chang,Yi-Min Hsiao

doi:10.3390/ijms21082904

Yuhan Chang, Mei-Feng Chen + Show 5 more

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https://doi.org/10.3390/ijms21082904

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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.

Highlights

Periprosthetic joint infection (PJI) is the most common cause of knee arthroplasty failure which accounts for 16% to 25% of all failed knee replacements [1,2,3,4] and is the third most common indication for revision hip arthroplasty [5,6,7,8,9]
After two months of antibiotic treatment and debridement, IL-16 expression levels were significantly reduced. We evaluated whether this increased IL-16 expression changed the cellular function of osteoclasts and osteoblasts
We investigated the molecular mechanism underlying the effects of Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) on the IL-16-induced increase in the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts

Summary

Introduction

Periprosthetic joint infection (PJI) is the most common cause of knee arthroplasty failure which accounts for 16% to 25% of all failed knee replacements [1,2,3,4] and is the third most common indication for revision hip arthroplasty [5,6,7,8,9]. IL-16 can activate monocytes and stimulate the secretion of inflammatory cytokines, tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-15 [11,15,16]. These cytokines are believed to promote the development of septic arthritis [17,18,19]

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