Anti-HMGB1 Neutralizing Antibody Attenuates Periodontal Inflammation and Bone Resorption in a Murine Periodontitis Model

Yoshihara-Hirata, Chiaki; Yamashiro, Keisuke; Yamamoto, Tadashi; Aoyagi, Hiroaki; Ideguchi, Hidetaka; Kawamura, Marenori; Suzuki, Risa; Ono, M.; Wake, Hidenori; Nishibori, Masahiro; Takashiba, Shogo

doi:10.1128/iai.00111-18

Cited by 43 publications

(42 citation statements)

References 35 publications

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“…According to Wolf et al's research, HMGB1 shows a RANKL-related activity in regulating periodontal remodeling during orthodontic tooth movement in rats [42]. Yoshihara-Hirata et al found that HMGB1 was involved in the development of periodontitis and anti-HMGB1 antibody treatment attenuated alveolar bone absorption and the progression of periodontitis [43]. These results provide strong support for this study.…”

supporting

confidence: 78%

Inhibition of HMGB1 Promotes Osseointegration under Hyperglycemic Condition through Improvement of BMSC Dysfunction

Liu

Gan

Zhao

et al. 2019

Oxidative Medicine and Cellular Longevity

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High mobility group box 1 (HMGB1) participates actively in oxidative stress damage and the latter relates closely to diabetic complications, including poor implant osseointegration. This article is aimed at investigating the effects of HMGB1 on dysfunction of bone marrow stromal cells (BMSCs) and impaired osseointegration under diabetic environment. In vitro, BMSCs were treated with normal glucose (NG), high glucose (HG), and HG+glycyrrhizin (HMGB1 inhibitor, HG+GL). Cell proliferation, osteogenic behaviors, and oxidative stress were determined. In vivo, 8-week-old Sprague-Dawley rats were categorized to control, streptozotocin-induced diabetic, and diabetic-GL groups. Rats received GL (50 mg/kg, i.p.) or vehicle treatment daily after titanium implants were planted into the tibiae. After 4 and 8 weeks, plasma lipoperoxide detection, μCT analysis, and histomorphometric evaluation were conducted. By these approaches, we demonstrated that inhibiting HMGB1 by GL significantly attenuated HG-induced upregulation of HMGB1, HMGB1 ligand receptor for advanced glycation end products (RAGE) and their interaction, relieved oxidative stress, and reversed the downregulation of osteogenic markers, resulting in improved osteogenic differentiation. In diabetic rats, GL administration suppressed the upregulation of HMGB1, attenuated the lipoperoxide, and ameliorated the impaired trabecular structure and osseointegration. Taken together, inhibiting HMGB1 can be an effective approach to relieve BMSC dysfunction and enhance osseointegration under diabetic environment.

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supporting

confidence: 78%

Inhibition of HMGB1 Promotes Osseointegration under Hyperglycemic Condition through Improvement of BMSC Dysfunction

Liu

Gan

Zhao

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Interestingly, several functional aspects of HMGB1 might be relevant to the periodontal and scarring phenotypes observed in pEDS patients. For example, several studies in rodents and humans suggest a significant role of HMGB1 in periodontal inflammatory infiltration and alveolar bone destruction or resorption (23,24). Normal human oral mucosa is continuously prone to micro-tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes

et al. 2019

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Ehlers-Danlos syndromes (EDS) are clinically and genetically heterogeneous disorders characterized by soft connective tissue alteration like joint hypermobility and skin hyper-extensibility. We previously identified heterozygous missense mutations in the C1R and C1S genes, coding for the complement C1 proteases, in patients affected by periodontal EDS, a specific EDS subtype hallmarked by early severe periodontitis leading to premature loss of teeth and connective tissue alterations. Up to now, there is no clear molecular link relating the nominal role of the C1r and C1s proteases, which is to activate the classical complement pathway, to these heterogeneous symptoms of periodontal EDS syndrome. We aim therefore to elucidate the functional effect of these mutations, at the molecular and enzymatic levels. To explore the molecular consequences, a set of cell transfection experiments, recombinant protein purification, mass spectroscopy and N-terminal analyses have been performed. Focusing on the results obtained on two different C1S variants, namely p.Val316del and p.Cys294Arg, we show that HEK293-F cells stably transfected with the corresponding C1s variant plasmids, unexpectedly, do not secrete the full-length mutated C1s, but only a truncated Fg40 fragment of 40 kDa, produced at very low levels. Detailed analyses of the Fg40 fragments purified for the two C1s variants show that they are identical, which was also unexpected. This suggests that local misfolding of the CCP1 module containing the patient mutation exposes a novel cleavage site, between Lys353 and Cys354, which is not normally accessible. The mutation-induced Fg40 fragment contains the intact C-terminal serine protease domain but not the N-terminal domain mediating C1s interaction with the other C1 subunits, C1r, and C1q. Thus, Fg40 enzymatic activity escapes the normal physiological control of C1s activity within C1, potentially providing a loss-of-control. Comparative enzymatic analyses show that Fg40 retains the native esterolytic activity of C1s, as well as its cleavage efficiency toward the ancillary alarmin HMGB1 substrate, for example, whereas the nominal complement C4 activation cleavage is impaired. These new results open the way to further molecular explorations possibly involving subsidiary C1s targets.

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“…HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis. The anti‐HMGB1 antibody reduces the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis (Yoshihara‐Hirata et al., ). Overall, these data are consistent with the beneficial effects of biological agents on the periodontal parameters as observed with humanized anti‐TNFα monoclonal antibody, adalimumab (Kobayashi et al., ) and infliximab (Mayer, Balbir‐Gurman, & Machtei, ) on the periodontal condition of patients with rheumatoid arthritis.…”

Section: Preamblementioning

confidence: 99%

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

Gruber

2019

J Clinic Periodontology

113

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Aim Osteoimmunology covers the cellular and molecular mechanisms responsible for inflammatory osteolysis that culminates in the degradation of alveolar bone. Osteoimmunology also focuses on the interplay of immune cells with bone cells during bone remodelling and regeneration. The aim of this review was to provide insights into how osteoimmunology affects alveolar bone health and disease. Method This review is based on a narrative approach to assemble mouse models that provide insights into the cellular and molecular mechanisms causing inflammatory osteolysis and on the impact of immune cells on alveolar bone regeneration. Results Mouse models have revealed the molecular pathways by which microbial and other factors activate immune cells that initiate an inflammatory response. The inflammation‐induced alveolar bone loss occurs with the concomitant suppression of bone formation. Mouse models also showed that immune cells contribute to the resolution of inflammation and bone regeneration, even though studies with a focus on alveolar socket healing are rare. Conclusions Considering that osteoimmunology is evolutionarily conserved, osteolysis removes the cause of inflammation by provoking tooth loss. The impact of immune cells on bone regeneration is presumably a way to reinitiate the developmental mechanisms of intramembranous and endochondral bone formation.

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Anti-HMGB1 Neutralizing Antibody Attenuates Periodontal Inflammation and Bone Resorption in a Murine Periodontitis Model

Cited by 43 publications

References 35 publications

Inhibition of HMGB1 Promotes Osseointegration under Hyperglycemic Condition through Improvement of BMSC Dysfunction

Inhibition of HMGB1 Promotes Osseointegration under Hyperglycemic Condition through Improvement of BMSC Dysfunction

Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

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