Effets de l’inhibition post-natale de RANKL sur l’éruption et la formation radiculaire des molaires de souris C57BL/6

Abstract

<jats:p><jats:bold>Introduction :</jats:bold> Des observations récentes effectuées dans le service d’ODF de la Pitié-Salpêtrière à Paris montrent une augmentation des altérations de l’éruption des molaires permanentes non-familiales. Nos travaux récents au laboratoire montrent l’implication des ostéoclastes (OC) dans les processus d’éruption et de rétention dentaires avec implication de la voie de signalisation RANKL/RANK/OPG. Ces faits nous ont amenés à émettre l’hypothèse d’une étiologie environnementale à l’origine de ces défauts d’éruption qui correspondrait à la perturbation des voies de signalisation cellulaires autocrines/paracrines telles que la voie RANKL/RANK/OPG. <jats:bold>Matériels et méthodes :</jats:bold> Des souris C57BL/6 ont subi des injections d’anticorps anti- RANKL à intervalles réguliers au cours des neuf premiers jours après la naissance. Une comparaison phénotypique avec les souris transgéniques RANK a permis la caractérisation fonctionnelle de la voie RANK/RANKL. Le complexe dento-alvéolaire a été analysé par micro-CT pour la densité osseuse, et la coloration au trichrome de Masson pour les examens histologiques. <jats:bold>Résultats :</jats:bold> L’invalidation transitoire de RANKL a conduit à un arrêt du développement radiculaire des molaires et l’inhibition de l’éruption dentaire contrairement au phénotype des souris surexprimant RANK. Le recrutement et l’activité des ostéoclastes ont été fortement altérés. <jats:bold>Discussion :</jats:bold> Ces recherches présentent un intérêt clinique tant direct concernant la compréhension des pathologies de l’éruption qu’indirect pour l’établissement des protocoles de traitements orthodontiques pour les cas particuliers.</jats:p>

Primary Retention of Molars and RANKL Signaling Alteration during Craniofacial Growth

“…Consequently, regarding the origins of the Primary Retentions of Molars (PRM), the RANKL signaling status may be proposed as a central promoting element [13]. The main hypothesis of the present studies was that during childhood, alterations to bone resorption associated with transitory RANKL signaling perturbations, regardless of their origin (genetic or environmental), were the condition for the PRM.…”

“…This blockage was further observed as a side effect in some of the young patients treated with bisphosphonates in an onco-pediatric context or in cases of osteogenesis imperfecta [17]. Additional preclinical studies in mice, consisting of grade shifting in the initiation of transitory inhibition of RANKL signaling, obtained with the IK22.5 antibody, evidenced that depending on age at the first injection, primary retention concerning only the first or the second molars could be obtained [13]. This result opens up new perspectives in the understanding of the origins of molar retention.…”

“…Concerning the study in mice on the consequences of the transient invalidation of RANKL signaling on molar eruption and craniofacial growth, two periods of RANKL inhibition were chosen, from postnatal days 1 to 9 (D1 group) and 7 to 15 (D7 group). The aim was to mainly target first and second molar eruptions respectively [13]. This type of mouse model was chosen for its transitory aspect, making it possible to clearly evidence the importance of the timing of RANKL inhibition in the occurrence of primary retention of molars.…”

“…OPG is a soluble protein that can bind to RANKL with high affinity and compete with RANK, so it acts as an inhibitor of the RANKL effect on osteoclastogenesis [10]. Studies have demonstrated the direct involvement of RANKL/RANK/OPG signaling in the morphogenesis of the craniofacial skeleton and its growth, including control of the alveolar bone remodeling necessary for tooth growth and eruption [11][12][13]. Interestingly, in mice, RANK overexpression in the monocyte/macrophage lineage (Rank Tg ) induces increased osteoclastic activity and premature dental eruption, while partial RANKL invalidation (Rankl +/-) induces decreased osteoclastic activity and a delay in dental eruption [14].…”

Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma

“…Similar data have been reported with zoledronic acid [ 8 , 9 , 10 , 11 ]. Interestingly, this bone growth arrest was rapidly reversed after the end of treatment with the RANKL inhibitor, in contrast to the tooth eruption process, which remained definitively blocked for certain teeth [ 7 , 12 , 13 ]. Bone resorption blockade results in an enlargement of the trabecular bone formed by osteoblasts associated with the endochondral process.…”