Genetically-achieved disturbances to the expression levels of TNFSF11 receptors modulate the effects of zoledronic acid on growing mouse skeletons

Royer

et al. 2022

Cancers

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Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.

Section: Introductionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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

Muñoz-García

Royer

et al. 2022

Cancers

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“…For the extrinsic origins, regardless of the way the bone remodeling is affected (e.g., a deficiency in RANKL/RANK inducing osteopetrosis [7,23,[30][31][32][33] or overactivation in RANKL/RANK inducing osteolytic diseases [8,9]), in both cases root formation is touched. The most representative feature of a root developmental defect of extrinsic origin was the ankylosis observed in osteopetrosis.…”

Section: Discussionmentioning

confidence: 99%

“…More specifically, it has been demonstrated that the activity of osteoclasts, controlled by the RANKL/RANK (Tumor Necrosis Factor Superfamily Member 11/Tumor Necrosis Factor Receptor Superfamily Member 11A) signaling pathway has an effect on root elongation and morphology [7,8]. The presence of an increased number of osteoclasts in alveolar bone (Rank Tg mice) was associated with earlier root elongation, while a reduction in this number (in Rankl +/mice) was associated with delayed elongation [7][8][9]. Interestingly, it has also been demonstrated that the overactivation of the osteoclastogenic pathway stimulates the proliferation of the epithelial cells in Hertwig's epithelial root sheath, in coordination with the mesenchymal cells in the apical papilla during the formation of the first third of the root [6,8].…”

Section: Introductionmentioning

confidence: 99%

Origins of Alterations to Rankl Null Mutant Mouse Dental Root Development

Gama

Mesa

et al. 2020

IJMS

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The purpose of the present study was to assess the early stages of development of mouse first molar roots in the osteopetrotic context of RANKL invalidation in order to demonstrate that the radicular phenotype observed resulted not only from defective osteoclasts, but also from loss of cell-to-cell communication among dental, periodontium and alveolar bone cells involving RANKL signaling. Two experimental models were used in this study: Rankl mutants with permanent RANKL invalidation, and C57BL/6J mice injected during the first postnatal week with a RANKL neutralizing antibody corresponding to a transient RANKL invalidation. The dento-alveolar complex was systematically analyzed using micro-CT, and histological and immunohistochemical approaches. These experiments showed that the root elongation alterations observed in the Rankl-/- mice were associated with reduced proliferation of the RANK-expressing HERS cells with a significant decrease in proliferating cell nuclear antigen (PCNA) expression and a significant increase in P21 expression. The phenotypic comparison of the adult first molar root at 35 days between permanent and transitory invalidations of RANKL made it possible to demonstrate that alterations in dental root development have at least two origins, one intrinsic and linked to proliferation/differentiation perturbations in dental-root-forming cells, the other extrinsic and corresponding to disturbances of bone cell differentiation/function.

“…The choice of landmarks was based on a pre-existing analysis [22]. The analysis presented makes it possible to measure several points on the same section in order to facilitate the study.…”

Section: Micro-ct Analysesmentioning

confidence: 99%

Primary Retention of Molars and RANKL Signaling Alteration during Craniofacial Growth

Gama

Maman

et al. 2020

JCM

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The primary retention of molars observed in clinic corresponds to a still-unexplained absence of molar eruption despite the presence of an eruption pathway, resembling the experimental transient inhibition of RANKL signaling in mice. The aim of the present study was to confront the hypothesis according to which the primary retention of molars is associated with transitory perturbations to RANKL signaling during growth as part of a wider craniofacial skeleton pattern. The experimental strategy was based on combining a clinical study and an animal study corresponding to the characterization of the craniofacial phenotypes of patients with primary retention of molars and analyses in mice of the consequences of transient inhibition of RANKL signaling on molar eruption and craniofacial growth. The clinical study validated the existence of a particular craniofacial phenotype in patients with primary retention of molars: a retromandibular skeletal class II typology with reduced mandibular dimensions which manifests itself at the dental level by a class II/2 with palatoversion of the upper incisors and anterior overbite. The animal study demonstrated that transient invalidation of RANKL signaling had an impact on the molar eruption process, the severity of which was dependent on the period of inhibition and was associated with a reduction in two craniofacial morphometric parameters: total skull length and craniofacial vault length. In conclusion, primary retention of molars may be proposed as part of the craniofacial skeleton phenotype associated with a transitory alteration in RANKL signaling during growth.