Anne-Laure Bonnet

La Vasorine (Vasn) est une protéine transmembranaire de type I initialement étudiée dans le contexte du développement. Vasn a été également mise en évidence chez la souris adulte où elle est fortement exprimée dans les gros vaisseaux, les os et les reins mais le rôle de Vasn est aujourd'hui inconnu. De nombreuses pathologies osseuses, rénales et vasculaires restent encore inexpliquées, et bien qu'à ce jour aucun variant de Vasn n'ait été associé à une pathologie humaine, il est nécessaire d'identifier des marqueurs précoces de ces pathologies ainsi que les voies moléculaires/protéines défaillantes. L'objectif de ce travail est de comprendre les principaux rôles et fonctions de Vasn à travers plusieurs modèles animaux ; les souris Vasn knock-out (KO) constitutives et les souris Vasn KO inductibles (Cassette Cre-Lox inductible). Les analyses ont montré que les souris Vasn KO développent un phénotype non viable, entrainant un décès précoce autour de 24 jours post-natal. Ces souris sont de petite taille, atteintes d'un syndrome néphrotique sévère s'installant à J14 et ont une microarchitecture osseuse anormale par rapport aux souris Wild-type (WT). Des anomalies majeures rénales ont été observées, notamment au sein des podocytes glomérulaires, avec la perte de leurs pédicelles et une absence de diaphragme de fente. Ces altérations expliquent l'accumulation des protéines retrouvées dans les tubules et l'urine. Ce syndrome néphrotique évolue vers une insuffisance rénale sévère. Les souris Vasn KO ont par ailleurs un os trabéculaire fémoral osteopénique, lié au moins en partie à une activité ostéoclastique augmentée. De plus, la média des gros vaisseaux est fortement altérée, se traduisant par une désorganisation des fibres élastiques et des cellules musculaires lisses hypertrophiques, voir totalement absentes de certaines zones. Les souris adultes Vasn KO inductibles présentent un phénotype comparable au souris Vasn KO. Un décès précoce survient autour de 24 jours après la délétion du gène. Le syndrome néphrotique sévère s'installe rapidement entre J15 et J17 post induction, caractérise par une protéinurie majeure et la présence d'une importante quantité d'ascite intrapéritonéal. La microarchitecture osseuse est étonnamment anormale par rapport aux souris contrôles, et cela est lié au moins en partie à une activité ostéoclastique augmentée. La rapidité de la mise en place de l'ostéopénie des souris Vasn KO inductible suggère un rôle direct de Vasn dans le remaniement osseux. A l'issu de ce travail, les répercussions de la perte Vasorine dans des modèles murins adultes ont été décrites, et plusieurs pistes fonctionnelles explorées. L'implication de Vasorine dans le dialogue os/rein est confirmée et son analyse sera poursuivie.

Parathyroid hormone (PTH), produced by the parathyroid glands, plays a critical role in the regulation of calcium and phosphate homeostasis, acting primarily on bone and kidney to maintain serum calcium levels within a narrow range. Parathyroid hormone also plays important roles in bone remodeling by directly stimulating osteoblasts and osteocytes, integrating its calcemic response with stimulation of bone formation. Through the RANK/RANK-ligand system, these cells activate osteoclasts, promoting a balanced process of bone formation and resorption that maintains bone density and strength. Dysregulation of PTH, as seen in disorders such as hyper- and hypoparathyroidism, can lead to significant clinical complications. In recent years, major advancements have been made in the development of PTH analogs, aimed at leveraging PTH’s physiological effects on bone to treat conditions such as osteoporosis and hypoparathyroidism. While PTH promotes both bone formation and bone resorption, the net outcome may be a gain or loss of bone mass, depending largely on the administration pattern of PTH or its analogs. When PTH is given intermittently (eg, as once-daily subcutaneous injection), bone formation is favored. Continuous administration of PTH or chronic elevation of blood PTH levels as seen in primary hyperparathyroidism tend to promote bone resorption. Parathyroid hormone analogs, such as teriparatide (PTH(1-34)) and the PTHrP analog abaloparatide, administered once daily, have significant efficacy in stimulating bone formation, making them valuable options for the treatment of osteoporosis. Given this capacity to improve bone structure, these analogs hold broader therapeutic potential for other skeletal disorders, including fracture healing and oral bone repair, which expands the scope of PTH-based therapies beyond osteoporosis. Long-acting PTH analogs have applications in treating hypoparathyroidism, offering an alternative to conventional treatment with calcium and active vitamin D. This article reviews the molecular mechanisms of approved and emerging PTH-based medicines, their clinical applications, and recent advances in optimizing their therapeutic potential. We also discuss ongoing research aimed at developing next-generation PTH analogs with improved efficacy for skeletal and metabolic disorders.

Bone diseases are increasing with aging populations and it is important to identify clues to develop innovative treatments. Vasn, which encodes vasorin (Vasn), a transmembrane protein involved in the pathophysiology of several organs, is expressed during the development in intramembranous and endochondral ossification zones. Here, we studied the impact of Vasn deletion on the osteoblast and osteoclast dialog through a cell Coculture model. In addition, we explored the bone phenotype of Vasn KO mice, either constitutive or tamoxifen‐inducible, or with an osteoclast‐specific deletion. First, we show that both osteoblasts and osteoclasts express Vasn. Second, we report that, in both KO mouse models but not in osteoclast‐targeted KO mice, Vasn deficiency was associated with an osteopenic bone phenotype, due to an imbalance in favor of osteoclastic resorption. Finally, through the Coculture experiments, we identify a dysregulation of the Wnt/β‐catenin pathway together with an increase in RANKL release by osteoblasts, which led to an enhanced osteoclast activity. This study unravels a direct role of Vasn in bone turnover, introducing a new biomarker or potential therapeutic target for bone pathologies.

Amelogenesis imperfecta (AI) represents rare tooth anomalies that affect the quality and/or quantity of the enamel. Clinical phenotypes display a wide spectrum, ranging from mild color changes to severe structural alterations with daily pain. However, all affect the quality of life because of mechanical, psychological, esthetic, and/or social repercussions. Several gene mutations have been linked to AI as a nonsyndromic (isolated) phenotype or a wider syndrome. This case report aimed to present a family with dental structure anomalies followed up in the dental department of the Louis Mourier Hospital (APHP, France) for their extremely poor dental condition. The proband and his mother were clinically diagnosed with AI, and genetic analysis revealed an already described variant in DLX3. Then, the family was further examined for tricho-dento-osseous syndrome. This report illustrates the challenge of diagnosing dental structure anomalies, specifically AI, in adults and highlights the need for an accurate and accessible molecular diagnosis for those anomalies to discriminate between isolated and syndromic pathologies.

Alagille syndrome (AGS) is a multisystem disorder classically involving liver and heart failure, characteristic vertebral and facial features and ocular abnormalities. AGS is caused by heterozygous mutations in JAG1 or NOTCH2, with variable phenotype penetrance. We report two cases of AGS in children with tooth defects characterised by green discolouration and hypomineralisation. The role of hyperbilirubinaemia (HB) in this atypical colour, a classical feature of AGS, has been well described. However, it does not totally explain the dental phenotype. As JAG1 and NOTCH2 mutations can affect bone development and considering common physiological pathways between bone and tooth mineralisation, both mutations could participate in this unusual dental phenotype. The role of HB and genetics in the development of the dental phenotype of AGS is discussed in two prototypical cases. Future research should focus on the underlying genetic component of tooth abnormalities.

This paper reports the case of a 3‐year‐old male patient with triple teeth in the right maxillary incisor region and double teeth in the left mandibular incisor region. He had pre‐existing medical conditions. The triple teeth were extracted and examined using micro‐computed tomography. A literature review was performed to discuss this abnormality.

First described in 1988, vasorin (VASN) is a transmembrane glycoprotein expressed during early mouse development, and with a less extent, in various organs and tissues (e.g., kidney, aorta, and brain) postnatally. Vasn KO mice die after 3 weeks of life from unknown cause(s). No human disease has been associated with variants of this gene so far, but VASN seems to be a potential biomarker for nephropathies and tumorigenesis. Its interactions with the TGF-β and Notch1 pathways offer the most serious assumptions regarding VASN functions. In this review, we will describe current knowledge about this glycoprotein and discuss its implication in various organ pathophysiology.