Characterizing the bone anabolic function of Wnt1

骨重建是一个生理相关的过程，发生在整个生命过程中，需要确保骨再生和长期稳定性。它是两种生理活动之间耦合的结果，即通过专门的骨巨噬细胞（破骨细胞）的骨吸收和通过间充质细胞类型（成骨细胞）的骨形成之间的耦合。随着年龄的增长，这种耦合将逐渐转移，有利于过度的骨吸收和减少的骨形成，导致骨质疏松症，一种以骨折风险增加为特征的病理学。到目前为止，骨质疏松症主要用抑制破骨细胞活性（二膦酸盐）或分化（Denosumab）的抗再吸收药物治疗。这些治疗的结果是中断骨吸收和骨形成之间的正常耦合，导致骨形成的继发性抑制，影响骨质量并导致新的病理（颌骨坏死和非典型骨折）。相反，通常认为增加骨形成不会干扰正常的骨结合，因此肯定会提供更好的替代方案。然而，不希望的副作用是否是骨合成代谢治疗的结果仍有待确定，这是本申请的中心点。事实上，我们观察到过表达Fra1（Fra1Tg）的成骨小鼠显示高水平的循环Wnt 1，一种新发现的人类骨合成代谢分子。重要的是，我们以前在Fra1Tg小鼠的特点，包括严重的脂肪营养不良，一般纤维化和受损的浆细胞分化的许多病理。我们现在建议，在小鼠模型的帮助下，在骨骼中有条件地过表达Wnt 1，以确定Wnt 1是否真的可以用作骨合成代谢治疗，而不会诱导在Fra1Tg小鼠中观察到的不必要的副作用。

Bone remodeling is a physiologically relevant process occurring throughout life required to ensure bone regeneration and long-term stability. It is the result of the coupling between two physiological activities i.e. the coupling between bone resorption by a specialized bone macrophage (the osteoclast) and bone formation by a mesenchymal cell type (the osteoblast). With age, this coupling will be progressively shifted in favor of an excess bone resorption and decreased bone formation leading to osteoporosis, a pathology characterized by an increased fracture risk. So far, osteoporosis is mainly treated with anti-resorptive drugs either inhibiting osteoclast activity (bisphosphonates) or differentiation (Denosumab). A consequence of these treatments is to interrupt the normal coupling between bone resorption and formation leading to a secondary inhibition of bone formation that affects the bone quality and lead to new pathologies (necrosis of the jaw and atypical bone fractures). In contrary, it is generally believed that increasing bone formation would not be disturbing the normal bone coupling and therefore would certainly offer a better alternative. However, whether unwanted side effects would be a consequence of bone anabolic therapies remains to be established and is the central point of this application. Indeed, we observed that osteosclerotic mice over-expressing Fra1 (Fra1Tg) display high levels of circulating Wnt1, a newly identified bone-anabolic molecule in humans. Importantly, we previously characterized numerous pathologies in Fra1Tg mice including severe lipodystrophy, general fibrosis and impaired plasma cell differentiation. We now propose, with the help of a mouse model conditionally over-expressing Wnt1 in the bone, to determine whether Wnt1 could indeed be used as a bone-anabolic therapy without inducing the unwanted side effects observed in Fra1Tg mice.