Characterizing the bone anabolic function of Wnt1

骨重建是一个生理学上相关的过程，发生在一生中，需要确保骨再生和长期稳定。它是两种生理活动耦合的结果，即特殊的骨巨噬细胞(破骨细胞)的骨吸收和间质细胞类型(成骨细胞)的骨形成之间的耦合。随着年龄的增长，这种耦合将逐渐改变，有利于过度的骨吸收和减少的骨形成导致骨质疏松症，这是一种以增加骨折风险为特征的病理。到目前为止，骨质疏松症的治疗主要是用抗吸收药物来抑制破骨细胞的活性(双磷酸盐)或分化(Denosumab)。这些治疗的结果是破坏骨吸收和骨形成之间的正常耦合，导致继发性骨形成抑制，从而影响骨质量并导致新的病理(颌骨坏死和不典型骨骨折)。相反，人们普遍认为，增加骨形成不会干扰正常的骨连接，因此肯定会提供更好的替代方案。然而，骨合成代谢疗法是否会产生不良副作用仍有待确定，这也是该应用的中心问题。事实上，我们观察到，过度表达Fra1(Fra1Tg)的骨硬化症小鼠表现出高水平的循环WNT1，这是一种新发现的人类骨合成分子。重要的是，我们之前描述了Fra1Tg小鼠的许多病理特征，包括严重的脂肪营养不良、全身纤维化和浆细胞分化受损。我们现在建议，在一个有条件地在骨骼中过表达Wnt1的小鼠模型的帮助下，确定Wnt1是否确实可以用作骨合成代谢疗法，而不会引起在Fra1Tg小鼠中观察到的不想要的副作用。

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.