Wnt signaling maintains homeostasis in the bone marrow cavity: if Wnt signaling is inhibited then bone volume and density would decline. In this study, we identified a population of Wnt-responsive cells as osteoprogenitor in the intact trabecular bone region, which were responsible for bone development and turnover. If an implant was placed into the long bone, this Wnt-responsive population and their progeny contributed to osseointegration. We employed Axin2Cre^CreERT2/+;R26^mTmG/+ transgenic mouse strain in which Axin2-positive, Wnt-responsive cells, and their progeny are permanently labeled by GFP upon exposure to tamoxifen. Each mouse received femoral implants placed into a site prepared solely by drilling, and a single-dose liposomal WNT3A protein was used in the treatment group. A lineage tracing strategy design allowed us to identify cells actively expressing Axin2 in response to Wnt signaling pathway. These tools demonstrated that Wnt-responsive cells and their progeny comprise a quiescent population residing in the trabecular region. In response to an implant placed, this population becomes mitotically active: cells migrated into the peri-implant region, up-regulated the expression of osteogenic proteins. Ultimately, those cells gave rise to osteoblasts that produced significantly more new bone in the peri-implant region. Wnt-responsive cells directly contributed to implant osseointegration. Using a liposomal WNT3A protein therapeutic, we showed that a single application at the time of implant placed was sufficient to accelerate osseointegration. The Wnt-responsive cell population in trabecular bone, activated by injury, ultimately contributes to implant osseointegration. Liposomal WNT3A protein therapeutic accelerates implant osseointegration in the long bone.

Wnt 信号维持骨髓腔内的稳态：如果 Wnt 信号被抑制，那么骨量和密度就会下降。在这项研究中，我们在完整的骨小梁区域鉴定了一群 Wnt 反应细胞作为骨祖细胞，它们负责骨发育和更新。如果将植入物放入长骨中，这种 Wnt 反应性群体及其后代会促进骨整合。我们采用了Axin2Cre ^{CreERT2/ +；}R26 ^{mTmG/ +}转基因小鼠品系，其中 Axin2 阳性、Wnt 反应性细胞及其后代在暴露于他莫昔芬后被 GFP 永久标记。每只小鼠都接受了放置在仅通过钻孔准备的部位的股骨植入物，并且在治疗组中使用单剂量脂质体 WNT3A 蛋白。谱系追踪策略设计使我们能够识别响应 Wnt 信号通路主动表达 Axin2 的细胞。这些工具表明，Wnt 响应细胞及其后代包括位于小梁区域的静止群体。作为对植入物的响应，该群体变得有丝分裂活跃：细胞迁移到植入物周围区域，上调成骨蛋白的表达。最终，这些细胞产生了成骨细胞，在种植体周围区域产生了更多的新骨。Wnt 反应细胞直接促成了种植体骨整合。使用脂质体 WNT3A 蛋白治疗剂，我们发现在植入时单次应用就足以加速骨整合。由损伤激活的骨小梁中的 Wnt 反应性细胞群最终有助于植入物骨整合。脂质体 WNT3A 蛋白治疗剂可加速长骨中的种植体骨整合。由损伤激活，最终有助于种植体骨整合。脂质体 WNT3A 蛋白治疗剂可加速长骨中的种植体骨整合。由损伤激活，最终有助于种植体骨整合。脂质体 WNT3A 蛋白治疗剂可加速长骨中的种植体骨整合。