破骨細胞分化是骨吸收細胞發展為具完整功能之破骨細胞的重要過程。在此過程中，Ca²⁺訊號在啟動下游訊號傳遞路徑中扮演關鍵角色。本研究利用RANKL刺激以探討Ca²⁺動態變化在破骨細胞生成中的作用。破骨細胞之成熟以細胞大小、多核融合以及TRAP表現作為判定標準。Ca²⁺訊號分析顯示，於RANKL刺激短時間內的Ca²⁺反應較為微弱，並未出現顯著變化；相對地，長時間觀察則顯示Ca²⁺訊號呈現動態振盪，並在分化過程中逐漸穩定。此結果指Ca²⁺的振盪模式，而非其絕對濃度，對破骨細胞生成至關重要。進一步透過BAPTA-AM抑制細胞內Ca²⁺來證實Ca²⁺的功能重要性，結果顯示抑制 Ca²⁺會影響細胞融合並阻礙破骨細胞成熟。Western blotting分析進一步顯示NF-κB與MAPK訊號路徑呈現協同活化，其中 NF-κB在早期迅速活化，而MAPK則維持較長時間的活化狀態，最終促使關鍵轉錄因子NFATc1上調。為了直接操控Ca²⁺訊號，本研究採用光遺傳學系統搭配 CatCh-Venus分子工具，透過藍光刺激精確控制Ca²⁺內流。低頻刺激（0.01 Hz）對細胞無毒性，且可維持細胞存活率。雖然光刺激可促進多核融合，但所得細胞體積較小，並呈現早期分化特徵。綜合而言，本研究顯示Ca²⁺動態振盪對破骨細胞分化與功能具有關鍵作用，並透過NF-κB、MAPK及NFATc1訊號路徑進行調控。雖然光遺傳學提供了一種有潛力的工具來操控破骨細胞生成，但仍需進一步研究以完全重現成熟破骨細胞的分化過程。

Osteoclast differentiation is a critical process for bone-resorbing cells, to develop into fully function osteoclasts. Ca2+ signaling plays an important role in activating downstream signaling cascades during this process. In this study, we investigated the contribution of Ca2+ dynamics to osteoclastogenesis using RANKL-stimulation. Mature osteoclasts were identified based on cell size, multinucleation and TRAP expression. Analysis of Ca2+ signaling revealed that short-term Ca2+ responses were minimal and did not show significant upon RANKL treatment. In contrast, long-term observations showed dynamic oscillatory changes that gradually stabilized during differentiation. The Ca2+ patterns suggest that Ca2+ oscillatory patterns are critical to osteoclastogenesis. The functional importance of intracellular Ca2+ was confirmed using BAPTA-AM inhibition, which impaired the cell fusion and hindered maturation of osteoclasts. Western blot analysis further demonstrated the coordinated activation of NF-κB and MAPK activation, with early NF-κB activation and sustained MAPK signaling resulting in the upregulation of master transcription factor NFATc1. We employed optogenetic system to directly manipulate Ca2+ signaling using CatCh-Venus to control Ca2+ influx in response to blue light stimulation. Low-frequency stimulation (0.01 Hz) displayed non-toxic and compatible with cell viability. While optogenetic activation promoted multinucleation, the resulting cells remained smaller with features of early-stage differentiation. In conclusion, our findings demonstrate that dynamic Ca2+ oscillations are essential for osteoclast differentiation and function, as demonstrated in NF-κB, MAPK and NFATc1 pathways. Although light stimulation of Ca2+ signaling provide a powerful tool to manipulate osteoclastogenesis, further studies are required to fully recapitulate mature osteoclast differentiation.

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