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<p>Dynamic transitions of mature osteoblasts between active and quiescent states are essential for bone homeostasis and present a promising target for osteoanabolic therapy. However, these transitions remain poorly understood due to cellular heterogeneity and limited spatial context. Here, we employed spatially resolved osteoblast-traced transcriptomics, integrating an osteoblast-specific lineage tracing study and spatially resolved laser-activated cell sorting (SLACS), to profile osteoblast states on quiescent bone surfaces. This approach identified transforming growth factor-beta (TGF-β) signaling as a regulator of osteoblast activation. We further validated this role using single-cell RNA sequencing, in vitro functional assays, and in vivo. In a hindlimb unloading mouse model, dual inhibition of TGF-β and sclerostin enhanced bone mass and mitigated bone loss more effectively than sclerostin inhibition alone. These findings reveal a mechanistic role for TGF-β in regulating osteoblast dynamics and propose a dual-target therapeutic strategy that enhances the efficacy of anti-sclerostin treatment in osteoporosis.</p>

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Spatially resolved osteoblast-traced transcriptomics uncovers TGF-β as a combination target with sclerostin in osteoporosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Ahyoun Choi,
  • Ji Yeon Lee,
  • Hyejin Yoon,
  • Xiangguo Che,
  • Minkyeong Choi,
  • Yongkuk Park,
  • Kyoungseob Shin,
  • Hyunho Lee,
  • Jimin Park,
  • Sung Hye Kong,
  • Jinhyun Kim,
  • Amos Chungwon Lee,
  • Chan Soo Shin,
  • Je-Yong Choi,
  • Jungwoo Lee,
  • Sunghoon Kwon,
  • Sang Wan Kim

摘要

Dynamic transitions of mature osteoblasts between active and quiescent states are essential for bone homeostasis and present a promising target for osteoanabolic therapy. However, these transitions remain poorly understood due to cellular heterogeneity and limited spatial context. Here, we employed spatially resolved osteoblast-traced transcriptomics, integrating an osteoblast-specific lineage tracing study and spatially resolved laser-activated cell sorting (SLACS), to profile osteoblast states on quiescent bone surfaces. This approach identified transforming growth factor-beta (TGF-β) signaling as a regulator of osteoblast activation. We further validated this role using single-cell RNA sequencing, in vitro functional assays, and in vivo. In a hindlimb unloading mouse model, dual inhibition of TGF-β and sclerostin enhanced bone mass and mitigated bone loss more effectively than sclerostin inhibition alone. These findings reveal a mechanistic role for TGF-β in regulating osteoblast dynamics and propose a dual-target therapeutic strategy that enhances the efficacy of anti-sclerostin treatment in osteoporosis.