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

Abstract

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.

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Funding

National Research Foundation of Korea (NRF)(2023R1A2C2003958)

Boramae Medical Center (02-2020-9)

Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs)(RS-2024-00468338)

Ministry of Trade, Industry and Energy (Ministry of Trade, Industry and Energy, Korea)(RS-2024-00508416)

Ministry of Education (Ministry of Education of the Republic of Korea)(Seoul National University in 2025)

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The Author(s)