Osteoporosis, a common skeletal disease, is characterized by decreased bone mass and deterioration of bone microstructure, making bones more porous and more susceptible to fracture. Bone health is maintained through a continuous remodeling process driven by two specialized cell types: osteoblasts, which build bone, and osteoclasts, which destroy bone. Disruption of this balance plays a central role in the progression of the disease. Current treatments broadly focus on slowing bone resorption by osteoclasts or promoting bone formation by osteoblasts.
One widely used approach is anti-sclerostin therapy. It promotes bone formation by reactivating bone lining cells (BLCs), a population of dormant osteoblasts found on inactive bone surfaces. However, the molecular mechanisms governing the reactivation of these dormant cells are still poorly understood.
To address this gap, a research team led by Professor Sunghoon Kwon of Seoul National University and Professor Sang Wan Kim of Seoul National University School of Medicine investigated the behavior of osteoblasts on static bone surfaces. Their findings were published in Volume 14 of the journal on April 2, 2026. bone research.
The research team employed spatially resolved osteoblast trace transcriptomics, an integrated method that combines osteoblast-specific lineage tracing and spatially resolved laser-activated cell sorting (SLACS). This approach allowed us to capture gene activity within osteoblasts while preserving the spatial context within the bone tissue.
“BLCs lack specific histological or genetic markers, making their identification very difficult. It is even more difficult to distinguish between reactivated BLCs and newly recruited osteoblasts after treatment with anti-sclerostin antibodies. Because they form thin, spatially confined layers, it is also important to capture molecular signaling while preserving spatial context. This method helped overcome these challenges and identify signaling pathways that act as key regulators of “osteoblast state transitions”. Professor Kwon talked about the thinking behind choosing an integrated approach.
The research team characterized osteoblasts in three different states, including active, inactive, and reactivated after anti-sclerostin treatment. The reactivated cells closely resembled active osteoblasts, whereas the inactive group exhibited a different profile. While elucidating the mechanisms underlying osteoblast state regulation, the research team identified TGF-β signaling as a potent regulator of osteoblast quiescence. The signaling pathway is downregulated in active and reactivated osteoblasts, suggesting that inhibition of TGF-β may help reactivate dormant osteoblasts.
In laboratory-cultured bone organoid systems, exposure to TGF-β pushed osteoblasts toward a BLC-like morphology, resulting in flatter cell aggregates, reduced vertical thickness, and reduced proliferative activity.
In experiments based on lineage-tracing mouse models, TGF-β treatment promoted the transition to inactivity, and blocking TGF-β promoted reactivation of these cells. Remarkably, the combination of TGF-β blocking antibody and anti-sclerostin treatment increased the thickness and number of cells of the osteoblast lineage more than anti-sclerostin treatment alone, supporting the idea that TGF-β functions as a regulator of osteoblast activation.
Therapeutic potential was analyzed using a hindlimb unloading mouse model used to mimic musculoskeletal unloading and bone loss. Combining TGF-β and sclerostin inhibition significantly increased trabecular bone volume fraction and thickness and decreased trabecular bone separation compared to either treatment alone. Dynamic bone measurements also showed stronger bone formation with the combination treatment than with anti-sclerostin drugs alone. At the same time, TGF-β inhibition significantly reduced bone resorption markers, suggesting that TGF-β inhibition not only helps reactivate bone-forming cells but also may contribute to limiting bone destruction.
“Anabolic drugs like romosozumab promote bone formation by osteoblasts by inhibiting sclerostin, but their long-term use is often associated with side effects. Our study will help develop combination therapies that allow rapid and effective bone regeneration and shorten the duration of treatment.” Professor Kim explained while talking about the significance of the research.
TGF-β signaling is a fundamental and pleiotropic pathway, and its inhibition can lead to deleterious side effects. Although further studies should focus on the safety and efficacy of this targeted therapy, the results of this study provide clearer insight into the molecular mechanisms associated with osteoblast reactivation and identify TGF-β as a promising combination target to enhance the efficacy of anti-sclerostin therapy in osteoporosis.
sauce:
Reference magazines:
Choi, A. others. (2026). Spatially resolved transcriptomics tracking of osteoblasts reveals TGF-β as a combined target with sclerostin in osteoporosis. Bone research. DOI: 10.1038/s41413-026-00521-9. https://www.nature.com/articles/s41413-026-00521-9
