Recent study links TGF-β signaling pathway to osteoblast dormancy and suggests an enhanced combination strategy with anti-sclerostin treatment in osteoporosis

A recent mouse model based study suggests that blocking TGF-β may improve osteoporosis treatment by helping quiescent osteoblasts in inactive bone surfaces return to an active state. Using spatial transcriptomics, single-cell analysis, and functional experiments, researchers identified TGF-β signaling as a regulator of osteoblast activation. In a bone-loss mouse model, dual inhibition of TGF-β and sclerostin increased bone mass more effectively than sclerostin inhibition alone, highlighting a promising combination strategy.

Osteoporosis, a common skeletal disorder, is marked by reduced bone mass and deterioration of bone microarchitecture, making bones more porous and prone to fractures. Bone health is maintained through a continuous remodeling process driven by two types of specialized cells: osteoblasts, which build bone, and osteoclasts, which break it down. Disruptions in this balance play a central role in the progression of the disease. Current treatments broadly focus on slowing osteoclast-driven bone resorption or enhancing osteoblast-mediated bone formation.

One widely used approach is anti-sclerostin therapy, which promotes bone formation by reactivating bone lining cells (BLCs), a population of quiescent osteoblasts found on inactive bone surfaces. However, the molecular mechanisms that govern the reactivation of these dormant cells remain poorly understood.

To address this gap, a research team led by Professor Sunghoon Kwon from Seoul National University and Professor Sang Wan Kim from Seoul National University College of Medicine investigated the behavior of osteoblasts on quiescent bone surfaces. Their findings were published on April 02, 2026, in Volume 14 of the journal Bone Research.

The team employed spatially resolved osteoblast-traced transcriptomics, an integrative method that combines osteoblast-specific lineage tracing with spatially resolved laser-activated cell sorting (SLACS). This approach allowed them to capture gene activity within osteoblasts while preserving their spatial context within bone tissue.

“BLCs lack specific histological or genetic markers, which makes their identification extremely difficult. This is even more challenging to distinguish reactivated BLCs from newly recruited osteoblasts following treatment with anti-sclerostin antibody. Also, as BLC form a thin, spatially-restricted layer, capturing the molecular signaling while keeping the spatial context preserved is also crucial. This method helped in overcoming these challenges and identifying the signaling pathway that acts as the key regulator of osteoblast state transition,” mentioned Prof. Kwon, while talking about the idea behind selecting the integrative approach.

The research team characterized osteoblasts in three different conditions, including active, inactive, and reactivated after anti-sclerostin treatment. The reactivated cells closely resembled active osteoblasts, while the inactive group showed a distinct profile. While elucidating mechanisms underlying osteoblast state regulation, the research team identified TGF-β signaling as a strong regulator of osteoblast quiescence. The signaling pathway was downregulated in active and reactivated osteoblasts, suggesting that TGF-β suppression can aid in reactivation of the dormant osteoblasts.

In laboratory-grown bone organoid systems, exposure to TGF-β pushed osteoblasts toward a BLC-like morphology, with flatter cellular assemblies and reduced vertical thickness and lower proliferative activity.

In lineage tracing mouse model-based experiments, TGF-β treatment promoted the transition toward inactivity, while blocking TGF-β encouraged reactivation of these cells. Notably, combining a TGF-β-blocking antibody with anti-sclerostin treatment increased the thickness and number of osteoblast-lineage cells more than anti-sclerostin treatment alone, supporting the idea that TGF-β acts as a regulator of osteoblast activation.

The therapeutic potential was also analyzed using a hindlimb unloading mouse model, which is used to mimic musculoskeletal unloading and bone loss. A combination of TGF-β inhibition and sclerostin inhibition produced greater gains in trabecular bone volume fraction and thickness, with decreased trabecular separation, compared to either treatment alone. Dynamic bone measurements also showed stronger bone formation with the combined treatment than with anti-sclerostin alone. At the same time, TGF-β inhibition resulted in significant decrease in markers of bone resorption, suggesting that TGF-β inhibition may contribute not only by helping reactivate bone-forming cells but also by limiting bone breakdown.

“While anabolic agents like romosozumab enhance osteoblast-driven bone formation by inhibiting sclerostin, its long-term use is often associated with adverse effects. Our study can help in development of a combination therapy, that allows rapid and effective bone regeneration and reduce the treatment duration,” explained Prof. Kim, while talking about the significance of the study.

As TGF-β signaling is a fundamental, multi-faceted pathway, its inhibition can lead to adverse side effects. While further studies should focus on the safety and efficacy of this targeted therapy, the results of this study offer a clearer insight of the molecular mechanism associated with osteoblast reactivation and identifies TGF-β as a promising combination target to enhance the efficacy of anti-sclerostin treatment in osteoporosis.


Reference
Title of original paper: Spatially resolved osteoblast-traced transcriptomics uncovers TGF-β as a combination target with sclerostin in osteoporosis
Journal: Bone Research
DOI: https://doi.org/10.1038/s41413-026-00521-9


About Seoul National University
Seoul National University, founded in 1946 as Korea’s first comprehensive national university, is widely regarded as one of the country’s leading centers for higher education and research. Its main campuses include Gwanak in Seoul and Yeongeon for medical studies, alongside several additional research sites. The university comprises of 27 schools and colleges, more than 30,000 students, over 6,000 faculty members, and extensive global partnerships. In recent international rankings listed by SNU, it placed 38th in the QS World University Rankings 2026 and 58th in the THE World University Rankings 2026.
Website: https://en.snu.ac.kr/

About Professor Sunghoon Kwon from Seoul National University
Prof. Sunghoon Kwon is a Professor of the Interdisciplinary Program in Bioengineering, Seoul National University, Republic of Korea. He completed his Ph.D. in Bioengineering from UCBerkeley, USA in 2004. His research interests include immunoprofiling, multi-omics analysis, deep learning, implantable device, rapid antimicrobial susceptibility testing. He actively collaborates with medical researchers for his research work. He has authored more than 300 highly cited research articles till date.

About Professor Sang Wan Kim from Seoul National University College of Medicine
Prof. Sang Wan Kim is a Professor in the Department of Internal Medicine at Seoul National University College of Medicine. He earned his MD. And Ph.D degree from Seoul National University. He specializes in internal medicine, endocrinology, bone and mineral metabolism. His research areas include parathyroid disorders, osteoporosis, and metabolism. He has authored more than 150 research articles which has been cited over 4,000 times.

Funding information
This work was supported by grants from the National Research Foundation of Korea (2023R1A2C2003958), Boramae Medical Center (02-2020-9), the Korea-US Collaborative Research Fund (KUCRF), funded by the Ministry of Science and ICT and Ministry of Health & Welfare, Republic of Korea (RS-2024-00508416), the Industrial Strategic Technology Development Program funded by the Ministry of Trade Industry & Energy (MOTIE) of Republic of Korea (RS-2024-00508416), and the BK21 FOUR program of the Education and Research Program for Future ICT Pioneers (Seoul National University in 2025).