Postmenopausal osteoporosis develops largely because the decline in estrogen disrupts the normal balance of bone remodeling. Throughout life, old or damaged bone is removed by osteoclasts and replaced by new tissue produced by osteoblasts. Estrogen deficiency can shift this equilibrium toward excessive resorption, weakening the skeleton and increasing the risk of fractures. Existing treatments can reduce osteoclast activity or stimulate bone formation, but therapies that coordinate both sides of the remodeling cycle remain an important scientific goal.

The new study focuses on neddylation, a biochemical modification in which the small protein NEDD8 is attached to target proteins. Similar to ubiquitination, neddylation can alter a protein’s stability, location, activity or interactions with other molecules. It is controlled by an enzyme system that includes NEDD8-activating, conjugating and ligating enzymes. Because this pathway influences the behavior of many regulatory proteins, abnormal neddylation has been linked to several diseases, including cancer, inflammatory disorders and abnormalities of cellular differentiation.

In bone biology, the researchers examined how neddylation affects NFATc1, a central regulator of osteoclast development. Osteoclasts arise from precursor cells in the monocyte–macrophage family and become specialized, multinucleated cells capable of dissolving mineralized bone. Signals such as receptor activator of nuclear factor κB ligand, or RANKL, activate transcriptional programs that drive this transformation. NFATc1 is widely regarded as a master transcription factor in that process because it turns on genes required for osteoclast formation, maturation and bone-resorbing function.

The study also investigated Runx2, a transcription factor essential for osteoblast differentiation. Osteoblasts originate from mesenchymal stem and progenitor cells and produce the collagen-rich matrix that later becomes mineralized. Runx2 activates genes associated with the osteoblast identity and is necessary for the progression of bone-forming cells. The opposing roles of NFATc1 and Runx2 make them attractive molecular landmarks for studying how the skeleton decides whether to remove existing tissue or build new tissue.

According to the researchers, neddylation functions as a regulatory layer for both factors, linking a shared biochemical pathway to the contrasting activities of osteoclasts and osteoblasts. By influencing NFATc1, the pathway can affect the genetic program that enables osteoclasts to resorb bone. Through Runx2, it can also influence the differentiation and activity of osteoblasts. This connection is significant because a treatment aimed at only one cell type may leave the underlying imbalance unresolved: suppressing resorption without restoring formation can limit recovery, while stimulating formation without controlling excessive resorption may produce an incomplete response.

The concept of targeting neddylation therefore offers a potential “two-for-one” approach to osteoporosis. Rather than treating NFATc1 and Runx2 as isolated targets, researchers propose manipulating the upstream modification system that helps regulate both. In principle, carefully calibrated intervention could restrain the molecular signals that generate overly active osteoclasts while preserving or enhancing the Runx2-dependent program of osteoblast development. Such an approach could be particularly valuable in postmenopausal disease, where accelerated resorption and inadequate replacement occur simultaneously.

However, neddylation is not exclusive to bone cells. The same pathway participates in fundamental processes such as protein turnover, cell-cycle control, stress responses and gene regulation across many tissues. That broad biological reach means that any drug designed to alter neddylation would need to achieve sufficient selectivity, dose control and tissue safety. A systemic inhibitor could potentially affect healthy cells, while a bone-directed therapy might need to exploit differences in enzyme expression, cellular uptake or disease-associated signaling between skeletal and non-skeletal tissues.

The findings establish a mechanistic rationale for further research rather than an immediately available treatment. Future studies will need to determine how neddylation changes in human postmenopausal bone, identify the precise molecular sites modified on NFATc1 and Runx2, and test whether manipulating the pathway improves bone density and strength in relevant disease models. Researchers will also need to establish whether the effects differ between cortical and trabecular bone, how the pathway interacts with current osteoporosis medications, and whether long-term modulation can avoid unwanted effects elsewhere in the body. If those challenges can be addressed, neddylation may become a promising dual-action target for restoring the balance between bone removal and bone formation.

Subject of Research: Neddylation regulation of NFATc1 and Runx2 in osteoclast–osteoblast balance and postmenopausal osteoporosis

Article Title: Neddylation of NFATc1 and Runx2 regulates osteoclast–osteoblast balance and represents a dual-action therapeutic target for postmenopausal osteoporosis

Article References: Lee, J., Lee, M.Y., Kim, H.S. et al. Neddylation of NFATc1 and Runx2 regulates osteoclast–osteoblast balance and represents a dual-action therapeutic target for postmenopausal osteoporosis. Exp Mol Med (2026). https://doi.org/10.1038/s12276-026-01784-2

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01784-2

Keywords: Neddylation, NFATc1, Runx2, osteoclasts, osteoblasts, bone remodeling, postmenopausal osteoporosis, osteoporosis therapy

One of the emerging therapeutic approaches targets sclerostin, a protein that inhibits bone formation by osteoblasts. Anti-sclerostin therapies have demonstrated promise by reactivating dormant bone lining cells (BLCs), a subset of quiescent osteoblasts residing on inactive bone surfaces. These BLCs are essential for recruiting active osteoblasts to repair and strengthen bone. Despite these therapeutic advances, the molecular switches that govern the transition of these dormant cells back to an active state have remained elusive, hindering the optimization of treatment protocols.

Pioneering this quest for understanding, a research team led by Professors Sunghoon Kwon and Sang Wan Kim utilized an integrative, spatially resolved transcriptomic technique to dissect osteoblast activity in unprecedented detail. The methodology involved osteoblast-specific lineage tracing coupled with spatially resolved laser-activated cell sorting (SLACS), allowing researchers to observe gene expression changes within osteoblasts while preserving their three-dimensional context within bone tissue. This approach overcame significant challenges in identifying BLCs, which lack unique histological or genetic markers, and in distinguishing reactivated BLCs from newly recruited osteoblasts following anti-sclerostin treatment.

The investigators categorized osteoblasts into three functional states: active, inactive (quiescent), and reactivated post-treatment. Transcriptomic profiling revealed that reactivated osteoblasts bore striking molecular resemblance to their active counterparts, whereas inactive osteoblasts displayed a distinct gene expression signature. Crucially, the study unveiled the transforming growth factor beta (TGF-β) signaling pathway as a key regulator enforcing osteoblast quiescence. TGF-β signaling was markedly suppressed in active and reactivated osteoblast populations, indicating that inhibition of this pathway might release the brakes on dormant osteoblasts, promoting their reactivation.

Supplementary experiments in bone organoid cultures corroborated these findings. When exposed to TGF-β, osteoblasts adopted a BLC-like phenotype characterized by flattened morphology, decreased vertical cellular thickness, and reduced proliferative capacity. Conversely, blocking TGF-β signaling encouraged a shift away from dormancy, underscoring its pivotal role in maintaining osteoblast inactivity. These observations were further confirmed in lineage tracing mouse models, where administration of TGF-β promoted osteoblast quiescence, while TGF-β blockade facilitated reactivation.

Most strikingly, the combination of TGF-β blockade with anti-sclerostin therapy amplified osteoblast lineage cell number and thickness beyond what was achievable with anti-sclerostin treatment alone. This synergy underscores the therapeutic potential of dual-targeted intervention in osteoporosis. To emulate conditions of bone loss and musculoskeletal disuse, the research team employed a hindlimb unloading mouse model. Here, combined inhibition of TGF-β and sclerostin significantly augmented trabecular bone volume fraction and thickness, while simultaneously reducing trabecular separation more effectively than monotherapies.

Dynamic bone formation metrics echoed these improvements, revealing elevated rates of osteoblastic bone deposition with combined treatment regimes. Beyond promoting bone formation, TGF-β inhibition also diminished markers indicative of osteoclastic bone resorption, hinting at a dual mechanism of action—both enhancing bone regeneration and mitigating bone degradation. This multi-faceted influence suggests that targeting TGF-β signaling could recalibrate skeletal homeostasis more comprehensively than currently available treatments.

Despite these promising outcomes, the complexity of TGF-β signaling raises concerns regarding potential side effects, as its biological functions extend far beyond the skeletal system. Future investigations will need to rigorously evaluate the safety profile and therapeutic window of this combination approach before clinical translation. Nevertheless, identifying TGF-β as a molecular gatekeeper of osteoblast quiescence and activation opens an exciting avenue for enhancing anabolic osteoporosis therapies.

Current anabolic treatments like romosozumab have demonstrated efficacy by inhibiting sclerostin, yet their long-term application poses safety challenges and side effects that limit broader usage. The integration of TGF-β inhibition may enable potent yet safer bone regeneration strategies by reducing treatment duration and possibly attenuating adverse outcomes. This research heralds a shift towards precision medicine in osteoporosis, leveraging a deeper molecular understanding to design combination therapies tailored for rapid and robust bone restoration.

The implications of reactivating quiescent osteoblast populations extend beyond osteoporosis to broader musculoskeletal health, potentially impacting recovery from fractures, bone defects, and degenerative diseases. By harnessing spatially resolved transcriptomics and lineage tracing, this study exemplifies how cutting-edge technologies can unravel complex cellular interactions within intricate tissue environments, fostering translational breakthroughs. The collaboration between bioengineering and medical disciplines at Seoul National University exemplifies multidisciplinary synergy driving innovation in skeletal biology.

In summary, this seminal work delineates TGF-β signaling as a fundamental inhibitory axis that maintains osteoblast dormancy, with its suppression serving as a catalyst for reactivating bone-forming cells. Combined with sclerostin inhibition, targeting TGF-β could significantly enhance therapeutic outcomes for osteoporosis patients, mitigating fracture risk and improving quality of life. As further clinical investigations progress, this molecular insight promises to reshape therapeutic paradigms and offers hope for millions affected by osteoporosis worldwide.

Subject of Research: Cells

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

News Publication Date: 2-Apr-2026

References: DOI: 10.1038/s41413-026-00521-9

Image Credits: German Tenorio from Openverse

Keywords: Osteoporosis, Osteoblast, Bone Remodeling, TGF-β Signaling, Anti-sclerostin Therapy, Bone Lining Cells, Lineage Tracing, Spatial Transcriptomics, Bone Formation, Bone Resorption, Musculoskeletal Health