For millions of people worldwide, osteoporosis is a silent thief. It steals bone mass gradually, without pain or warning, until a routine fall or a simple stumble suddenly becomes a life-altering fracture. Postmenopausal women bear the heaviest burden: as estrogen levels plummet after menopause, the delicate balance of bone remodeling tips decisively toward destruction, leaving the skeleton porous, fragile, and vulnerable.
The statistics are sobering. Osteoporosis affects a substantial proportion of aging populations, and the consequences extend far beyond broken bones. Hip fractures can lead to permanent disability, loss of independence, and even death. Yet despite decades of research, existing treatments remain fundamentally limited in one crucial respect: they typically work on only one side of the bone remodeling equation.
Now, a discovery from Seoul National University may have found a way to flip the entire balance at once. The research team, led by Professor Yang-Sook Chun, has identified a molecular switch called neddylation that simultaneously drives bone destruction and suppresses bone formation in postmenopausal osteoporosis. Even more remarkably, they have shown that blocking this switch with an existing drug candidate can reverse bone loss in animal models, preserving both bone density and architecture.
The findings, published in Experimental & Molecular Medicine in 2026, represent what the researchers describe as the first demonstration that a single protein modification can tip the balance between bone-destroying and bone-building cells in opposite directions simultaneously. This dual-action mechanism opens a fundamentally new therapeutic strategy for a disease that has long resisted truly comprehensive treatment.
To appreciate the significance of this discovery, it is essential to understand the dynamic nature of bone tissue. Far from being an inert scaffold, bone is constantly being broken down and rebuilt through a process called remodeling. Two specialized cell types orchestrate this lifelong renovation project: osteoclasts, which resorb old or damaged bone, and osteoblasts, which synthesize new bone matrix to replace what has been removed.
In healthy young adults, these two cell populations work in harmonious opposition. Osteoclasts clear away microscopic areas of damage, while osteoblasts fill in the excavated cavities with fresh, strong bone. The result is a skeleton that maintains its structural integrity despite the daily wear and tear of life. This equilibrium depends on a complex network of signaling molecules, transcription factors, and post-translational modifications that regulate the differentiation and activity of both cell types.
The master regulator of osteoclast differentiation is a transcription factor called NFATc1 (nuclear factor of activated T cells, cytoplasmic 1). When the cytokine RANKL binds to its receptor on osteoclast precursors, it triggers a signaling cascade that culminates in NFATc1 activation. NFATc1 then drives the expression of genes required for osteoclast maturation, fusion, and bone-resorbing activity. Without NFATc1, osteoclasts cannot form or function.
On the other side of the equation, osteoblast differentiation is governed by Runx2 (Runt-related transcription factor 2), often described as the master regulator of bone formation. Runx2 controls the expression of osteoblast-specific genes including osteocalcin, alkaline phosphatase, and type I collagen. Its activity is essential for the transition of mesenchymal stem cells into mature, bone-forming osteoblasts.
In postmenopausal osteoporosis, estrogen deficiency disrupts this carefully balanced system. Osteoclast activity increases dramatically while osteoblast function declines, creating a double-negative effect on bone mass. Current treatments address this imbalance by targeting one side or the other: bisphosphonates and denosumab inhibit osteoclasts, while parathyroid hormone analogs and romosozumab stimulate osteoblasts. But none of these approaches simultaneously corrects both sides of the equation.
The Seoul National University team's discovery emerged from an exploration of post-translational modifications in bone tissue. Post-translational modifications are chemical changes made to proteins after they are synthesized, altering their stability, localization, or activity. Among these modifications, neddylation has emerged as a critical regulator of diverse cellular processes, yet its role in bone biology had remained largely unexplored.
Neddylation is a process whereby a small ubiquitin-like protein called NEDD8 is covalently attached to target proteins through an enzymatic cascade involving E1, E2, and E3 enzymes. The most well-studied substrates of neddylation are cullin proteins, which serve as scaffolds for cullin-RING E3 ubiquitin ligases (CRLs). When NEDD8 is attached to cullins, CRLs become activated and can ubiquitinate their target proteins, marking them for degradation.
However, neddylation also modifies non-cullin proteins, and its effects are highly substrate-specific. In some cases, neddylation promotes protein degradation, while in others it stabilizes proteins by blocking their ubiquitination. This dual regulatory capacity makes neddylation an attractive mechanism for coordinating complex biological processes—and, as the Korean team discovered, for driving the coordinated dysregulation of bone remodeling.
The researchers began by examining bone tissue from patients with postmenopausal osteoporosis. They found that neddylation-related factors, including NAE1 (the E1 activating enzyme subunit) and NEDD8 itself, were elevated in osteoporotic bone compared with non-osteoporotic controls. Moreover, the levels of these factors correlated inversely with bone mineral density, suggesting a direct link between neddylation activity and bone loss.
But the most striking finding came when they traced the specific effects of neddylation in each bone cell type. In osteoclasts, neddylation stabilized NFATc1, the master transcription factor for bone resorption. By modifying NFATc1, neddylation protected it from degradation, allowing it to accumulate and drive the differentiation of bone-destroying cells. In osteoblasts, however, neddylation had the opposite effect: it targeted Runx2, the master regulator of bone formation, for degradation. The modification marked Runx2 for destruction, suppressing the cells' ability to build new bone.
This reciprocal regulation—stabilizing the destroyer while eliminating the builder—revealed neddylation as a molecular switch that coordinates both arms of the osteoporotic imbalance. As Professor Chun explained, "We showed for the first time how a single protein modification tips the balance between bone-destroying and bone-building cells in opposite directions at once".
Identifying a mechanism is one thing; demonstrating that it can be therapeutically exploited is another. To test whether blocking neddylation could reverse osteoporosis, the researchers turned to MLN4924 (also known as pevonedistat), a small molecule inhibitor of NAE1 that has already been evaluated in phase I and II clinical trials for cancer.
MLN4924 works by forming a covalent adduct with NEDD8, preventing its activation and conjugation to target proteins. In the context of bone, this should theoretically destabilize NFATc1 in osteoclasts while stabilizing Runx2 in osteoblasts—exactly the dual effect needed to restore bone balance.
The researchers tested this hypothesis in a mouse model of postmenopausal osteoporosis induced by ovariectomy (removal of the ovaries, which mimics the estrogen loss of menopause). Mice received intraperitoneal injections of MLN4924 at a dose of 20 mg/kg every three days for four weeks. The results were remarkable.
Micro-CT analysis of the distal femur revealed that MLN4924 treatment preserved bone mineral density, bone volume fraction, trabecular thickness, and trabecular number compared with untreated ovariectomized mice. The drug also prevented the deterioration of trabecular microarchitecture—the delicate lattice-like structure that gives bone its strength. Histological analysis confirmed that osteoclast numbers were reduced while osteoblast numbers were maintained or increased in the treated animals.
Serum biomarker analysis provided further evidence of the dual mechanism. CTX-1, a marker of bone resorption, was decreased in MLN4924-treated mice, while P1NP, a marker of bone formation, was elevated. This pattern—less destruction combined with more construction—is precisely what one would predict from the molecular mechanism identified in cell culture experiments.
Immunohistochemical analysis of bone tissue from the treated mice confirmed that the drug was working through the predicted pathway. NFATc1 levels were reduced in osteoclasts, while Runx2 levels were preserved in osteoblasts. The correlation between NAE1/NEDD8 expression and NFATc1/Runx2 expression that was observed in untreated osteoporotic bone was attenuated in the treated animals, indicating that MLN4924 was disrupting the pathological neddylation signaling.
The researchers also examined human bone samples to validate the clinical relevance of their findings. Immunohistochemistry of femoral heads from patients with postmenopausal osteoporosis revealed elevated NAE1 and NEDD8 expression, increased NFATc1, and decreased Runx2 compared with non-osteoporotic controls. Correlation analysis confirmed that NAE1 and NEDD8 levels positively correlated with NFATc1 and negatively correlated with Runx2 in human bone tissue—the same pattern observed in the mouse model.
The Seoul National University study is not the only recent investigation to identify neddylation as a therapeutic target for osteoporosis. A separate study published in Autophagy in 2026 by researchers at Zhejiang University independently identified NAE1 as a critical regulator of osteoclast differentiation, though through a different mechanistic lens.
The Zhejiang team found that NAE1-mediated neddylation regulates osteoclastogenesis through two distinct metabolic mechanisms. First, Nae1 depletion disrupted intracellular iron metabolism, suppressing ferritinophagy—the selective degradation of ferritin that releases free iron for cellular use. Second, NAE1 neddylates ACSL3 (acyl-CoA synthetase long-chain family member 3), modulating monounsaturated fatty acid biosynthesis and regulating the sensitivity of osteoclast precursors to ferroptosis, an iron-dependent form of cell death. Pharmacological inhibition or genetic ablation of Nae1 attenuated osteoclastogenesis in vitro and ameliorated ovariectomy-induced osteoporosis in vivo without impairing osteoblast function.
These two studies, conducted independently on different continents, converge on the same conclusion: neddylation is a critical regulator of bone remodeling, and its inhibition represents a promising therapeutic strategy. The Zhejiang study adds metabolic dimensions to the picture, showing that neddylation influences not only transcription factor stability but also iron and lipid metabolism in osteoclasts. Together, the findings paint a rich portrait of neddylation as a central node in the regulatory network controlling bone homeostasis.
The discovery of neddylation as a dual-action switch in osteoporosis is undeniably exciting, but translating this basic science into clinical practice will require overcoming significant challenges. The most obvious concern is safety: neddylation regulates diverse cellular processes in multiple cell types throughout the body. Systemic inhibition of this pathway could have unintended consequences beyond bone.
MLN4924 itself has been extensively studied in oncology, where it has shown a manageable safety profile in phase I trials. Common adverse events include fatigue, nausea, anemia, and transient liver enzyme elevations. The pharmacokinetic profile is characterized by a short half-life of approximately 8.5 hours, with little drug accumulation after multiple dosing. Pharmacodynamic markers of NAE inhibition, including increased CDT-1 and NRF-2 levels, have been validated in clinical samples.
However, cancer patients typically receive MLN4924 for limited treatment durations, whereas osteoporosis is a chronic condition requiring long-term management. The safety profile of prolonged neddylation inhibition remains unknown. The Seoul National University researchers acknowledge this limitation explicitly, noting that "because neddylation regulates diverse cellular processes in multiple cell types, systemic inhibition of this pathway may carry potential adverse effects beyond bone." They emphasize that their findings should be regarded as "proof-of-concept" and that "further studies will be required to define long-term safety, optimal dosing, and strategies to improve tissue selectivity".
Tissue selectivity is perhaps the most critical hurdle. An ideal osteoporosis therapy would inhibit neddylation specifically in osteoclasts and osteoblasts, sparing other tissues. Targeted delivery approaches—such as bone-seeking nanoparticles or bisphosphonate-conjugated inhibitors—could potentially achieve this goal. Alternatively, identifying downstream effectors specific to bone cells might allow for more selective intervention.
The mechanism itself also presents challenges. Neddylation modifies hundreds of proteins, and the specific E3 ligases responsible for NFATc1 and Runx2 modification—c-Cbl and Rbx1, respectively—are themselves involved in numerous other cellular processes. Selectively targeting these enzymes in bone cells without disrupting their functions elsewhere would be difficult.
Despite these challenges, the therapeutic promise is substantial. Current osteoporosis treatments are limited by their unidirectional mechanism, their inability to fully restore bone architecture, and concerns about long-term safety. A therapy that simultaneously reduces bone resorption and enhances bone formation could offer superior efficacy, potentially reversing rather than merely halting bone loss. The fact that MLN4924 has already undergone clinical testing provides a head start on the path to approval, though it may ultimately be succeeded by more selective next-generation inhibitors.
The neddylation discovery represents more than just a potential new drug target. It reflects a broader shift in how researchers conceptualize osteoporosis—from a disease of simple hormone deficiency to a disorder of complex molecular regulation. Estrogen loss initiates the pathological cascade, but the downstream effectors that actually execute bone destruction and suppress bone formation are increasingly being identified and, crucially, found to be druggable.
This shift has important implications for patient care. If neddylation inhibitors prove safe and effective in clinical trials, they could offer an alternative for patients who cannot tolerate existing medications, who fail to respond adequately to monotherapy, or who require more aggressive bone-building effects than current drugs can provide. They could also potentially be used in combination with existing agents, though the safety of such combinations would need careful evaluation.
The discovery also underscores the value of basic research in post-translational modifications. Neddylation was first characterized in the context of cullin activation and cancer biology. Its role in bone was entirely unexpected. This pattern—basic science yielding unexpected clinical insights—is a recurring theme in biomedical research. The more we understand about the fundamental mechanisms of cellular regulation, the more likely we are to stumble upon therapeutic opportunities in unexpected places.
Osteoporosis has long been a disease of partial solutions. Treatments that target osteoclasts reduce fracture risk but do not restore lost bone. Treatments that stimulate osteoblasts build bone but are limited by safety concerns and the need for sequential therapy. The discovery of neddylation as a molecular switch that simultaneously controls both sides of bone remodeling offers a rare opportunity to address the disease at its root.
The Seoul National University team's demonstration that MLN4924 reverses bone loss in ovariectomized mice, combined with independent validation of neddylation as a therapeutic target by other research groups, provides a strong foundation for further development. The challenges of safety, selectivity, and long-term tolerability are real, but they are not insurmountable. The fact that MLN4924 is already a clinical-stage drug with a known safety profile in oncology settings provides a valuable starting point.
For the millions of people living with osteoporosis, the promise of a therapy that flips the bone remodeling balance back toward health is a reason for cautious optimism. The switch exists. The researchers have found it. The question now is whether medicine can flip it safely and effectively in patients. The answer, hopefully, is just a few years of rigorous clinical research away.