ABSTRACT
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in the elderly, characterized by the progressive destruction of cartilage, synovial inflammation, and subchondral bone remodeling. While mechanical stress, metabolic derangements, and systemic inflammation are recognized contributors, accumulating evidence underscores the pivotal role of impaired macroautophagy/autophagy in disease pathogenesis. Autophagy declines with age, depriving chondrocytes and synovial cells of their cytoprotective capacity and rendering them vulnerable to apoptosis, matrix degradation, and inflammatory activation. Recent work has identified DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) as an extracellular hormone that represses autophagy through binding to the GABRG2/GABAARγ2 (gamma-aminobutyric type A receptor subunit gamma2) subunit of the GABA type A receptor. Plasma levels of DBI/ACBP are elevated in metabolic syndrome, obesity, diabetes, and aging, all known OA risk factors, and are upregulated in patients at risk of severe OA. In murine models of experimental OA, genetic deletion or antibody-mediated neutralization of DBI/ACBP mitigates joint inflammation, reduces cartilage destruction, and improves functional outcomes. These findings establish DBI/ACBP as a central pathogenic mediator linking aging-associated autophagy decline to osteoarthritis progression. Targeting DBI/ACBP represents a promising strategy to restore tissue homeostasis and modify the natural course of OA, with direct translational potential.
KEYWORDS: Aging, autophagy, immunosurveillance, inflammation, senescence
Main Text
Osteoarthritis (OA) represents the most prevalent degenerative joint disease in aging populations and remains one of the leading causes of disability worldwide. Among U.S. seniors aged > 65, OA affects an estimated 35%–80% (depending on diagnostic criteria), burdens more than half of this group, and doubles the risk of developing daily-living disabilities within two years. OA hallmarks include progressive cartilage destruction, subchondral bone remodeling, osteophyte formation, synovial inflammation, and a pervasive imbalance between anabolic and catabolic processes in the joint microenvironment. Although mechanical stress and metabolic insults provide initiating factors, the chronic progression of OA reflects a failure of intrinsic cytoprotective mechanisms. Among these, autophagy, the intracellular recycling pathway critical for maintaining cellular homeostasis, emerges as a decisive determinant of chondrocyte viability and tissue resilience. Multiple studies demonstrate that aging-associated decline in autophagy predisposes to chondrocyte apoptosis, matrix degradation, and disease onset. Pharmacological induction of autophagy by agents such as rapamycin, metformin, or fenofibrate mitigates experimental OA in rodents, underscoring the therapeutic potential of modulating this pathway.
In this context, recent work has revealed an unexpected endocrine-like regulator of autophagy: DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein). Originally identified as a lipid carrier, DBI/ACBP is secreted under stress conditions and functions as an extracellular tissue hormone. By engaging the GABRG2 subunit of the GABA type A receptor, DBI/ACBP exerts a powerful inhibitory effect on autophagy. Elevated circulating levels of DBI/ACBP have been reported in metabolic syndrome, obesity, diabetes, and aging, all established risk factors for OA. Moreover, transcriptomic and proteomic studies confirm that cartilage and synovial tissues from OA patients exhibit marked upregulation of both DBI/ACBP and its receptor GABRG2. These findings suggest a pathophysiological link between extracellular control of autophagy and the chronic degenerative course of OA.
Our experimental data corroborate this hypothesis [1]. In a mouse model of OA induced by destabilization of the medial meniscus and collateral ligaments, plasma DBI/ACBP concentrations rise sharply following joint injury. This systemic surge is abolished in tamoxifen-inducible dbi knockout mice, which are simultaneously protected from cartilage destruction and synovial inflammation. Likewise, pharmacological neutralization of extracellular DBI/ACBP with monoclonal antibodies recapitulates the protective phenotype. Intraperitoneal administration of anti-DBI/ACBP antibodies reduces cartilage degradation, whereas local intra-articular injection produces more pronounced benefits: restoration of autophagic markers in chondrocytes, reduced histological synovitis, improved weight-bearing symmetry, and dampened systemic inflammatory responses. These convergent results highlight DBI/ACBP as a pathogenic amplifier of OA through its autophagy-repressive and pro-inflammatory actions (Figure 1).
Figure 1.
Schematic overview of DBI/ACBP in the pathogenesis of osteoarthritis. Joint damage disrupts tissue homeostasis, leading to the extracellular release of DBI/ACBP and pro-inflammatory mediators such as IL6, and IL1B, as well as extracellular matrix-degrading enzymes including MMPs. The increased levels of DBI/ACBP enhance its interaction with the GABRG2 subunit of the GABAA receptor (GABAAR). Together, these processes drive cartilage degradation, synovial membrane inflammation and impaired autophagy. As a therapeutic intervention, intra-articular administration of the monoclonal antibody anti-DBI inhibits the extracellular release of DBI/ACBP, resulting in reduced pro-inflammatory mediators, attenuation of pain, decreased synovitis and cartilage damage and ultimately the restoration of joint homeostasis.
Mechanistically, the blockade of DBI/ACBP reinstates autophagy within the joint microenvironment. In OA cartilage, autophagic flux is blunted, as evidenced by reduced LC3B positivity and the accumulation of damaged organelles. Neutralization of DBI/ACBP restores autophagy, thereby preventing chondrocyte apoptosis and preserving extracellular matrix integrity. This finding aligns with prior genetic studies in which cartilage-specific deletion of Mtor, a central autophagy inhibitor, confers resistance to experimental OA. Thus, DBI/ACBP appears to act as an upstream, extracellular autophagy checkpoint whose chronic overexpression during metabolic stress and aging locks joint tissues into a vulnerable, degeneration-prone state.
The inflammatory cascade provides an additional layer of pathogenicity. OA is not merely a passive “wear and tear” disorder, but a metabolically active disease characterized by synovial infiltration and cytokine production. Pro-inflammatory mediators such as IL1A, IL1B, IL6, TNF/TNFα, and IL33 are abundant in OA joints and might contribute to the induction of DBI/ACBP production. Of note, local, intra-articular injection of a monoclonal antibody against DBI/ACBP reduces plasma levels of IL1A, IL33, and TNF, synovitis scores diminish, and systemic inflammation subsides. This observation places DBI/ACBP at the intersection of metabolic, inflammatory, and autophagy-regulatory networks driving OA progression.
The translational relevance of these findings is underscored by human data. Large-scale biobank analyses demonstrate that elevated plasma DBI/ACBP levels predict joint replacement surgery within two years. Independent meta-analyses reveal consistent upregulation of DBI/ACBP mRNA in OA cartilage. Immunohistochemical analyses confirm the presence of both the ligand and its receptor in patient samples. Together, these lines of evidence strongly support the view that DBI/ACBP is not an epiphenomenon but a causal contributor to OA pathogenesis.
From a therapeutic perspective, neutralization of DBI/ACBP emerges as a novel disease-modifying strategy. Unlike conventional OA therapies, which predominantly alleviate symptoms without halting joint destruction, antibody-mediated blockade of DBI/ACBP targets a central pathogenic mechanism: the suppression of autophagy. By reinstating cellular recycling, preserving cartilage viability, and reducing inflammation, anti-DBI/ACBP antibodies demonstrate curative rather than palliative effects in preclinical models. Moreover, the discovery of cross-species reactive monoclonal antibodies paves the way for translational development in human OA.
Importantly, the safety profile of DBI/ACBP blockade appears favorable. Systemic administration of anti-DBI/ACBP antibodies has shown protective effects in models of heart, liver, and lung injury, with no evidence of long-term toxicity. Genetic deletion of Dbi or mutation of GABRG2 confers resistance to stress-induced organ damage without deleterious phenotypes. These findings suggest that local intra-articular antibody injections, or systemic depot formulations, could be deployed in clinical settings with manageable risks.
In conclusion, the identification of DBI/ACBP as an autophagy-repressive tissue hormone in OA represents a conceptual shift. It highlights the importance of extracellular signals in modulating intracellular stress responses and illuminates how metabolic dysregulation converges with joint mechanics and inflammation to drive age-related degeneration. By releasing the autophagy brake imposed by DBI/ACBP, it may be possible to modify the natural course of OA, preserve mobility, and reduce disability in the elderly population. The next steps will require translational validation in larger animal models and ultimately in human trials. If successful, DBI/ACBP neutralization could inaugurate a new class of autophagy-targeted therapeutics for age-related degenerative diseases.
Funding Statement
GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR-22-CE14-0066 VIVORUSH, ANR-23-CE44-0030 COPPERMAC, ANR-23-R4HC-0006 Ener-LIGHT); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); European Research Council Advanced Investigator Award (ERC-2021-ADG, Grant No. 101052444; project acronym: ICD-Cancer, project title: Immunogenic cell death (ICD) in the cancer-immune dialogue); The ERA4 Health Cardinoff Grant Ener-LIGHT; European Union Horizon 2020 research and innovation program Oncobiome (grant agreement number: 825410, Project Acronym: ONCOBIOME, Project title: Gut OncoMicrobiome Signatures [GOMS] associated with cancer incidence, prognosis and prediction of treatment response, Prevalung (grant agreement number 101095604, Project Acronym: PREVALUNG EU, project title: Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception), Neutrocure (grant agreement number 861878 : Project Acronym: Neutrocure; project title: Development of “smart” amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of inflammatory and autoimmune diseases, cancer and myeloablation); National support managed by the Agence Nationale de la Recherche under the France 2030 programme (reference number 21-ESRE-0028, ESR/Equipex+ Onco-Pheno-Screen); Hevolution Network on Senescence in Aging (reference HF-E Einstein Network); Institut National du Cancer (INCa); Institut Universitaire de France; PAIR-Obésité INCa_18713, the RHUs Immunolife and LUCA-pi (ANR-21-RHUS-0017 and ANR-23-RHUS-0010, both dedicated to France Relance 2030); Seerave Foundation; SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by Institut National du Cancer, Ministère des Solidarités et de la Santé and INSERM). This study contributes to the IdEx Université de Paris Cité ANR-18-IDEX-0001.
Conflicts of interest
GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier, and Rejuveron Life Sciences/Centenara Labs AG. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. Among these patents, one “Methods for weight reduction” (US11905330B1) is relevant to this study. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. GK’s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. IM is a consultant of Osasuna Therapeutics. The funders had no role in the design of the study, in the writing of the manuscript, or in the decision to publish the results.
Reference
- [1].Nogueira-Recalde U, Lambertucci F, Montégut L, et al. Neutralization of acyl CoA binding protein (ACBP) for the experimental treatment of osteoarthritis. Cell Death Differ. 2025. Aug;32(8):1484–1498. doi: 10.1038/s41418-025-01474-y [DOI] [PMC free article] [PubMed] [Google Scholar]