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Osteocyte-specific deletion of Gasdermin D drives osteoarthritis cartilage degeneration by promoting inflammation and remodeling in subchondral bone

ABSTRACT: In osteoarthritis, we discovered that the number of osteocytes in the subchondral bone is reduced. By investigating the interaction between chondrocytes and osteocytes, we aim to elucidate the underlying pathological mechanisms.

ORGANISM(S): Mus musculus

PROVIDER: GSE305276 | GEO | 2026/06/15

REPOSITORIES: GEO

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Osteocyte-specific deletion of Gasdermin D drives osteoarthritis cartilage degeneration by promoting inflammation and remodeling in subchondral bone.

Project description:In osteoarthritis, we discovered that pyroptosis of osteocytes in the subchondral bone contributes to disease progression. Ongoing studies using knockout mouse models aim to elucidate the effects of inhibiting this pathological pathway on disease progression .

2026-06-15 | GSE301329 | GEO

Osteocyte-derived extracellular vesicles mediate the bone-to-cartilage crosstalk and promote osteoarthritis progression [only osteocyte-enriched subchondral bone]

Project description:Osteoarthritis (OA) is the most common degenerative joint disease. During its initiation and early progression a disruption in subchondral bone (SCB) remodeling, induced by excessive and cumulative mechanical loading, occurs before cartilage degeneration. While it is known that osteocytes in the SCB are mainly responsible for mechanosensing, their role in the early phases of OA are still unclear. Here, we found that mechanical stress induces SCB osteocytes to secrete extracellular vesicles (EVs) that accelerate cartilage metabolic dysregulation. By gain- and loss-of function experiments we show that such EVs via miR-23b-3p promote cartilage catabolism while inhibiting their anabolism. Mechanistically, miR-23b-3p inhibits mitophagy by targeting OTUD4 to promote this metabolic skewing. Further, by inhibiting miR-23b-3p in either osteocytes or chondrocytes we could alleviate cartilage degeneration and OA progression in a mouse model. Together, our findings show that SCB osteocytes communicate with chondrocytes via EVs and that targeting a key EV-derived miRNA can ameliorate OA progression.

2025-04-12 | GSE284357 | GEO

Osteocyte-derived extracellular vesicles mediate the bone-to-cartilage crosstalk and promote osteoarthritis progression [EVs from osteocyte-enriched subchondral bone]

2025-04-12 | GSE284359 | GEO

Osteocyte-derived extracellular vesicles mediate the bone-to-cartilage crosstalk and promote osteoarthritis progression [primary chondrocytes]

2025-04-12 | GSE284358 | GEO

Osteocyte-derived extracellular vesicles mediate the bone-to-cartilage crosstalk and promote osteoarthritis progression [EVs from plasma]

2025-04-12 | GSE284361 | GEO

Targeting long non-coding RNA H19 in Subchondral Bone Osteocytes Alleviates Cartilage Degradation in Osteoarthritis

Project description:Introduction: Emerging evidence suggests long non-coding RNA (lncRNA) H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biological function of H19 in OA subchondral bone remodeling and OA progression. Methods: Clinical joint samples and OA animal models induced by medial meniscus destabilization (DMM) surgery were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechano-response. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles in order to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment. Results: Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass with more H19 expressing osteocytes. On the contrary, osteocyte-specific deletion of H19 mice is less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechano-response through PI3K/AKT/GSK3 signals activation by EZH2-induced H3K27me3 regulation on PP2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype. Discussion: In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.

2025-03-05 | GSE254053 | GEO

Osteocyte Parvalbumin Mediates Mechanotransduction to Attenuate Osteoarthritis

Project description:Osteoarthritis (OA) is a leading cause of disability among the elderly, characterized by aberrant subchondral bone remodeling that precedes cartilage degeneration. We identify parvalbumin (Pvalb) in osteocytes as a critical mechanosensory regulator of this pathological process. Pvalb expression is significantly reduced in osteocytes from both OA patients and male murine models of the disease. Conditional deletion of Pvalb in osteocytes accelerates OA progression, whereas bone-targeted restoration of Pvalb expression mitigates disease manifestations. Mechanistically, Pvalb maintains calcium homeostasis by competing with CaMKIV for calmodulin binding. Under excessive mechanical loading, Pvalb expression is suppressed, leading to activation of the Ca²+-CaMKIV-CREB signaling pathway, increased RANKL production, and subsequent osteoclast activation and pathological bone remodeling. These findings identifies an osteocyte-mediated mechanotransduction pathway in OA pathogenesis and underscore Pvalb as a promising therapeutic target.

2026-06-16 | GSE334726 | GEO

Angptl7+ chondrocytes and Sparc+ osteoblasts mediated the increased angiogenesis and abnormal remodeling of subchondral bone in the development of knee osteoarthritis

Project description:With an increasing number of affected individuals and a trend towards younger age of onset, research on the treatment of knee osteoarthritis (KOA) is facing significant challenges. The pathogenesis of KOA is complex for being a multifactorial disease affecting the entire joint, and pathological remodeling of subchondral bone may be one of the key factors mediating the degeneration of the overlying cartilage. This study constructed a postmenopausal KOA mice model in bipedal mice to better understand how subchondral bone remodeling and cartilage degeneration interact during KOA development. The femoral condyle tissue, excluding the growth plate, was isolated from the distal epiphyseal line in KOA mice for single cell RNA sequencing and analysis. And a single-cell atlas of the osteochondral composite tissue, including chondrocytes, endothelia cells, osteoblasts, progenitor cells, and so on, was successfully constructed. Furthermore, three novel subtypes of chondrocytes, including Smoc2+ angiogenic chondrocytes, Angptl7+ angiogenic chondrocytes, and Col1a1+ osteogenic chondrocytes, were identified. Angptl7+ chondrocytes activated endothelia cells via the Fgf2-Fgfr2 interaction pathway, and promoted angiogenesis and vascular invasion in subchondral bone of KOA mice. The quantity of H-type vessels, which recruit numerous osterix+ osteoprogenitor cells and stimulate osteogenesis, exhibited an increase within the subchondral bone of mice with KOA. While Sparc+ osteoblast negatively regulated the bone mineralization and osteoblastic differentiation, aggravated the pathological remodeling of subchondral bone and KOA progression. These findings suggest that there are new avenues for potential therapeutic interventions in the treatment of KOA.

2025-02-12 | GSE267616 | GEO

Targeting long non-coding RNA H19 in Subchondral Bone Osteocytes Alleviates Cartilage Degradation in Osteoarthritis

Project description:Targeting long non-coding RNA H19 in Subchondral Bone Osteocytes Alleviates Cartilage Degradation in Osteoarthritis

| PRJNA1068443 | ENA

Cholesterol metabolism regulates cartilage metabolic-inflammatory crosstalk by triggering osteocyte mitochondria transfer as a therapeutic target for osteoarthritis

Project description:Osteoarthritis (OA) is considered as a metabolic related inflammatory disease in the joint affecting both cartilage and subchondral bone. Cholesterol metabolism has been implicated in the pathogenesis of OA, yet the underlying mechanism still remains elusive. Understanding the role of cholesterol metabolism in the joint inflammation will provide treatment alternatives of OA. Here, we found that the disordered cholesterol metabolism in joint do not directly target cartilage and synovium but target subchondral bone by transferring osteocyte mitochondria to amplify inflammatory phenotype in the cartilage. In detail, Nudt8 in osteocyte mitochondria serves as a metabolic-inflammatory switch point to alter cholesterol metabolism by degrading coenzyme A (CoA) and further increase the cytosolic mitochondrial DNA (mtDNA) stress to activate cGAS-STING pathway in chondrocytes, resulting in exacerbated inflammation and OA severity. Inhibiting the transfer of osteocyte mitochondria ameliorated joint inflammation and OA progression. Pharmacological targeting osteocyte mitochondria regulated cholesterol metabolism by supplementation of pantethine - an important precursor metabolite of CoA - ameliorated osteocyte mitochondria activated cGAS-STING pathway and OA phenotype in chondrocytes, and subsequent improved the joint damage and reduced painful behavior in OA mice. Targeting cholesterol-mitochondria regulated metabolic-inflammatory crosstalk represents a promising treatment strategy for OA.

2025-09-28 | MTBLS11733 | MetaboLights

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