The role of hypertrophic chondrocytes in regulation of the cartilage-to-bone transition in fracture healing

Kodama, Joe; Wilkinson, Kevin J.; Iwamoto, Masahiro; Otsuru, Satoru; Enomoto‐Iwamoto, Motomi

doi:10.1016/j.bonr.2022.101616

Cited by 15 publications

(10 citation statements)

References 96 publications

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“…When stem cells differentiate into chondrocytes, some genes induce chondrocyte hypertrophy, such as Runx2 [21]. Studies have shown that affecting chondrocyte hypertrophy can lead to delayed healing of fracture [13]. So, we detected the expression of Sox9 in fracture healing tissues, the expression level of Sox9 had a decrease trend but no statistical difference at 7dpf in the mean while the expression level was signi cantly lower at 10dpf in Dnmt3b Gli1ER mice (Fig.…”

Section: Resultsmentioning

confidence: 79%

Dnmt3b ablation affects fracture repair process by regulating apoptosis

Wang,

Ge,

Zeng

et al. 2023

Preprint

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Purpose Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and chondrocyte cells both delayed fracture repair. Our study aims to explore the influence of Dnmt3b ablation in Gli1-positive stem cells in fracture healing mice and the underlying mechanism. Methods We generated Gli1-CreERT2; Dnmt3bflox/flox (Dnmt3bGli1ER) mice to operated tibia fracture. Fracture callus tissues of Dnmt3bGli1ER mice and control mice were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and TUNEL assay. Results The cartilaginous callus significantly decrease in ablation of Dnmt3b in Gli1-positive stem cells during fracture repair. The chondrogenic and osteogenic indicators (Sox9 and Runx2) in the fracture healing tissues in Dnmt3bGli1ER mice much less than control mice. Dnmt3bGli1ER mice led to delayed bone callus remodeling and decreased biomechanical properties of the newly formed bone during fracture repair. Both the expressions of Caspase-3 and Caspase-8 were upregulated in Dnmt3bGli1ER mice as well as the expressions of BCL-2. Conclusions Our study provides an evidence that Dnmt3b ablation Gli1-positive stem cells can affect fracture healing and lead to poor fracture healing by regulating apoptosis to decrease chondrocyte hypertrophic maturation.

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Section: Resultsmentioning

confidence: 79%

Dnmt3b ablation affects fracture repair process by regulating apoptosis

Wang,

Ge,

Zeng

et al. 2023

Preprint

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“…Additionally, the emergence of osteoblastic lineage markers, Runx2, Alpl, Sp7, Ibsp, and Bglap , is seen in this sub-cluster, highlighting a potential developmental relationship or trans-differentiation between chondrocytes and cells of the osteoblast lineage. 70 …”

Section: Resultsmentioning

confidence: 99%

Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone

Lung,

Wentworth,

Moody

et al. 2024

JBMR Plus

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G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in GNAS. There are no effective therapies for FD. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages using an engineered receptor strategy, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD. The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remain largely unknown. Single cell RNA sequencing on long-bone stromal cells of 9-week-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or down-regulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.

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“…Chondrocytes are hypothesized to transform into osteoblasts, as demonstrated in Agc1CreERT::Ai9 mice, in which SRY (sex determining region Y)-box 2 (SOX2), octamerbinding transcription factor 4 (OCT4), and NANOG were co-stained in chondrocyte-stemcell-like cells. This mechanism may be perturbed in non-unions [71,72]. In fact, chondrocyte trans-differentiation may be the primary path of endochondral bone formation in bone repair [72].…”

Section: Chondrocytesmentioning

confidence: 99%

Bone Healing Gone Wrong: Pathological Fracture Healing and Non-Unions—Overview of Basic and Clinical Aspects and Systematic Review of Risk Factors

et al. 2023

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Bone healing is a multifarious process involving mesenchymal stem cells, osteoprogenitor cells, macrophages, osteoblasts and -clasts, and chondrocytes to restore the osseous tissue. Particularly in long bones including the tibia, clavicle, humerus and femur, this process fails in 2–10% of all fractures, with devastating effects for the patient and the healthcare system. Underlying reasons for this failure are manifold, from lack of biomechanical stability to impaired biological host conditions and wound-immanent intricacies. In this review, we describe the cellular components involved in impaired bone healing and how they interfere with the delicately orchestrated processes of bone repair and formation. We subsequently outline and weigh the risk factors for the development of non-unions that have been established in the literature. Therapeutic prospects are illustrated and put into clinical perspective, before the applicability of biomarkers is finally discussed.

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The role of hypertrophic chondrocytes in regulation of the cartilage-to-bone transition in fracture healing

Cited by 15 publications

References 96 publications

Dnmt3b ablation affects fracture repair process by regulating apoptosis

Dnmt3b ablation affects fracture repair process by regulating apoptosis

Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone

Bone Healing Gone Wrong: Pathological Fracture Healing and Non-Unions—Overview of Basic and Clinical Aspects and Systematic Review of Risk Factors

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