Promoting Endochondral Bone Repair Using Human Osteoarthritic Articular Chondrocytes

Bahney, Chelsea S.; Jacobs, Laurie; Tamai, Robert; Hu, Diane; Wang, Miqi; Reddy, Sanjay; Park, Michelle; Limburg, Sonja; Kim, Hubert T.; Marcucio, Ralph; Kuo, Alfred C.

doi:10.1089/ten.tea.2014.0705

Cited by 14 publications

(10 citation statements)

References 31 publications

(38 reference statements)

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“…Promoting interaction between the implanted cartilage graft and the host has been shown to be a key consideration for endochondral bone repair strategies [56]. Here, for all histological staining it was evident that the incorporation of printed microchannels enhanced host interaction in vivo.…”

Section: Discussionmentioning

confidence: 75%

3D printed microchannel networks to direct vascularisation during endochondral bone repair

et al. 2018

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Bone tissue engineering strategies that recapitulate the developmental process of endochondral ossification offer a promising route to bone repair. Clinical translation of such endochondral tissue engineering strategies will require overcoming a number of challenges, including the engineering of large and often anatomically complex cartilage grafts, as well as the persistence of core regions of avascular cartilage following their implantation into large bone defects. Here 3D printing technology is utilized to develop a versatile and scalable approach to guide vascularisation during endochondral bone repair. First, a sacrificial pluronic ink was used to 3D print interconnected microchannel networks in a mesenchymal stem cell (MSC) laden gelatin-methacryloyl (GelMA) hydrogel. These constructs (with and without microchannels) were next chondrogenically primed in vitro and then implanted into critically sized femoral bone defects in rats. The solid and microchanneled cartilage templates enhanced bone repair compared to untreated controls, with the solid cartilage templates (without microchannels) supporting the highest levels of total bone formation. However, the inclusion of 3D printed microchannels was found to promote osteoclast/immune cell invasion, hydrogel degradation, and vascularisation following implantation. In addition, the endochondral bone tissue engineering strategy was found to support comparable levels of bone healing to BMP-2 delivery, whilst promoting lower levels of heterotopic bone formation, with the microchanneled templates supporting the lowest levels of heterotopic bone formation. Taken together, these results demonstrate that 3D printed hypertrophic cartilage grafts represent a promising approach for the repair of complex bone fractures, particularly for larger defects where vascularisation will be a key challenge.

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Section: Discussionmentioning

confidence: 75%

3D printed microchannel networks to direct vascularisation during endochondral bone repair

et al. 2018

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“…Wnt and NGF signaling have been major therapeutic targets to inhibit the progression and pain associated with osteoarthritis 72,75,76 . Our group has previously exploited these parallels by engineering osteoarthritic cartilage to promote endochondral bone repair 77 .…”

Section: Discussionmentioning

confidence: 99%

Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion

Rivera

Russo

Boileau

et al. 2020

Sci Rep

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There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF’s ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.

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“…Survival mechanisms against hypoxia include autophagy, which is a common mechanism for the removal of excess or damaged organelles in the process of development and aging (6). On the other hand, previous studies had shown that the autophagy could promote the chondrocyte differentiation and hypertrophy of chondrocytes (7,16).…”

Section: Mag Induced Autophagy and Promoted Autophagic Flux In Bmsc-dmentioning

confidence: 99%

Mangiferin enhances endochondral ossification‐based bone repair in massive bone defect by inducing autophagy through activating AMP‐activated protein kinase signaling pathway

Bai

Liu

et al. 2018

FASEB j.

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Endochondral ossification is crucial for bone formation in both adult bone repair process and embryo long-bone development. In endochondral ossification, bone marrow-derived mesenchymal stem cells (BMSCs) first differentiate to chondrocytes, then BMSC-derived chondrocytes endure a hypertrophic process to generate new bone. Endochondral ossification-based bone repair is a promising strategy to cure massive bone defect, which is a major clinical issue in orthopedics. However, challenges still remain for this novel strategy. One challenge is to ensure the sufficient hypertrophic differentiation. Another is to maintain the survival of the above hypertrophic chondrocytes under the hypoxic environment of massive bone defect. To solve this issue, mangiferin (MAG) was introduced to endochondral ossification-based bone repair. In this report, we proved MAG to be a novel autophagy inducer, which promoted BMSC-derived hypertrophic chondrocyte survival against hypoxia-induced injury through inducing autophagy. Furthermore, MAG enhances hypertrophic differentiation of BMSC-derived chondrocytes via upregulating key hypertrophic markers. Mechanistically, MAG induced autophagy in BMSC-derived chondrocytes by promoting AMPKα phosphorylation. Additionally, MAG balanced the expression of sex-determining region Y-box 9 and runt-related transcription factor 2 to facilitate hypertrophic differentiation. These results indicated that MAG was a potential drug to improve the efficacy of endochondral ossification-based bone repair in massive bone defects.-Bai, Y., Liu, C., Fu, L., Gong, X., Dou, C., Cao, Z., Quan, H., Li, J., Kang, F., Dai, J., Zhao, C., Dong, S. Mangiferin enhances endochondral ossification-based bone repair in massive bone defect by inducing autophagy through activating AMP-activated protein kinase signaling pathway.

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Promoting Endochondral Bone Repair Using Human Osteoarthritic Articular Chondrocytes

Cited by 14 publications

References 31 publications

3D printed microchannel networks to direct vascularisation during endochondral bone repair

3D printed microchannel networks to direct vascularisation during endochondral bone repair

Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion

Mangiferin enhances endochondral ossification‐based bone repair in massive bone defect by inducing autophagy through activating AMP‐activated protein kinase signaling pathway

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