Discoidin domain receptor 1 regulates endochondral ossification through terminal differentiation of chondrocytes

Chou, Liang-Yin; Ch, Chen; Lin, Yi‐Hsiung; Chuang, Shu‐Chun; Chou, Hsin-Chiao; Lin, Sung‐Yen; Fu, Yin-Chi; Chang, Je-Ken; Ho, Mei-Ling; Wang, Chau-Zen

doi:10.1096/fj.201901852rr

Cited by 18 publications

(19 citation statements)

References 37 publications

(95 reference statements)

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“…Our recent research, investigating the role of Ddr1 in the regulation of EO, has indicated that the chondrocyte-specific Ddr1 knockout can delay the EO and accompany decreased chondrocyte proliferation, terminal differentiation, and apoptosis in growth plates of mice [ 8 ]. Accordingly, we hypothesized that the Ddr1 inhibitor (7 rh) may maintain the survival of articular chondrocytes and reduce the progression of OA.…”

Section: Discussionmentioning

confidence: 99%

“…The Ddr2 ablation reduces the chondrocyte proliferation and thus decreases bone growth; however, the reasons for dwarfism in Ddr1 ablation mice remain unclear. Our recent study using chondrocyte-specific Ddr1 knockout mice demonstrated that the Ddr1 ablation resulted in a decreased chondrocyte proliferation, terminal differentiation, and apoptosis in growth plates and caused a delayed EO [ 8 ]. Our findings indicated that Ddr1 is an imperative regulator of EO in the growth plate and maybe also a potential target for OA treatment.…”

Section: Introductionmentioning

confidence: 99%

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Discoidin Domain Receptors 1 Inhibition Alleviates Osteoarthritis via Enhancing Autophagy

Chou

et al. 2020

IJMS

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We recently reported that the chondrocyte-specific knockout of discoidin domain receptors 1 (Ddr1) delayed endochondral ossification (EO) in the growth plate by reducing the chondrocyte hypertrophic terminal differentiation, and apoptosis. The biologic and phenotypic changes in chondrocytes in the articular cartilage with osteoarthritis (OA) are similar to the phenomena observed in the process of EO. Additionally, autophagy can promote chondrocyte survival and prevent articular cartilage from degradation in OA. On this basis, we explored the effect of Ddr1 inhibition on OA prevention and further investigated the roles of autophagy in treating OA with a Ddr1 inhibitor (7 rh). The anterior cruciate ligament transection (ACLT)–OA model was used to investigate the role of 7 rh in vivo. Forty 8-week-old mice were randomly assigned to four groups, including the sham group, ACLT group, and two treated groups (ACLT with 7 rh 6.9 nM or 13.8 nM). According to the study design, normal saline or 7 rh were intra-articular (IA) injected into studied knees 3 times per week for 2 weeks and then once per week for 4 weeks. The results showed that 7 rh treatment significantly improved the functional performances (the weight-bearing ability and the running endurance), decreased cartilage degradation, and also reduced the terminal differentiation markers (collagen type X, Indian hedgehog, and matrix metalloproteinase 13). Moreover, 7 rh decreased chondrocyte apoptosis by regulating chondrocyte autophagy through reducing the expression of the mammalian target of rapamycin and enhancing the light chain 3 and beclin-1 expression. These results demonstrated that the IA injection of 7 rh could reduce the chondrocyte apoptosis and promote chondrocyte autophagy, leading to the attenuation of cartilage degradation. Our observations suggested that the IA injection of 7 rh could represent a potential disease-modifying therapy to prevention OA progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discoidin Domain Receptors 1 Inhibition Alleviates Osteoarthritis via Enhancing Autophagy

Chou

et al. 2020

IJMS

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“…For scanning, the scan settings were an aluminum filter of 0.5 mm, 9 µm scanning resolution, X-ray voltage of 50 kV, X-ray current of 200 mA, and exposure time of 600 ms. The analysis began from the proximal tibia and through the whole fracture site until the distal tibia [19,[21][22][23][24][25][26].…”

Section: Radiographic and µCt Analysesmentioning

confidence: 99%

Green Tea Catechin (-)-Epigallocatechin-3-Gallate (EGCG) Facilitates Fracture Healing

et al. 2020

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Green tea drinking can ameliorate postmenopausal osteoporosis by increasing the bone mineral density. (-)-Epigallocatechin-3-gallate (EGCG), the abundant and active compound of tea catechin, was proven to be able to reduce bone loss and ameliorate microarchitecture in female ovariectomized rats. EGCG can also enhance the osteogenic differentiation of murine bone marrow mesenchymal stem cells and inhibit the osteoclastogenesis in RAW264.7 cells by modulation of the receptor activator of nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegrin (OPG) (RANK/RANKL/OPG) pathway. Our previous study also found that EGCG can promote bone defect healing in the distal femur partially via bone morphogenetic protein-2 (BMP-2). Considering the osteoinduction property of BMP-2, we hypothesized that EGCG could accelerate the bone healing process with an increased expression of BMP-2. In this manuscript, we studied whether the local use of EGCG can facilitate tibial fracture healing. Fifty-six 4-month-old rats were randomly assigned to two groups after being weight-matched: a control group with vehicle treatment (Ctrl) and a study group with 10 µmol/L, 40 µL, EGCG treatment (EGCG). Two days after the operation, the rats were treated daily with EGCG or vehicle by percutaneous local injection for 2 weeks. The application of EGCG enhanced callus formation by increasing the bone volume and subsequently improved the mechanical properties of the tibial bone, including the maximal load, break load, stiffness, and Young’s modulus. The results of the histology and BMP-2 immunohistochemistry staining showed that EGCG treatment accelerated the bone matrix formation and produced a stronger expression of BMP-2. Taken together, this study for the first time demonstrated that local treatment of EGCG can accelerate the fracture healing process at least partly via BMP-2.

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“…All animal experiments were approved by the Kaohsiung Medical University Animal Care and Use Committee (IACUC105127, 1 August 2017). In our previous work, we generated conditional Ddr1 floxed/floxed mice ( Ddr1 f/f ) [ 33 ]. The inducible a1(I)-collagen-CreERT [B6.Cg.Tg(Col1a1-Cre/ERT2)1Crm/J] cassette contains a 2.3 kb fragment of the Col1a1 promoter, Cre recombinase, ERT2, and polyA and was purchased from Jackson Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Discoidin Domain Receptor 1 Regulates Runx2 during Osteogenesis of Osteoblasts and Promotes Bone Ossification via Phosphorylation of p38

Chou

Chuang

et al. 2020

IJMS

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Discoidin domain receptor 1 (Drd1) is a collagen-binding membrane protein, but its role in osteoblasts during osteogenesis remains undefined. We generated inducible osteoblast-specific Ddr1 knockout (OKOΔDdr1) mice; their stature at birth, body weight and body length were significantly decreased compared with those of control Ddr1f/f-4OHT mice. We hypothesize that Ddr1 regulates osteogenesis of osteoblasts. Micro-CT showed that compared to 4-week-old Ddr1f/f-4OHT mice, OKOΔDdr1 mice presented significant decreases in cancellous bone volume and trabecular number and significant increases in trabecular separation. The cortical bone volume was decreased in OKOΔDdr1 mice, resulting in decreased mechanical properties of femurs compared with those of Ddr1f/f-4OHT mice. In femurs of 4-week-old OKOΔDdr1 mice, H&E staining showed fewer osteocytes and decreased cortical bone thickness than Ddr1f/f-4OHT. Osteoblast differentiation markers, including BMP2, Runx2, alkaline phosphatase (ALP), Col-I and OC, were decreased compared with those of control mice. Ddr1 knockdown in osteoblasts resulted in decreased mineralization, ALP activity, phosphorylated p38 and protein levels of BMP2, Runx2, ALP, Col-I and OC during osteogenesis. Overexpression and knockdown of Ddr1 in osteoblasts demonstrated that DDR1 mediates the expression and activity of Runx2 and the downstream osteogenesis markers during osteogenesis through regulation of p38 phosphorylation.

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Discoidin domain receptor 1 regulates endochondral ossification through terminal differentiation of chondrocytes

Cited by 18 publications

References 37 publications

Discoidin Domain Receptors 1 Inhibition Alleviates Osteoarthritis via Enhancing Autophagy

Discoidin Domain Receptors 1 Inhibition Alleviates Osteoarthritis via Enhancing Autophagy

Green Tea Catechin (-)-Epigallocatechin-3-Gallate (EGCG) Facilitates Fracture Healing

Discoidin Domain Receptor 1 Regulates Runx2 during Osteogenesis of Osteoblasts and Promotes Bone Ossification via Phosphorylation of p38

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