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10 pages, 291 KiB

Open AccessArticle

Polymorphisms within the Tumor Necrosis Factor-Alpha Gene Is Associated with Preeclampsia in Taiwanese Han Populations

by Chih-Wei Lin, Chung-Hwan Chen, Meng-Hsing Wu, Fong-Ming Chang and Lin Kang

Biomedicines 2023, 11(3), 862; https://doi.org/10.3390/biomedicines11030862 - 11 Mar 2023

Cited by 2 | Viewed by 1329

Abstract

Preeclampsia (PE) occurs in women pregnant for more than 20 weeks with de novo hypertension and proteinuria, and is a devastating disease in maternal–fetal medicine. Cytokine tumor necrosis factor (TNF)-α may play a key role in the pathogenesis of PE. We conducted this [...] Read more.

Preeclampsia (PE) occurs in women pregnant for more than 20 weeks with de novo hypertension and proteinuria, and is a devastating disease in maternal–fetal medicine. Cytokine tumor necrosis factor (TNF)-α may play a key role in the pathogenesis of PE. We conducted this study to investigate the regulatory regions of the TNF genes, by investigating two promoter polymorphisms, TNFA-308G/A (rs1800629) and -238G/A (rs361525), known to influence TNF expression, and their relationship to PE. An observational, monocentric, case–control study was conducted. We retrospectively collected 74 cases of severe PE and 119 pregnant women without PE as control. Polymerase chain reaction (PCR) was carried out for allele analysis. Higher A allele in women with PE was found in rs1800629 but not rs361525. In this study, we first found that polymorphism at the position -308, but not -238, in the promoter region of the TNF-α gene can contribute to severe PE in Taiwanese Han populations. The results of our study are totally different to previous Iranian studies, but have some similarity to a previous UK study. Further studies are required to confirm the roles of rs1800629 and rs361525 in PE with circulating TNF-α in PE. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

16 pages, 8049 KiB

Open AccessArticle

Micro Ribonucleic Acid−29a (miR−29a) Antagonist Normalizes Bone Metabolism in Osteogenesis Imperfecta (OI) Mice Model

by Jih-Yang Ko, Feng-Sheng Wang, Sung-Hsiung Chen and Shu-Jui Kuo

Biomedicines 2023, 11(2), 465; https://doi.org/10.3390/biomedicines11020465 - 5 Feb 2023

Cited by 2 | Viewed by 1473

Abstract

Osteogenesis imperfecta (OI) is not curative nowadays. This study tried to unriddle the therapeutic potential of micro ribonucleic acid-29a (miR-29a) antagonist in treating OI in a mouse animal model (B6C3Fe a/a-Col1a2oim/J). We showed that the expression levels of miR-29a were higher in bone [...] Read more.

Osteogenesis imperfecta (OI) is not curative nowadays. This study tried to unriddle the therapeutic potential of micro ribonucleic acid-29a (miR-29a) antagonist in treating OI in a mouse animal model (B6C3Fe a/a-Col1a2oim/J). We showed that the expression levels of miR-29a were higher in bone tissues obtained from the OI mice than from wild-type mice demonstrated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization assay. We established lentivirus-shuttled vector expressing miR-29a antisense oligonucleotide (miR-29a-AS) and miR-29a precursors (pre-miR-29a), showing that the inferior bony architecture in micro-computed tomography and pertinent morphometric parameters could be rescued by miR-29a-AS and deteriorated by pre-miR-29a. The decreased proliferating cell nuclear antigen (PCNA), increased Dickkopf-1 (DKK1), and decreased β-catenin expression in OI mice could be accentuated by pre-miR-29a and normalized by miR-29a-AS. The decreased osteogenesis and increased osteoclastogenesis in OI mice could also be accentuated by pre-miR-29a and normalized by miR-29a-AS. miR-29a-AS did not seem to possess severe hepatic or renal toxicities. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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15 pages, 4829 KiB

Open AccessArticle

Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

by Hsin-Chiao Chou, Sung-Yen Lin, Liang-Yin Chou, Mei-Ling Ho, Shu-Chun Chuang, Tsung-Lin Cheng, Lin Kang, Yi-Shan Lin, Yan-Hsiung Wang, Chun-Wang Wei, Chung-Hwan Chen and Chau-Zen Wang

Biomedicines 2022, 10(9), 2173; https://doi.org/10.3390/biomedicines10092173 - 2 Sep 2022

Cited by 5 | Viewed by 2288

Abstract

Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). [...] Read more.

Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). However, the detailed pathophysiological effects of DDR1 on bone development throughout adulthood have remained unclear. This study aims to identify how DDR1 regulates osteoblast and osteocyte functions in vivo and in vitro during bone development in adulthood. The metabolic changes in bone tissues were analyzed using Micro-CT and immunohistochemistry staining (IHC) in vivo; the role of DDR1 in regulating osteoblasts was examined in MC3T3-E1 cells in vitro. The Micro-CT analysis results demonstrated that OKO mice showed a 10% reduction in bone-related parameters from 10 to 14 weeks old and a significant reduction in cortical thickness and diameter compared with flox/flox control mice (FF) mice. These results indicated that DDR1 knockout in OKO mice exhibiting significant bone loss provokes an osteopenic phenotype. The IHC staining revealed a significant decrease in osteogenesis-related genes, including RUNX2, osteocalcin, and osterix. We noted that DDR1 knockout significantly induced osteoblast/osteocyte apoptosis and markedly decreased autophagy activity in vivo. Additionally, the results of the gain- and loss-of-function of the DDR1 assay in MC3T3-E1 cells indicated that DDR1 can regulate the osteoblast differentiation through activating autophagy by regulating the phosphorylation of the mechanistic target of rapamycin (p-mTOR), light chain 3 (LC3), and beclin-1. In conclusion, our study highlights that the ablation of DDR1 results in cancellous bone loss by regulating osteoblast/osteocyte autophagy. These results suggest that DDR1 can act as a potential therapeutic target for managing cancellous bone loss. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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18 pages, 9329 KiB

Open AccessArticle

Multilayer Electrospun-Aligned Fibroin/Gelatin Implant for Annulus Fibrosus Repair: An In Vitro and In Vivo Evaluation

by Ming-Hsiao Hu, Kai-Chiang Yang, Chih-Wei Chen, Po-Han Chu, Yun-Liang Chang, Yuan-Hui Sun, Feng-Huei Lin and Shu-Hua Yang

Biomedicines 2022, 10(9), 2107; https://doi.org/10.3390/biomedicines10092107 - 29 Aug 2022

Viewed by 2146

Abstract

Annulus fibrosus (AF) damage is proven to prompt intervertebral disc (IVD) degeneration, and unrepaired AF lesions after surgical discectomy may boost herniation of the nucleus pulposus (NP) which may lead to further compression of neural structures. Moreover, vascular and neural ingrowth may occur [...] Read more.

Annulus fibrosus (AF) damage is proven to prompt intervertebral disc (IVD) degeneration, and unrepaired AF lesions after surgical discectomy may boost herniation of the nucleus pulposus (NP) which may lead to further compression of neural structures. Moreover, vascular and neural ingrowth may occur within the defect which is known as a possible reason for discogenic pain. Due to a limited healing capacity, an effective strategy to repair and close the AF defect is necessary. In this study, using electrospinning technology, two nature polymers, silk fibroin and gelatin, were linked to imitate the unique lamellae structure of native AF. Our findings revealed that a multilayer electrospun-aligned fibroin/gelatin scaffold with mechanical and morphological properties mimicking those of native AF lamellae have been developed. The average diameter of the nanofiber is 162.9 ± 38.8 nm. The young’s modulus is around 6.70 MPa with an ultimate tensile strength of around 1.81 MP along preferred orientation. The in vitro test confirmed its biocompatibility and ability to maintain cell viability and colonization. Using a porcine model, we demonstrated that the multilayer-aligned scaffold offered a crucial microenvironment to induce collagen fibrous tissue production within native AF defect. In the implant-repaired AF, H&E staining showed homogeneous fibroblast-like cell infiltration at the repaired defect with very little vascular ingrowth, which was confirmed by magnetic resonance imaging findings. Picrosirius red staining and immunohistochemical staining against type I collagen revealed positively stained fibrous tissue in an aligned pattern within the implant-integrated site. Relative to the intact control group, the disc height index of the serial X-ray decreased significantly in both the injury control and implant group at 4 weeks and 8 weeks (p < 0.05) which indicated this scaffold may not reverse the degenerative process. However, the results of the discography showed that the effectiveness of annulus repair of the implant group is much superior to that of the untreated group. The scaffold, composed with nature fibroin/gelatin polymers, could potentially enhance AF healing that could prevent IVD recurrent herniation, as well as neural and neovascular ingrowth after discectomy surgeries. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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13 pages, 3691 KiB

Open AccessArticle

Anabolic Effects of a Novel Simvastatin Derivative on Treating Rat Bone Defects

by Tien-Ching Lee, Hui-Ting Chen, I-Chun Tai, Li-Ting Kao, Ming-Hsin Hung, Chung-Hwan Chen, Yin-Chih Fu, Yan-Hsiung Wang, Chih-Ming Kao, Je-Ken Chang and Mei-Ling Ho

Biomedicines 2022, 10(8), 1915; https://doi.org/10.3390/biomedicines10081915 - 8 Aug 2022

Cited by 1 | Viewed by 1517

Abstract

Large bone defects may develop fracture nonunion, leading to disability and psychosocial burdens. Bone grafting with anabolic agents is a good autografting alternative. Simvastatin, as a cholesterol-lowering agent worldwide, is proven to enhance osteogenesis. Considering its dose-dependent adverse effects, we developed a simvastatin [...] Read more.

Large bone defects may develop fracture nonunion, leading to disability and psychosocial burdens. Bone grafting with anabolic agents is a good autografting alternative. Simvastatin, as a cholesterol-lowering agent worldwide, is proven to enhance osteogenesis. Considering its dose-dependent adverse effects, we developed a simvastatin derivative, named KMUHC-01, which has bone anabolic capacity and lower cytotoxicity than simvastatin. We hypothesize that KMUHC-01 could help bone formation in bone-defect animal models. We used rat models of critical calvarial and long-bone defects to evaluate the effects of KMUHC-01 and simvastatin on biological changes at the bone defect through histology, immunohistology, and mechanical testing using three-point bending and evaluated the new bone formation microstructure through microcomputed tomography analysis. The newly formed bone microstructure at the calvarial defect site showed a significantly improved trabecular bone volume in the KMUHC-01 1-μM group compared with that in the control and simvastatin groups. The biomechanical study revealed a significantly increased maximal strength in the KMUHC-01 1-μM group compared with that in the control group. KUMHC-01, as a simvastatin derivative, showed a great anabolic effect in promoting bone defect healing. However, further studies will be conducted to prove the bioavailability and bone-forming efficacy of KMUHC-01 via systemic administration. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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18 pages, 6299 KiB

Open AccessArticle

Dietary Collagen Hydrolysates Retard Estrogen Deficiency-Induced Bone Loss through Blocking Osteoclastic Activation and Enhancing Osteoblastic Matrix Mineralization

by Soo-Il Kim, Sin-Hye Park, Woojin Na, Yong Chul Shin, Moon-Sik Oh, Young Eun Sim, Yulong Zheng, Ae Hyang Kim, Il-Jun Kang and Young-Hee Kang

Biomedicines 2022, 10(6), 1382; https://doi.org/10.3390/biomedicines10061382 - 10 Jun 2022

Cited by 1 | Viewed by 2800

Abstract

Osteoporosis manifest in postmenopausal women is an osteolytic disease characterized by bone loss, leading to increased susceptibility to bone fractures and frailty. The use of complementary therapies to alleviate postmenopausal osteoporosis is fairly widespread among women. The current study examined that Pangasius hypophthalmus [...] Read more.

Osteoporosis manifest in postmenopausal women is an osteolytic disease characterized by bone loss, leading to increased susceptibility to bone fractures and frailty. The use of complementary therapies to alleviate postmenopausal osteoporosis is fairly widespread among women. The current study examined that Pangasius hypophthalmus fish skin collagen hydrolysates (fsCH) inhibited ovariectomy (OVX)-induced bone loss by conducting inter-comparative experiments for anti-osteoporotic activity among 206–618 mg/kg fsCH, 2 mg/kg isoflavone, 15 mg/kg glycine–proline–hydroxyproline (GPH) tripeptide, and calcium lactate. Surgical estrogen loss of mice for 8 weeks reduced serum 17β-estradiol levels with uterus atrophy, which was ameliorated by orally administering fsCH or isoflavone to mice. Similar to isoflavone, fsCH containing GPH-enhanced bone mineral density reduced levels of cathepsin K and proton-handling proteins, and elevated collagen 1 level in OVX bones. The treatment with fsCH and isoflavone enhanced the serum levels of collagen synthesis-related procollagen type 1 carboxy/amino-terminal propeptides reduced by OVX, whereas serum levels of osteocalcin and alkaline phosphatase, as well as collagen breakdown-related carboxy/amino-terminal telopeptides of type 1 collagen were reduced in OVX mice treated with fsCH, isoflavone, and calcium lactate. The trabecular bones were newly formed in OVX bones treated with isoflavone and fsCH, but not with calcium lactate. However, a low-dose combination of fsCH and calcium lactate had a beneficial synergy effect on postmenopausal osteoporosis. Furthermore, similar to isoflavone, 15–70 μg/mL fsCH, with its constituents of GPH and dipeptides of glycine–proline and proline–hydroxyproline, enhanced osteogenesis through stimulating differentiation, matrix mineralization, and calcium deposition of MC3T3-E1 osteoblasts. Accordingly, the presence of fsCH may encumber estrogen deficiency-induced bone loss through enhancing osteoclastogenic differentiation and matrix collagen synthesis. Therefore, fsCH may be a natural compound retarding postmenopausal osteoporosis and pathological osteoresorptive disorders. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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19 pages, 11952 KiB

Open AccessArticle

Cre/LoxP Genetic Recombination Sustains Cartilage Anabolic Factor Expression in Hyaluronan Encapsulated MSCs Alleviates Intervertebral Disc Degeneration

by Long-Yi Chan, Cheng-Chung Chang, Po-Liang Lai, Tomoji Maeda, Horng-Chaung Hsu, Chin-Yu Lin and Shu-Jui Kuo

Biomedicines 2022, 10(3), 555; https://doi.org/10.3390/biomedicines10030555 - 26 Feb 2022

Cited by 5 | Viewed by 2231

Abstract

(1) Background: Inexplicable low back and neck pain frequently results from spinal disc degeneration with an imbalanced intervertebral disc (IVD) cell homeostasis. We hypothesize that introducing MSC expressing a sustained cartilage-anabolic factor in the IVD may stimulate the mucoid materials secreted from the [...] Read more.

(1) Background: Inexplicable low back and neck pain frequently results from spinal disc degeneration with an imbalanced intervertebral disc (IVD) cell homeostasis. We hypothesize that introducing MSC expressing a sustained cartilage-anabolic factor in the IVD may stimulate the mucoid materials secreted from the IVD cells, promote the MSC’s chondrogenesis and maintain the hydration content providing mechanical strength to decelerate the disc degeneration progression; (2) Methods: This study expressed a cartilage-anabolic factor runx1 by a baculoviral vector (BV) transduced MSCs through a Cre/LoxP gene editing and recombination system for sustained recombinant runx1 transcription factor production. The Cre/LoxP BV modified MSCs were encapsulated by hyaluronan hydrogel, due to its’ vital composition in ECM of a healthy disc and transplanted to a punctured coccygeal disc in rats through micro-injection, followed by X-ray radiography and histological analysis at the 4- and 12-weeks post-transplantation; (3) Results: Data reveals the Cre/LoxP BV system-mediated long-termed runx1 gene expression, possessing good biosafety characteristics in the in vitro cell transduction and in vivo MSCs transplantation, and maintained superior hydration content in the disc than that of mock transduced MSCs; (4) Conclusions: This proof-of-concept study fulfills the need of implanting therapeutic cells accompanied with microinjection in the disc, such as a discography and paves a road to manufacture composite hyaluronan, such as peptide modified hyaluronan as an MSC carrier for IVD regeneration in the future study. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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16 pages, 5309 KiB

Open AccessCommunication

Muscular and Tendon Degeneration after Achilles Rupture: New Insights into Future Repair Strategies

by Lara Gil-Melgosa, Jorge Grasa, Ainhoa Urbiola, Rafael Llombart, Miguel Susaeta Ruiz, Verónica Montiel, Cristina Ederra, Begoña Calvo, Mikel Ariz, Purificación Ripalda-Cemborain, Felipe Prosper, Carlos Ortiz-de-Solórzano, Juan Pons-Villanueva and Ana Pérez Ruiz

Biomedicines 2022, 10(1), 19; https://doi.org/10.3390/biomedicines10010019 - 23 Dec 2021

Cited by 6 | Viewed by 3522

Abstract

Achilles tendon rupture is a frequent injury with an increasing incidence. After clinical surgical repair, aimed at suturing the tendon stumps back into their original position, the repaired Achilles tendon is often plastically deformed and mechanically less strong than the pre-injured tissue, with [...] Read more.

Achilles tendon rupture is a frequent injury with an increasing incidence. After clinical surgical repair, aimed at suturing the tendon stumps back into their original position, the repaired Achilles tendon is often plastically deformed and mechanically less strong than the pre-injured tissue, with muscle fatty degeneration contributing to function loss. Despite clinical outcomes, pre-clinical research has mainly focused on tendon structural repair, with a lack of knowledge regarding injury progression from tendon to muscle and its consequences on muscle degenerative/regenerative processes and function. Here, we characterize the morphological changes in the tendon, the myotendinous junction and muscle belly in a mouse model of Achilles tendon complete rupture, finding cellular and fatty infiltration, fibrotic tissue accumulation, muscle stem cell decline and collagen fiber disorganization. We use novel imaging technologies to accurately relate structural alterations in tendon fibers to pathological changes, which further explain the loss of muscle mechanical function after tendon rupture. The treatment of tendon injuries remains a challenge for orthopedics. Thus, the main goal of this study is to bridge the gap between clinicians’ knowledge and research to address the underlying pathophysiology of ruptured Achilles tendon and its consequences in the gastrocnemius. Such studies are necessary if current practices in regenerative medicine for Achilles tendon ruptures are to be improved. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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Review

Jump to: Research

25 pages, 700 KiB

Open AccessReview

The Role of Mitochondrial Metabolism, AMPK-SIRT Mediated Pathway, LncRNA and MicroRNA in Osteoarthritis

by Hao-Yu Liu, Chi-Fen Chang, Cheng-Chang Lu, Shun-Cheng Wu, Bin Huang, Tsung-Lin Cheng, Sung-Yen Lin, Cheng-Jung Ho, Mon-Juan Lee, Chung-Da Yang, Ying-Chun Wang, Jhong-You Li, Ping-Cheng Liu, Chun-Wang Wei, Lin Kang and Chung-Hwan Chen

Biomedicines 2022, 10(7), 1477; https://doi.org/10.3390/biomedicines10071477 - 22 Jun 2022

Cited by 2 | Viewed by 3252

Abstract

Osteoarthritis (OA) is the most common joint disease characterized by degeneration of articular cartilage and causes severe joint pain, physical disability, and impaired quality of life. Recently, it was found that mitochondria not only act as a powerhouse of cells that provide energy [...] Read more.

Osteoarthritis (OA) is the most common joint disease characterized by degeneration of articular cartilage and causes severe joint pain, physical disability, and impaired quality of life. Recently, it was found that mitochondria not only act as a powerhouse of cells that provide energy for cellular metabolism, but are also involved in crucial pathways responsible for maintaining chondrocyte physiology. Therefore, a growing amount of evidence emphasizes that impairment of mitochondrial function is associated with OA pathogenesis; however, the exact mechanism is not well known. Moreover, the AMP-activated protein kinase (AMPK)–Sirtuin (SIRT) signaling pathway, long non-coding RNA (lncRNA), and microRNA (miRNA) are important for regulating the physiological and pathological processes of chondrocytes, indicating that these may be targets for OA treatment. In this review, we first focus on the importance of mitochondria metabolic dysregulation related to OA. Then, we show recent evidence on the AMPK-SIRT mediated pathway associated with OA pathogenesis and potential treatment options. Finally, we discuss current research into the effects of lncRNA and miRNA on OA progression or inhibition. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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11 pages, 295 KiB

Open AccessReview

Mesenchymal Stromal Cells in Osteoarthritis: Evidence for Structural Benefit and Cartilage Repair

by Yujie Song and Christian Jorgensen

Biomedicines 2022, 10(6), 1278; https://doi.org/10.3390/biomedicines10061278 - 30 May 2022

Cited by 13 | Viewed by 2011

Abstract

Osteoarthritis (OA) presents a major clinical challenge to rheumatologists and orthopedists due to the lack of available drugs reducing structural degradation. Mesenchymal stromal cells (MSCs) may represent new therapeutic approaches in cartilage regeneration. In this review, we highlight the latest knowledge on the [...] Read more.

Osteoarthritis (OA) presents a major clinical challenge to rheumatologists and orthopedists due to the lack of available drugs reducing structural degradation. Mesenchymal stromal cells (MSCs) may represent new therapeutic approaches in cartilage regeneration. In this review, we highlight the latest knowledge on the biological properties of MSC, such as their chondrogenic and immunomodulatory potential, and we give a brief overview of the effects of MSCs in preclinical and clinical studies of OA treatment and also compare different MSC sources, with the adipose tissue-derived MSCs being promising. Then, we focus on their structural benefit in treating OA and summarize the current evidence for the assessment of cartilage in OA according to magnetic resonance imaging (MRI) and second-look arthroscopy after MSC therapy. Finally, this review provides a brief perspective on enhancing the activity of MSCs. Full article

(This article belongs to the Special Issue From Pathophysiology to Novel Therapeutic Approaches in Musculoskeletal System)

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