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27 pages, 8222 KiB

Open AccessArticle

Promotion of Bone Formation in a Rat Osteoporotic Vertebral Body Defect Model via Suppression of Osteoclastogenesis by Ectopic Embryonic Calvaria Derived Mesenchymal Stem Cells

by Yerin Yu, Somin Lee, Minsung Bock, Seong Bae An, Hae Eun Shin, Jong Seop Rim, Jun-oh Kwon, Kwang-Sook Park and Inbo Han

Int. J. Mol. Sci. 2024, 25(15), 8174; https://doi.org/10.3390/ijms25158174 - 26 Jul 2024

Viewed by 985

Abstract

Osteoporotic vertebral compression fractures (OVCFs) are the most prevalent fractures among patients with osteoporosis, leading to severe pain, deformities, and even death. This study explored the use of ectopic embryonic calvaria derived mesenchymal stem cells (EE-cMSCs), which are known for their superior differentiation [...] Read more.

Osteoporotic vertebral compression fractures (OVCFs) are the most prevalent fractures among patients with osteoporosis, leading to severe pain, deformities, and even death. This study explored the use of ectopic embryonic calvaria derived mesenchymal stem cells (EE-cMSCs), which are known for their superior differentiation and proliferation capabilities, as a potential treatment for bone regeneration in OVCFs. We evaluated the impact of EE-cMSCs on osteoclastogenesis in a RAW264.7 cell environment, which was induced by the receptor activator of nuclear factor kappa-beta ligand (RANKL), using cytochemical staining and quantitative real-time PCR. The osteogenic potential of EE-cMSCs was evaluated under various hydrogel conditions. An osteoporotic vertebral body bone defect model was established by inducing osteoporosis in rats through bilateral ovariectomy and creating defects in their coccygeal vertebral bodies. The effects of EE-cMSCs were examined using micro-computed tomography (μCT) and histology, including immunohistochemical analyses. In vitro, EE-cMSCs inhibited osteoclast differentiation and promoted osteogenesis in a 3D cell culture environment using fibrin hydrogel. Moreover, μCT and histological staining demonstrated increased new bone formation in the group treated with EE-cMSCs and fibrin. Immunostaining showed reduced osteoclast activity and bone resorption, alongside increased angiogenesis. Thus, EE-cMSCs can effectively promote bone regeneration and may represent a promising therapeutic approach for treating OVCFs. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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13 pages, 2547 KiB

Open AccessArticle

Establishment of a Triple Quadrupole HPLC-MS Quantitation Method for Dystrophin Protein in Mouse and Human Skeletal Muscle

by Tsukasa Tominari, Masaru Takatoya, Toshiya Matsubara, Michio Matsunobe, Daichi Arai, Chiho Matsumoto, Michiko Hirata, Shosei Yoshinouchi, Chisato Miyaura, Yoshifumi Itoh, Hirofumi Komaki, Shin’ichi Takeda, Yoshitsugu Aoki and Masaki Inada

Int. J. Mol. Sci. 2024, 25(1), 303; https://doi.org/10.3390/ijms25010303 - 25 Dec 2023

Viewed by 1420

Abstract

Duchenne muscular dystrophy (DMD) is the most common type of neuromuscular disease caused by mutations in the DMD gene encoding dystrophin protein. To quantitively assess human dystrophin protein in muscle biopsy samples, it is imperative to consistently detect as low as 0.003% of [...] Read more.

Duchenne muscular dystrophy (DMD) is the most common type of neuromuscular disease caused by mutations in the DMD gene encoding dystrophin protein. To quantitively assess human dystrophin protein in muscle biopsy samples, it is imperative to consistently detect as low as 0.003% of the dystrophin protein relative to the total muscle protein content. The quantitation of dystrophin protein has traditionally been conducted using semiquantitative immunoblotting or immunohistochemistry; however, there is a growing need to establish a more precise quantitative method by employing liquid chromatography-mass spectrometry (LC-MS) to measure dystrophin protein. In this study, a novel quantification method was established using a mouse experiment platform applied to the clinical quantification of human dystrophin protein. The method using a spike-in approach with a triple quadrupole LC-MS quantitated the amount of dystrophin in wild-type and human DMD transgenic mice but not in DMD-null mice. In conclusion, we established a quantitating method of dystrophin using HPLC-LC-MS with a novel spike-in approach. These results indicate that our methodology could be applied to several LC-MS devices to enable the accurate measurement of dystrophin protein in patients with DMD. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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12 pages, 9346 KiB

Open AccessArticle

WISP1 Is Involved in the Pathogenesis of Kashin-Beck Disease via the Autophagy Pathway

by Ping Li, Bolun Cheng, Yao Yao, Wenxing Yu, Li Liu, Shiqiang Cheng, Lu Zhang, Mei Ma, Xin Qi, Chujun Liang, Xiaomeng Chu, Jing Ye, Shiquan Sun, Yumeng Jia, Xiong Guo, Yan Wen and Feng Zhang

Int. J. Mol. Sci. 2023, 24(22), 16037; https://doi.org/10.3390/ijms242216037 - 7 Nov 2023

Cited by 2 | Viewed by 1279

Abstract

Objective: Kashin-Beck disease (KBD) is a kind of endemic and chronic osteochondropathy in China. This study aims to explore the functional relevance and potential mechanism of Wnt-inducible signaling pathway protein 1 (WISP1) in the pathogenesis of KBD. Design: KBD and control cartilage specimens [...] Read more.

Objective: Kashin-Beck disease (KBD) is a kind of endemic and chronic osteochondropathy in China. This study aims to explore the functional relevance and potential mechanism of Wnt-inducible signaling pathway protein 1 (WISP1) in the pathogenesis of KBD. Design: KBD and control cartilage specimens were collected for tissue section observation and primary chondrocyte culture. Firstly, the morphological and histopathological observations were made under a light and electron microscope. Then, the expression levels of WISP1 as well as molecular markers related to the autophagy pathway and extracellular matrix (ECM) synthesis were detected in KBD and control chondrocytes by qRT-PCR, Western blot, and immunohistochemistry. Furthermore, the lentiviral transfection technique was applied to make a WISP1 knockdown cell model based on KBD chondrocytes. In vitro intervention experiments were conducted on the C28/I2 human chondrocyte cell line using human recombinant WISP1 (rWISP1). Results: The results showed that the autolysosome appeared in the KBD chondrocytes. The expression of WISP1 was significantly higher in KBD chondrocytes. Additionally, T-2 toxin, a risk factor for KBD onset, could up-regulate the expression of WISP1 in C28/I2. The autophagy markers ATG4C and LC3II were upregulated after the low-concentration treatment of T-2 toxin and downregulated after the high-concentration treatment. After knocking down WISP1 expression in KBD chondrocytes, MAP1LC3B decreased while ATG4C and COL2A1 increased. Moreover, the rWISP1 protein treatment in C28/I2 chondrocytes could upregulate the expression of ATG4C and LC3II at the beginning and downregulate them then. Conclusions: Our study suggested that WISP1 might play a role in the pathogenesis of KBD through autophagy. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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19 pages, 4951 KiB

Open AccessArticle

Persicae Semen Promotes Bone Union in Rat Fractures by Stimulating Osteoblastogenesis through BMP-2 and Wnt Signaling

by Jae-Yun Jun, Jae-Hyun Kim, Minsun Kim, Sooyeon Hong, Myunghyun Kim, Gwang-Hyun Ryu, Jae Ho Park, Hyuk-Sang Jung and Youngjoo Sohn

Int. J. Mol. Sci. 2023, 24(8), 7388; https://doi.org/10.3390/ijms24087388 - 17 Apr 2023

Cited by 9 | Viewed by 1988

Abstract

Fractures cause extreme pain to patients and impair movement, thereby significantly reducing their quality of life. However, in fracture patients, movement of the fracture site is restricted through application of a cast, and they are reliant on conservative treatment through calcium intake. Persicae [...] Read more.

Fractures cause extreme pain to patients and impair movement, thereby significantly reducing their quality of life. However, in fracture patients, movement of the fracture site is restricted through application of a cast, and they are reliant on conservative treatment through calcium intake. Persicae semen (PS) is the dried mature seeds of Prunus persica (L.) Batsch, and in this study the effects of PS on osteoblast differentiation and bone union promotion were investigated. The osteoblast-differentiation-promoting effect of PS was investigated through alizarin red S and Von Kossa staining, and the regulatory role of PS on BMP-2 (Bmp2) and Wnt (Wnt10b) signaling, representing a key mechanism, was demonstrated at the protein and mRNA levels. In addition, the bone-union-promoting effect of PS was investigated in rats with fractured femurs. The results of the cell experiments showed that PS promotes mineralization and upregulates RUNX2 through BMP-2 and Wnt signaling. PS induced the expression of various osteoblast genes, including Alpl, Bglap, and Ibsp. The results of animal experiments show that the PS group had improved bone union and upregulated expression of osteogenic genes. Overall, the results of this study suggest that PS can promote fracture recovery by upregulating osteoblast differentiation and bone formation, and thus can be considered a new therapeutic alternative for fracture patients. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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13 pages, 3034 KiB

Open AccessArticle

Dental Pulp Stem Cell-Derived Exosomes Alleviate Mice Knee Osteoarthritis by Inhibiting TRPV4-Mediated Osteoclast Activation

by Yu Fu, Shengjie Cui, Yanheng Zhou and Lixin Qiu

Int. J. Mol. Sci. 2023, 24(5), 4926; https://doi.org/10.3390/ijms24054926 - 3 Mar 2023

Cited by 8 | Viewed by 3144

Abstract

Osteoarthritis (OA) is a degenerative disease that causes chronic pain and joint swelling and even disables millions of patients. However, current non-surgical treatment for OA can only relieve pain without obvious cartilage and subchondral bone repair. Mesenchymal stem cell (MSC)-secreted exosomes have promising [...] Read more.

Osteoarthritis (OA) is a degenerative disease that causes chronic pain and joint swelling and even disables millions of patients. However, current non-surgical treatment for OA can only relieve pain without obvious cartilage and subchondral bone repair. Mesenchymal stem cell (MSC)-secreted exosomes have promising therapeutic effects on knee OA, but the efficacy of MSC-exosome therapy is not well determined, and the mechanisms involved are still unclear. In this study, we isolated dental pulp stem cell (DPSC)-derived exosomes by ultracentrifugation and determined the therapeutic effects of a single intra-articular injection of DPSC-derived exosomes in a mice knee OA model. The results showed that the DPSC-derived exosomes effectively improved abnormal subchondral bone remodeling, inhibited the occurrence of bone sclerosis and osteophytes, and alleviated cartilage degradation and synovial inflammation in vivo. Moreover, transient receptor potential vanilloid 4 (TRPV4) was activated during the progression of OA. Enhanced TRPV4 activation facilitated osteoclast differentiation, and TRPV4 inhibition blocked this process in vitro. DPSC-derived exosomes repressed osteoclast activation in vivo by inhibiting TRPV4 activation. Our findings demonstrated that a topical, single injection of DPSC-derived exosomes is a potential strategy for knee OA treatment, and that the exosomes regulated osteoclast activation by TRPV4 inhibition, which may act as a promising target for clinical OA treatment. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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11 pages, 2058 KiB

Open AccessArticle

Vitamin D Increases Irisin Serum Levels and the Expression of Its Precursor in Skeletal Muscle

by Lorenzo Sanesi, Manuela Dicarlo, Patrizia Pignataro, Roberta Zerlotin, Flavia Pugliese, Carla Columbu, Vincenzo Carnevale, Silvia Tunnera, Alfredo Scillitani, Maria Grano, Graziana Colaianni and Silvia Colucci

Int. J. Mol. Sci. 2023, 24(4), 4129; https://doi.org/10.3390/ijms24044129 - 18 Feb 2023

Cited by 12 | Viewed by 5169

Abstract

Irisin is a myokine synthesized by skeletal muscle, which performs key actions on whole-body metabolism. Previous studies have hypothesized a relationship between irisin and vitamin D, but the pathway has not been thoroughly investigated. The purpose of the study was to evaluate whether [...] Read more.

Irisin is a myokine synthesized by skeletal muscle, which performs key actions on whole-body metabolism. Previous studies have hypothesized a relationship between irisin and vitamin D, but the pathway has not been thoroughly investigated. The purpose of the study was to evaluate whether vitamin D supplementation affected irisin serum levels in a cohort of 19 postmenopausal women with primary hyperparathyroidism (PHPT) treated with cholecalciferol for six months. In parallel, to understand the possible link between vitamin D and irisin, we analyzed the expression of the irisin precursor, Fndc5, in the C2C12 myoblast cell line treated with a biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Our results demonstrate that vitamin D supplementation resulted in a significant increase in irisin serum levels (p = 0.031) in PHPT patients. In vitro, we show that vitamin D treatment on myoblasts enhanced Fndc5 mRNA after 48 h (p = 0.013), while it increased mRNAs of sirtuin 1 (Sirt1) (p = 0.041) and peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1α) (p = 0.017) over a shorter time course. Overall, our data suggest that vitamin-D-induced modulation of Fndc5/irisin occurs through up-regulation of Sirt1, which together with Pgc1α, is an important regulator of numerous metabolic processes in skeletal muscle. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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Review

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24 pages, 2043 KiB

Open AccessReview

Stem Cell and Regenerative Therapies for the Treatment of Osteoporotic Vertebral Compression Fractures

by Songzi Zhang, Yunhwan Lee, Yanting Liu, Yerin Yu and Inbo Han

Int. J. Mol. Sci. 2024, 25(9), 4979; https://doi.org/10.3390/ijms25094979 - 2 May 2024

Cited by 1 | Viewed by 1861

Abstract

Osteoporotic vertebral compression fractures (OVCFs) significantly increase morbidity and mortality, presenting a formidable challenge in healthcare. Traditional interventions such as vertebroplasty and kyphoplasty, despite their widespread use, are limited in addressing the secondary effects of vertebral fractures in adjacent areas and do not [...] Read more.

Osteoporotic vertebral compression fractures (OVCFs) significantly increase morbidity and mortality, presenting a formidable challenge in healthcare. Traditional interventions such as vertebroplasty and kyphoplasty, despite their widespread use, are limited in addressing the secondary effects of vertebral fractures in adjacent areas and do not facilitate bone regeneration. This review paper explores the emerging domain of regenerative therapies, spotlighting stem cell therapy’s transformative potential in OVCF treatment. It thoroughly describes the therapeutic possibilities and mechanisms of action of mesenchymal stem cells against OVCFs, relying on recent clinical trials and preclinical studies for efficacy assessment. Our findings reveal that stem cell therapy, particularly in combination with scaffolding materials, holds substantial promise for bone regeneration, spinal stability improvement, and pain mitigation. This integration of stem cell-based methods with conventional treatments may herald a new era in OVCF management, potentially improving patient outcomes. This review advocates for accelerated research and collaborative efforts to translate laboratory breakthroughs into clinical practice, emphasizing the revolutionary impact of regenerative therapies on OVCF management. In summary, this paper positions stem cell therapy at the forefront of innovation for OVCF treatment, stressing the importance of ongoing research and cross-disciplinary collaboration to unlock its full clinical potential. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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18 pages, 1559 KiB

Open AccessReview

Macrophages and Intervertebral Disc Degeneration

by Jinsha Koroth, Erick O. Buko, Rebecca Abbott, Casey P. Johnson, Brenda M. Ogle, Laura S. Stone, Arin M. Ellingson and Elizabeth W. Bradley

Int. J. Mol. Sci. 2023, 24(2), 1367; https://doi.org/10.3390/ijms24021367 - 10 Jan 2023

Cited by 22 | Viewed by 4744

Abstract

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. [...] Read more.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration. Full article

(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies 2.0)

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