Noncoding RNAs in subchondral bone osteoclast function and their therapeutic potential for osteoarthritis

AbstractOsteoclasts are the only cells that perform bone resorption. Noncoding RNAs (ncRNAs) are crucial epigenetic regulators of osteoclast biological behaviors ranging from osteoclast differentiation to bone resorption. The main ncRNAs, including miRNAs, circRNAs, and lncRNAs, compose an intricate network that influences gene transcription processes related to osteoclast biological activity. Accumulating evidence suggests that abnormal osteoclast activity leads to the disturbance of subchondral bone remodeling, thus initiating osteoarthritis (OA), a prevalent joint disease characterized mainly by cartilage degradation and subchondral bone remodeling imbalance. In this review, we delineate three types of ncRNAs and discuss their related complex molecular signaling pathways associated with osteoclast function during bone resorption. We specifically focused on the involvement of noncoding RNAs in subchondral bone remodeling, which participate in the degradation of the osteochondral unit during OA progression. We also discussed exosomes as ncRNA carriers during the bone remodeling process. A better understanding of the roles of ncRNAs in osteoclast biological behaviors will contribute to the treatment of bone resorption-related skeletal diseases such as OA.

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Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis

Cells ◽

10.3390/cells9040927 ◽

2020 ◽

Vol 9 (4) ◽

pp. 927 ◽

Cited By ~ 5

Author(s):

Szu-Yu Chien ◽

Chun-Hao Tsai ◽

Shan-Chi Liu ◽

Chien-Chung Huang ◽

Tzu-Hung Lin ◽

...

Keyword(s):

Articular Cartilage ◽

Signaling Pathways ◽

Bone Remodeling ◽

Subchondral Bone ◽

Bone Destruction ◽

Cartilage Degeneration ◽

Cartilage Degradation ◽

Mitogen Activated Protein Kinase ◽

Bone Morphogenetic Protein 2 ◽

Joint Disease

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

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Jintiange Capsules Ameliorate Osteoarthritis by Modulating Subchondral Bone Remodeling and Protecting Cartilage Against Degradation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.762543 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chenyang Zhuang ◽

Zixiang Wang ◽

Weisin Chen ◽

Hanquan Wang ◽

Bo Tian ◽

...

Keyword(s):

Bone Remodeling ◽

Subchondral Bone ◽

Cruciate Ligament ◽

Osteoclast Differentiation ◽

Nuclear Factor Κb ◽

Osteoclast Formation ◽

Joint Disease ◽

Chondrocyte Apoptosis ◽

And Cartilage

Osteoarthritis (OA) is the most prevalent joint disease worldwide, making it a major cause of pain and disability. Identified as a chronic and progressive disease, effective treatment at the early stages of OA has become critical to its management. Jintiange (Jtg) capsules are a traditional Chinese medicine produced from multiple organic components of various animal bones and routinely used to treat osteoporosis in China. However, the effect of Jtg on subchondral bone and cartilage degeneration in OA remains unknown. The purpose of the present study was to investigate the biomolecular role and underlying mechanisms of Jtg in OA progression. Herein, we found that Jtg inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation and it functions through the NF-κB signaling pathway. Jtg also inhibited chondrocyte apoptosis via reducing the reactive oxygen species concentration in these cells. Moreover, in vivo evaluation revealed that Jtg significantly attenuates subchondral bone remodeling and cartilage destruction in anterior cruciate ligament transection (ACLT) mouse models. Taken together, our data demonstrate that Jtg inhibits osteoclast differentiation in subchondral bone and chondrocyte apoptosis in cartilage, supporting its potential therapeutic value for treating OA.

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Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.687033 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiyuan Yan ◽

Yingchi Zhang ◽

Gaohong Sheng ◽

Bowei Ni ◽

Yifan Xiao ◽

...

Keyword(s):

Therapeutic Potential ◽

Cartilage Damage ◽

Cartilage Degradation ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Therapeutic Effects ◽

Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

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The P2X7 Receptor in Osteoarthritis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.628330 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zihao Li ◽

Ziyu Huang ◽

Lunhao Bai

Keyword(s):

Cell Death ◽

P2x7 Receptor ◽

Therapeutic Potential ◽

Purinergic Receptor ◽

Treatment Options ◽

Cartilage Degradation ◽

Joint Disease ◽

Inflammatory Factors ◽

Inflammatory Factor ◽

Inflammatory Reactions

Osteoarthritis (OA) is the most common joint disease. With the increasing aging population, the associated socio-economic costs are also increasing. Analgesia and surgery are the primary treatment options in late-stage OA, with drug treatment only possible in early prevention to improve patients’ quality of life. The most important structural component of the joint is cartilage, consisting solely of chondrocytes. Instability in chondrocyte balance results in phenotypic changes and cell death. Therefore, cartilage degradation is a direct consequence of chondrocyte imbalance, resulting in the degradation of the extracellular matrix and the release of pro-inflammatory factors. These factors affect the occurrence and development of OA. The P2X7 receptor (P2X7R) belongs to the purinergic receptor family and is a non-selective cation channel gated by adenosine triphosphate. It mediates Na+, Ca2+ influx, and K+ efflux, participates in several inflammatory reactions, and plays an important role in the different mechanisms of cell death. However, the relationship between P2X7R-mediated cell death and the progression of OA requires investigation. In this review, we correlate potential links between P2X7R, cartilage degradation, and inflammatory factor release in OA. We specifically focus on inflammation, apoptosis, pyroptosis, and autophagy. Lastly, we discuss the therapeutic potential of P2X7R as a potential drug target for OA.

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Involvement of Noncoding RNAs in the Differentiation of Osteoclasts

Stem Cells International ◽

10.1155/2020/4813140 ◽

2020 ◽

Vol 2020 ◽

pp. 1-23 ◽

Cited By ~ 1

Author(s):

Yi Zhao ◽

Lingfei Jia ◽

Yunfei Zheng ◽

Weiran Li

Keyword(s):

Osteoclast Differentiation ◽

Noncoding Rnas ◽

Osteoclast Formation ◽

Bone Diseases ◽

Bone Biology ◽

Skeletal Health ◽

Osteoclast Function ◽

Bone Physiology ◽

Bone Resorbing Activity

As the most important bone-resorbing cells, osteoclasts play fundamental roles in bone remodeling and skeletal health. Much effort has been focused on identifying the regulators of osteoclast metabolism. Noncoding RNAs (ncRNAs) reportedly regulate osteoclast formation, differentiation, survival, and bone-resorbing activity to participate in bone physiology and pathology. The present review intends to provide a general framework for how ncRNAs and their targets regulate osteoclast differentiation and the important events of osteoclastogenesis they are involved in, including osteoclast precursor generation, early differentiation, mononuclear osteoclast fusion, and multinucleated osteoclast function and survival. This framework is beneficial for understanding bone biology and for identifying the potential biomarkers or therapeutic targets of bone diseases. The review also summarizes the results of in vivo experiments and classic experiment methods for osteoclast-related researches.

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Rhus javanicaGall Extract Inhibits the Differentiation of Bone Marrow-Derived Osteoclasts and Ovariectomy-Induced Bone Loss

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/3284704 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Tae-Ho Kim ◽

Eui Kyun Park ◽

Man-Il Huh ◽

Hong Kyun Kim ◽

Shin-Yoon Kim ◽

...

Keyword(s):

Bone Marrow ◽

Bone Resorption ◽

Bone Loss ◽

Bone Turnover ◽

Bone Remodeling ◽

Bone Mineral ◽

Osteoclast Differentiation ◽

Protective Effects ◽

Mineral Density ◽

Femoral Bone Mineral Density

Inhibition of osteoclast differentiation and bone resorption is a therapeutic strategy for the management of postmenopausal bone loss. This study investigated the effects ofRhus javanica(R. javanica) extracts on bone marrow cultures to develop agents from natural sources that may prevent osteoclastogenesis. Extracts ofR. javanica(eGr) cocoons spun byRhus javanica(Bell.) Baker inhibited the osteoclast differentiation and bone resorption. The effects of aqueous extract (aeGr) or 100% ethanolic extract (eeGr) on ovariectomy- (OVX-) induced bone loss were investigated by various biochemical assays. Furthermore, microcomputed tomography (µCT) was performed to study bone remodeling. Oral administration of eGr (30 mg or 100 mg/kg/day for 6 weeks) augmented the inhibition of femoral bone mineral density (BMD), bone mineral content (BMC), and other factors involved in bone remodeling when compared to OVX controls. Additionally, eGr slightly decreased bone turnover markers that were increased by OVX. Therefore, it may be suggested that the protective effects of eGr could have originated from the suppression of OVX-induced increase in bone turnover. Collectively, the findings of this study indicate that eGr has potential to activate bone remodeling by inhibiting osteoclast differentiation and bone loss.

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Articular Cartilage Degradation and Aberrant Subchondral Bone Remodeling in Patients with Osteoarthritis and Osteoporosis

Journal of Bone and Mineral Research ◽

10.1002/jbmr.3909 ◽

2019 ◽

Vol 35 (3) ◽

pp. 505-515 ◽

Cited By ~ 6

Author(s):

Linyang Chu ◽

Xuqiang Liu ◽

Zihao He ◽

Xuequan Han ◽

Mengning Yan ◽

...

Keyword(s):

Articular Cartilage ◽

Bone Remodeling ◽

Subchondral Bone ◽

Cartilage Degradation

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Cart Overexpression Is the Only Identifiable Cause of High Bone Mass in Melanocortin 4 Receptor Deficiency

Endocrinology ◽

10.1210/en.2006-0281 ◽

2006 ◽

Vol 147 (7) ◽

pp. 3196-3202 ◽

Cited By ~ 67

Author(s):

Jong Deok Ahn ◽

Beatrice Dubern ◽

Cecile Lubrano-Berthelier ◽

Karine Clement ◽

Gerard Karsenty

Keyword(s):

Energy Metabolism ◽

Bone Resorption ◽

Bone Mass ◽

Bone Remodeling ◽

Neural Control ◽

Osteoclast Differentiation ◽

Serum Levels ◽

High Bone Mass ◽

Melanocortin 4 Receptor ◽

High Bone

The neural regulation of bone remodeling has proven to be increasingly complex at the molecular level because it involves both positive and negative mediators of bone formation and resorption. One of the mediators expressed in hypothalamic neurons that leptin uses to inhibit osteoclast differentiation and thereby bone resorption is cocaine- and amphetamine-regulated transcript (CART). CART expression in the hypothalamus is increased in mice lacking melanocortin 4 receptor (Mc4r−/− mice). Moreover, we show here that humans or mice lacking only one allele of Mc4r display a decrease in bone resorption parameters, high bone mass, and an increase in CART serum levels and/or hypothalamic expression. To demonstrate that the Cart overexpression is the only identifiable cause for the high bone mass observed upon Mc4r inactivation, we removed one allele of Cart from mice either heterozygous or homozygous for Mc4r inactivation. This manipulation sufficed to either significantly improve or normalize bone resorption parameters, without improving the energy metabolism disturbance that characterizes Mc4r-deficient mice. These results identify CART signaling as the main if not only molecular pathway accounting for the decrease in bone resorption leading to high bone mass in mice and humans deficient in Mc4r. As importantly, they also indicate that CART regulates bone resorption independently of the role it may exert in energy metabolism, suggesting that the neural control of appetite and bone remodeling are independent of each other.

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Identifying genes that regulate bone remodeling as potential therapeutic targets

Journal of Experimental Medicine ◽

10.1084/jem.20050354 ◽

2005 ◽

Vol 201 (6) ◽

pp. 841-843 ◽

Cited By ~ 43

Author(s):

Stephen M. Krane

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Remodeling ◽

Osteoblast Differentiation ◽

Osteoclast Differentiation ◽

Protein Signaling ◽

Coupled Process ◽

Systemic Factors ◽

And Function ◽

Deficient Mice

Bone remodeling, a coupled process involving bone resorption and formation, is initiated by mechanical signals and is controlled by local and systemic factors that regulate osteoblast and osteoclast differentiation and function. An excess of resorption over formation leads to the bone loss and increased propensity to fracture that is characteristic of osteoporosis. A newly described inhibitor of osteoblast differentiation, Ciz, interferes with bone morphogenic protein signaling. As a consequence, Ciz-deficient mice develop increased bone mass.

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MicroRNA-29b Promotes Subchondral Bone Loss in TMJ Osteoarthritis

Journal of Dental Research ◽

10.1177/0022034520937617 ◽

2020 ◽

Vol 99 (13) ◽

pp. 1469-1477

Author(s):

J.L. Sun ◽

J.F. Yan ◽

S.B. Yu ◽

J. Zhao ◽

Q.Q. Lin ◽

...

Keyword(s):

Gene Expression ◽

Bone Loss ◽

Bone Remodeling ◽

Subchondral Bone ◽

Volume Fraction ◽

Cartilage Degradation ◽

Specific Inhibition ◽

Mineral Density ◽

Bone Volume Fraction ◽

Trabecular Thickness

Abnormal subchondral bone remodeling plays important roles during osteoarthritis (OA) pathology. Recent studies show that bone marrow mesenchymal stem cells (BMSCs) in osteoarthritic subchondral bones exhibit a prominent pro-osteoclastic effect that contributes to abnormal subchondral bone remodeling; however, the pathologic mechanism remains unclear. In the present study, we used a mouse model with OA-like change in the temporomandibular joint (TMJ) induced by an experimentally unilateral anterior crossbite (UAC) and found that the level of microRNA-29b ( miR-29b), but not miR-29a or miR-29c, was markedly lower in BMSCs from subchondral bones of UAC mice as compared with that from the sham control mice. With an intra-articular aptamer delivery system, BMSC-specific overexpression of miR-29b by aptamer-agomiR-29b rescued subchondral bone loss and osteoclast hyperfunction in UAC mice, as demonstrated by a significant increase in bone mineral density, bone volume fraction, trabecular thickness, and the gene expression of osteocalcin and Runx2 but decreased trabecular separation, osteoclast number and osteoclast surface/bone surface, and the gene expression of cathepsin K, Trap, Wnt5a, Rankl, and Rank as compared with those in the UAC mice treated by aptamer-NC (all P < 0.05). In addition, BMSC-specific inhibition of miR-29b by aptamer-antagomiR-29b exacerbated those responses in UAC mice. Notably, although it primarily affected miR-29b levels in the subchondral bone (but not in cartilage and synovium), BMSC-specific overexpression of miR-29b in UAC mice largely rescued OA-like cartilage degradation, including decreased chondrocyte density, cartilage thickness, and the percentage areas of proteoglycans and type II collagen, while BMSC-specific inhibition of miR-29b aggravated these characteristics of cartilage degradation in UAC mice. Moreover, we identified Wnt5a, but not Rankl or Sdf-1, as the direct target of miR-29b. The results of the present study indicate that miR-29b is a key regulator of the pro-osteoclastic effects of BMSCs in TMJ-OA subchondral bones and plays important roles in the TMJ-OA progression.

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