Transcriptional network systems in cartilage development and disease.
Nishimura Riko,Hata Kenji,Nakamura Eriko,Murakami Tomohiko,Takahata Yoshifumi
Histochemistry and cell biology
Transcription factors play important roles in the regulation of cartilage development by controlling the expression of chondrogenic genes. Genetic studies have revealed that Sox9/Sox5/Sox6, Runx2/Runx3 and Osterix in particular are essential for the sequential steps of cartilage development. Importantly, these transcription factors form network systems that are also required for appropriate cartilage development. Molecular cloning approaches have largely contributed to the identification of several transcriptional partners for Sox9 and Runx2 during cartilage development. Although the importance of a negative-feedback loop between Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP) in chondrocyte hypertrophy has been well established, recent studies indicate that several transcription factors interact with the Ihh-PTHrP loop and demonstrated that Ihh has multiple functions in the regulation of cartilage development. The most common cartilage disorder, osteoarthritis, has been reported to result from the pathological action of several transcription factors, including Runx2, C/EBPβ and HIF-2α. On the other hand, NFAT family members appear to play roles in the protection of cartilage from osteoarthritis. It is also becoming important to understand the homeostasis and regulation of articular chondrocytes, because they have different cellular and molecular features from chondrocytes of the growth plate. This review summarizes the regulation and roles of transcriptional network systems in cartilage development and their pathological roles in osteoarthritis.
10.1007/s00418-017-1628-7
Ablation of protein phosphatase 5 (PP5) leads to enhanced both bone and cartilage development in mice.
Wang Jun,Cao Yong,Qiu Bin,Du Jianyong,Wang Tingting,Wang Chao,Deng Ran,Shi Xudong,Gao Kai,Xie Zhongwen,Yong Weidong
Cell death & disease
This study aimed to investigate the role of protein phosphatase 5 (PP5) on bone and cartilage development using both in vivo and in vitro approaches. Six- to 8-week- old male PP5 knockout mice (KO) and their wild-type (WT) littermate controls were randomly selected for this study, and their body weights and bone (femur) lengths were measured. Micro-computed tomography scanning (Micro-CT) was performed to determine femoral bone density and micro-architecture. Mesenchymal stem cells (MSCs) isolated from bone marrow were used to examine the effects of PP5 on osteogenesis in vitro. Whole-mount Alcian blue and Alizarin red staining were used to detect cartilage formation in newborn vertebrae, limbs, and feet. Hematoxylin and eosin (H&E) staining was performed to determine growth plate thickness. Real-time PCR analysis, western blotting, and immunohistochemistry were used to detect the expression of genes and proteins in bone marrow-derived MSCs as well as in bone and cartilage tissues. The results showed PP5 KO mice exhibited significantly reduced body weight and shorter femur length compared to WT controls. The KO mice also had significantly higher volumetric bone mineral density (BMD), trabecular bone volume, and cortical thickness in the femur. The deficiency of PP5 significantly enhanced the formation of cartilage in vertebrae, limbs, and feet. In addition, KO mice possessed a wider distal femur growth plates containing significantly more chondrocytes than WT mice. Furthermore, higher expressions of several cartilage-specific genes were observed in the articular cartilage of PP5 KO mice. Immunohistochemical labeling of growth plates demonstrated that phospho-PPARγ, Runx1, and Runx2 levels were considerably higher in the KO mice. In conclusion, PP5 is a significant negative regulator on the regulation of bone and cartilage development.
10.1038/s41419-017-0254-6
IRE1α dissociates with BiP and inhibits ER stress-mediated apoptosis in cartilage development.
Han Xiaofeng,Zhou Jinghua,Zhang Peng,Song Fangzhou,Jiang Rong,Li Meiling,Xia Fei,Guo Feng-Jin
Cellular signalling
Bone morphogenetic protein 2 is known to activate unfolded protein response signaling molecules, including XBP1S, BiP and IRE1α. Endoplasmic reticulum stress is induced in chondrogenesis and activates IRE1α signal pathway, which is associated with ER stress-mediated apoptosis. However, the influence on IRE1α and BiP in BMP2-induced chondrocyte differentiation has not yet been elucidated; the molecular mechanism remains unexplored. In this study, we demonstrate that IRE1α interacts with BiP in unstressed cells and dissociates from BiP in the course of cartilage development. Induction of ER stress-responsive proteins (XBP1S, IRE1α, BiP) was also observed in differentiating cells. IRE1α inhibition ER stress-mediated apoptosis lies in the process of chondrocyte differentiation. Furthermore, knockdown of IRE1α expression by way of the RNAi approach accelerates ER stress-mediated apoptosis in chondrocyte differentiation induced by BMP2, as revealed by enhanced expressions of cleaved caspase3, CHOP and p-JNK1; and this IRE1α inhibition effect on ER stress-mediated apoptosis is required for BiP in chondrogenesis. Collectively, the ER stress sensors were activated during apoptosis in cartilage development, suggesting that selective activation of ER stress signaling was sufficient for induction of apoptosis. These findings reveal a novel critical role of IRE1α in ER stress-mediated apoptosis and the molecular mechanisms involved. These results suggest that activation of p-JNK1, caspase3 and CHOP was detected in developing chondrocytes and that specific ER stress signaling leads to naturally occurring apoptosis during cartilage development.
10.1016/j.cellsig.2013.06.011
Primary cilia: Versatile regulator in cartilage development.
Tao Fenghua,Jiang Ting,Tao Hai,Cao Hui,Xiang Wei
Cell proliferation
Cartilage is a connective tissue in the skeletal system and has limited regeneration ability and unique biomechanical reactivity. The growth and development of cartilage can be affected by different physical, chemical and biological factors, such as mechanical stress, inflammation, osmotic pressure, hypoxia and signalling transduction. Primary cilia are multifunctional sensory organelles that regulate diverse signalling transduction and cell activities. They are crucial for the regulation of cartilage development and act in a variety of ways, such as react to mechanical stress, mediate signalling transduction, regulate cartilage-related diseases progression and affect cartilage tumorigenesis. Therefore, research on primary cilia-mediated cartilage growth and development is currently extremely popular. This review outlines the role of primary cilia in cartilage development in recent years and elaborates on the potential regulatory mechanisms from different aspects.
10.1111/cpr.12765
HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development.
Rutkowski Timothy P,Kohn Anat,Sharma Deepika,Ren Yinshi,Mirando Anthony J,Hilton Matthew J
Journal of cell science
RBPjκ-dependent Notch signaling regulates multiple processes during cartilage development, including chondrogenesis, chondrocyte hypertrophy and cartilage matrix catabolism. Select members of the HES- and HEY-families of transcription factors are recognized Notch signaling targets that mediate specific aspects of Notch function during development. However, whether particular HES and HEY factors play any role(s) in the processes during cartilage development is unknown. Here, for the first time, we have developed unique in vivo genetic models and in vitro approaches demonstrating that the RBPjκ-dependent Notch targets HES1 and HES5 suppress chondrogenesis and promote the onset of chondrocyte hypertrophy. HES1 and HES5 might have some overlapping function in these processes, although only HES5 directly regulates Sox9 transcription to coordinate cartilage development. HEY1 and HEYL play no discernable role in regulating chondrogenesis or chondrocyte hypertrophy, whereas none of the HES or HEY factors appear to mediate Notch regulation of cartilage matrix catabolism. This work identifies important candidates that might function as downstream mediators of Notch signaling both during normal skeletal development and in Notch-related skeletal disorders.
10.1242/jcs.181271
Galectin-3: A key player in arthritis.
Hu Yong,Yéléhé-Okouma Mélissa,Ea Hang-Korng,Jouzeau Jean-Yves,Reboul Pascal
Joint bone spine
Arthritis is more and more considered as the leading reason for the disability in the world, particularly regarding its main entities, rheumatoid arthritis and osteoarthritis. The common feature of arthritis is inflammation, which is mainly supported by synovitis (synovial inflammation), although the immune system plays a primary role in rheumatoid arthritis and a secondary one in osteoarthritis. During the inflammatory phase of arthritis, many pro-inflammatory cytokines and mediators are secreted by infiltrating immune and resident joint cells, which are responsible for cartilage degradation and excessive bone remodeling. Amongst them, a β-galactoside-binding lectin, galectin-3, has been reported to be highly expressed and secreted by inflamed synovium of rheumatoid arthritis and osteoarthritis patients. Furthermore, galectin-3 has been demonstrated to induce joint swelling and osteoarthritis-like lesions after intra-articular injection in laboratory animals. However, the mechanisms underlying its pathophysiological role in arthritis have not been fully elucidated. This review deals with the characterization of arthritis features and galectin-3 and summarizes our current knowledge of the contribution of galectin-3 to joint tissue lesions in arthritis.
10.1016/j.jbspin.2016.02.029
Role of Galectin-3 in Bone Cell Differentiation, Bone Pathophysiology and Vascular Osteogenesis.
Iacobini Carla,Fantauzzi Claudia Blasetti,Pugliese Giuseppe,Menini Stefano
International journal of molecular sciences
Galectin-3 is expressed in various tissues, including the bone, where it is considered a marker of chondrogenic and osteogenic cell lineages. Galectin-3 protein was found to be increased in the differentiated chondrocytes of the metaphyseal plate cartilage, where it favors chondrocyte survival and cartilage matrix mineralization. It was also shown to be highly expressed in differentiating osteoblasts and osteoclasts, in concomitance with expression of osteogenic markers and Runt-related transcription factor 2 and with the appearance of a mature phenotype. Galectin-3 is expressed also by osteocytes, though its function in these cells has not been fully elucidated. The effects of galectin-3 on bone cells were also investigated in galectin-3 null mice, further supporting its role in all stages of bone biology, from development to remodeling. Galectin-3 was also shown to act as a receptor for advanced glycation endproducts, which have been implicated in age-dependent and diabetes-associated bone fragility. Moreover, its regulatory role in inflammatory bone and joint disorders entitles galectin-3 as a possible therapeutic target. Finally, galectin-3 capacity to commit mesenchymal stem cells to the osteoblastic lineage and to favor transdifferentiation of vascular smooth muscle cells into an osteoblast-like phenotype open a new area of interest in bone and vascular pathologies.
10.3390/ijms18112481
Effect of cadmium on bone tissue in growing animals.
Rodríguez Juliana,Mandalunis Patricia Mónica
Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie
Accumulation of cadmium (Cd), an extremely toxic metal, can cause renal failure, decreased vitamin D synthesis, and consequently osteoporosis. The aim of this work was to evaluate the effect of Cd on two types of bone in growing Wistar rats. Sixteen 21-day-old male Wistar rats were assigned to one of two groups. The Cd group subcutaneously received 0.5mg/kg of CdCl2 5 times weekly for 3 months. The control group similarly received bidistilled water. Following euthanasia, the mandibles and tibiae were resected, fixed, decalcified and processed histologically to obtain sections for H&E and tartrate-resistant acid phosphatase (TRAP) staining. Photomicrographs were used to determine bone volume (BV/TV%), total growth cartilage width (GPC.Wi) hypertrophic cartilage width (HpZ.Wi), percentage of yellow bone marrow (%YBM), megakaryocyte number (N.Mks/mm(2)), and TRAP+osteoclast number (N.TRAP+Ocl/mm(2)). Results were statistically analyzed using Student's t test. Cd exposed animals showed a significant decrease in subchondral bone volume and a significant increase in TRAP+ osteoclast number and percentage of yellow bone marrow in the tibia, and an increase in megakaryocyte number in mandibular interradicular bone. No significant differences were observed in the remaining parameters. The results obtained with this experimental design show that Cd would seemingly have a different effect on subchondral and interradicular bone. The decrease in bone volume and increase in tibial yellow bone marrow suggest that cadmium inhibits differentiation of mesenchymal cells to osteoblasts, favoring differentiation into adipocytes. The different effects of Cd on interradicular bone might be due to the protective effect of the mastication forces.
10.1016/j.etp.2016.06.001
Impact of cadmium toxicity on cartilage loss in a 3D in vitro model.
Yessica Eduviges Zamudio-Cuevas,Martínez-Nava Gabriela,Reyes-Hinojosa Daniel,Mendoza-Soto Luzia,Fernández-Torres Javier,López-Reyes Alberto,Olivos-Meza Anell,Armienta-Hernández María Aurora,Ruíz-Huerta Esther Aurora,de Jesús González-Guadarrama María,Sandoval Bertha Vargas,Landa-Solís Carlos,Sánchez-Sánchez Roberto,Suarez-Ahedo Carlos,Lozada-Pérez Carlos Alberto,Gutiérrez-Ruiz María Concepción,Clavijo-Cornejo Denise,Pineda Carlos,Jacobo-Albavera Leonor,Domínguez-Pérez Mayra,Martínez-Flores Karina
Environmental toxicology and pharmacology
Osteoarthritis (OA) is the gradual loss of articular cartilage and decrease in subchondral space. One of the risk factors Exposure to cadmium (Cd) through tobacco smoke has been identified as a major OA risk factor. There are no reports addressing the role of Cd in OA progression at the molecular level. Our findings revealed that Cd can promote the activation of metalloproteinases (MMP1, MMP3, MMP9 y MMP13), affecting the expression of COL2A1 and ACAN, and decreasing the presence of glycosaminoglycans and proteoglycans through an inflammatory response related to IL-1β y a IL-6, as well as oxidative by producing ROS like O and HO. In conclusion, our findings suggest a cytotoxic role of Cd in the articular cartilage, which could affect OA development.
10.1016/j.etap.2019.103307