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1.
Molecular basis of osteoarthritis: biomechanical aspects 总被引:5,自引:0,他引:5
Kerin A Patwari P Kuettner K Cole A Grodzinsky A 《Cellular and molecular life sciences : CMLS》2002,59(1):27-35
The unique biomechanical properties of healthy cartilage ensure that articular cartilage is able to transmit force between
the joints while maintaining almost friction-free limb movement. In osteoarthritis, the biomechanical properties are compromised,
but we still do not understood whether this precedes the onset of the disease or is a result of it. This review focuses on
the physical changes to cartilage with age, disease, and mechanical loading, with specific reference to the increased collagen
cross-linking that occurs with age (nonenzymatic glycation), and the response of chondrocytes to physiological and pathological
loads. In addition, the biomechanical properties and matrix biosynthesis of cartilage from various joint surfaces of the knee
and ankle are compared to elucidate reasons why the ankle is less affected by progressive osteoarthritis than the knee. 相似文献
2.
Arthritic diseases cause enormous burdens in terms of pain, crippling, and disability. Osteoarthritis (OA), the most common
form of arthritis, is characterized by a slow progressive degeneration of articular cartilage. The exact etiology of OA is
not known, but the degradation of cartilage matrix components is generally agreed to be due to an increased synthesis and
activation of extracellular proteinases, mainly matrix metalloproteinases. Insufficient synthesis of new matrix macromolecules
is also thought to be involved, possibly as a consequence of deficient stimulation by growth factors. Although OA is defined
as a noninflammatory arthropathy, proinflammatory cytokines such as interleukin-1 have been implicated as important mediators
in the disease. In response to interleukin-1, chondrocytes upregulate the production of nitric oxide and prostaglandin E2, two factors that have been shown to induce a number of the cellular changes associated with OA. The generation of these
key signal molecules depends on inducible enzymes and can be suppressed by pharmacological inhibitors. 相似文献
3.
Molecular pathology and pathobiology of osteoarthritic cartilage 总被引:14,自引:0,他引:14
The biochemical properties of articular cartilage rely on the biochemical composition and integrity of its extracellular
matrix. This matrix consists mainly of a collagen network and the proteoglycan-rich ground substance. In osteoarthritis, ongoing
cartilage matrix destruction takes place, leading to a progressive loss in joint function. Beside the degradation of molecular
matrix components, destabilization of supramolecular structures such as the collagen network and changes in the expression
profile of matrix molecules also take place. These processes, as well as the pattern of cellular reaction, explain the pathology
of osteoarthritic cartilage degeneration. The loss of histochemical proteoglycan staining reflects the damage at the molecular
level, whereas the supramolecular matrix destruction leads to fissuring and finally to the loss of the cartilage. Chondrocytes
react by increasing matrix synthesis, proliferating, and changing their cellular phenotype. Gene expression mapping in situ
and gene expression profiling allows characterization of the osteoarthritic cellular phenotype, a key determinant for understanding
and manipulating the osteoarthritic disease process. 相似文献
4.
5.
Dudhia J 《Cellular and molecular life sciences : CMLS》2005,62(19-20):2241-2256
The primary function of articular cartilage to act as a self-renewing, low frictional material that can distribute load efficiently at joints is critically dependent upon the composition and organisation of the extracellular matrix. Aggrecan is a major component of the extracellular matrix, forming high molecular weight aggregates necessary for the hydration of cartilage and to meet its weight-bearing mechanical demands. Aggregate assembly is a highly ordered process requiring the formation of a ternary complex between aggrecan, link protein and hyaluronan. There is extensive age-associated heterogeneity in the structure and molecular stoichiometry of these components in adult human articular cartilage, resulting in diverse populations of complexes with a range of stabilities that have implications for cartilage mechanobiology and integrity. Recent findings have demonstrated that aggrecan can form ligands with other matrix proteins. These findings provide new insights into mechanisms for aggregate assembly and functional protein networks in different cartilage compartments with maturation and aging. 相似文献
6.
Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50% increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA. 相似文献
7.
A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint 总被引:1,自引:1,他引:0
Boris Schminke Hayat Muhammad Christa Bode Boguslawa Sadowski Regina Gerter Nikolaus Gersdorff Ralf Bürgers Efrat Monsonego-Ornan Vicki Rosen Nicolai Miosge 《Cellular and molecular life sciences : CMLS》2014,71(6):1081-1096
Discoidin domain receptor 1 (DDR-1)-deficient mice exhibited a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) as early as 9 weeks of age. They showed typical histological signs of OA, including surface fissures, loss of proteoglycans, chondrocyte cluster formation, collagen type I upregulation, and atypical collagen fibril arrangements. Chondrocytes isolated from the TMJs of DDR-1-deficient mice maintained their osteoarthritic characteristics when placed in culture. They expressed high levels of runx-2 and collagen type I, as well as low levels of sox-9 and aggrecan. The expression of DDR-2, a key factor in OA, was increased. DDR-1-deficient chondrocytes from the TMJ were positively influenced towards chondrogenesis by a three-dimensional matrix combined with a runx-2 knockdown or stimulation with extracellular matrix components, such as nidogen-2. Therefore, the DDR-1 knock-out mouse can serve as a novel model for temporomandibular disorders, such as OA of the TMJ, and will help to develop new treatment options, particularly those involving tissue regeneration. 相似文献
8.
Articular chondrocytes express the matrix receptors CD44 and integrins. Both of these receptors exhibit interactions with adjacent extracellular matrix macromolecules. In addition, both integrins and CD44 have the capacity for signal transduction as well as modulated interactions with the actin cytoskeleton. As such, both receptor families provide the chondrocytes a means to detect changes in matrix composition or to function as mechanotransducers. Disruption of CD44 or integrin-mediated cell-matrix interactions, either experimentally induced or when present in osteoarthritis, have profound effects on cartilage metabolism. Thus, CD44 and integrin receptors play a critical role in maintaining cartilage homeostasis. 相似文献
9.
Annexin V was originally identified as a collagen-binding protein called anchorin CII and was isolated from chondrocyte membranes
by affinity chromatography on native type II collagen. The binding of annexin V to native collagen type II is stable at physiological
ionic strength when annexin V is reconstituted in liposomes. The binding to native collagen types II and X, and to some extent
to type I as well, was confirmed using recombinant annexin V. A physiological role for annexin V interactions with extracellular
collagen is consistent with the localization of annexin V on the outer cell surface of chondrocytes, microvilli of hypertrophic
chondrocytes, fibroblasts and osteoblasts. A breakthrough in our understanding of the function of annexin V was made with
the discovery of its calcium channel activity. At least one of several putative functions of annexin V became obvious from
studies on matrix vesicles derived from calcifying cartilage. It was found that calcium uptake by matrix vesicles depend on
collagen type II and type X binding to annexin V in the vesicles and was lost when collagens were digested with collagenase;
calcium influx was reconstituted after adding back native collagen II or V. These findings indicate that annexin V plays a
major role in matrix vesicle-initiated cartilage calcification as a collagen-regulated calcium channel. 相似文献
10.
El-Osta A 《Cellular and molecular life sciences : CMLS》2004,61(17):2135-2136
11.
Differentiation of L6 myoblastic cells into chondrocytes 总被引:1,自引:0,他引:1
Under the influence of demineralized bone pieces L6 cells differentiate into chondrocytes. The cartilage formed is identifiable histologically. The results demonstrate that these myoblastic cells, which are committed to produce muscle, may still be influenced to express another potentiality of their genome. 相似文献
12.
Summary Under the influence of demineralized bone pieces L6 cells differentiate into chondrocytes. The cartilage formed is identifiable histologically. The results demonstrate that these myoblastic cells, which are committed to produce muscle, may still be influenced to express another potentiality of their genome. 相似文献
13.
Noncollagenous, nonproteoglycan macromolecules of cartilage 总被引:4,自引:0,他引:4
Extracellular matrix comprises approximately 90% of cartilage, with collagens and proteoglycans making up the bulk of the tissue. In recent years, several abundant cartilage proteins that are neither collagens nor proteoglycans have been characterized in detail. The putative roles of these proteins range from involvement in matrix organization or matrix-cell signaling (PRELP, chondroadherin, cartilage oligomeric protein and cartilage matrix protein) through to molecules that are likely to be involved with modulation of the chondrocyte phenotype (CD-RAP, CDMPs, chondromodulin and pleiotrophin). Other molecules, such as the cartilage-derived C-type lectin and cartilage intermediate layer protein have no role as yet. Due to the difficulties associated with experimentally manipulating a tissue that is 90% extracellular matrix in a manner that can be readily transferred to the whole organism, many of these molecules have been focused on by a surprisingly small number of researchers. This review focuses on newly discovered proteins and glycoproteins in cartilage, with a bias towards those that have structural roles or that are unique to cartilage. Received 7 January 1999; accepted 11 March 1999 相似文献
14.
Kramer J Böhrnsen F Lindner U Behrens P Schlenke P Rohwedel J 《Cellular and molecular life sciences : CMLS》2006,63(5):616-626
Microfracture of subchondral bone results in intrinsic repair of cartilage defects. Stem or progenitor cells from bone marrow
have been proposed to be involved in this regenerative process. Here, we demonstrate for the first time that mesenchymal stem
(MS) cells can in fact be recovered from matrix material saturated with cells from bone marrow after microfracture. This also
introduces a new technique for MS cell isolation during arthroscopic treatment. MS cells were phenotyped using specific cell
surface antibodies. Differentiation of the MS cells into the adipogenic, chondrogenic and osteogenic lineage could be demonstrated
by cultivation of MS cells as a monolayer, as micromass bodies or mesenchymal microspheres. This study demonstrates that MS
cells can be attracted to a cartilage defect by guidance of a collagenous matrix after perforating subchondral bone. Protocols
for application of MS cells in restoration of cartilage tissue include an initial invasive biopsy to obtain the MS cells and
time-wasting in vitro proliferation and possibly differentiation of the cells before implantation. The new technique already includes attraction
of MS cells to sites of cartilage defects and therefore may overcome the necessity of in vitro proliferation and differentiation of MS cells prior to transplantation.
Received 3 November 2005; received after revision 15 December 2005; accepted 4 January 2006 相似文献
15.
Lilian I. Plotkin Joseph P. Stains 《Cellular and molecular life sciences : CMLS》2015,72(15):2853-2867
Regulation of bone homeostasis depends on the concerted actions of bone-forming osteoblasts and bone-resorbing osteoclasts, controlled by osteocytes, cells derived from osteoblasts surrounded by bone matrix. The control of differentiation, viability and function of bone cells relies on the presence of connexins. Connexin43 regulates the expression of genes required for osteoblast and osteoclast differentiation directly or by changing the levels of osteocytic genes, and connexin45 may oppose connexin43 actions in osteoblastic cells. Connexin37 is required for osteoclast differentiation and its deletion results in increased bone mass. Less is known on the role of connexins in cartilage, ligaments and tendons. Connexin43, connexin45, connexin32, connexin46 and connexin29 are expressed in chondrocytes, while connexin43 and connexin32 are expressed in ligaments and tendons. Similarly, although the expression of pannexin1, pannexin2 and pannexin3 has been demonstrated in bone and cartilage cells, their function in these tissues is not fully understood. 相似文献
16.
Double-strand breaks (DSBs) are the most detrimental form of DNA damage. Failure to repair these cytotoxic lesions can result
in genome rearrangements conducive to the development of many diseases, including cancer. The DNA damage response (DDR) ensures
the rapid detection and repair of DSBs in order to maintain genome integrity. Central to the DDR are the DNA damage checkpoints.
When activated by DNA damage, these sophisticated surveillance mechanisms induce transient cell cycle arrests, allowing sufficient
time for DNA repair. Since the term “checkpoint” was coined over 20 years ago, our understanding of the molecular mechanisms
governing the DNA damage checkpoint has advanced significantly. These pathways are highly conserved from yeast to humans.
Thus, significant findings in yeast may be extrapolated to vertebrates, greatly facilitating the molecular dissection of these
complex regulatory networks. This review focuses on the cellular response to DSBs in Saccharomyces cerevisiae, providing a comprehensive overview of how these signalling pathways function to orchestrate the cellular response to DNA
damage and preserve genome stability in eukaryotic cells. 相似文献
17.
Xuemei Fu Ke Cui Qiuxiang Yi Lili Yu Yang Xu 《Cellular and molecular life sciences : CMLS》2017,74(3):487-493
Embryonic stem cells (ESCs) can undergo unlimited self-renewal and retain the pluripotency to differentiate into all cell types in the body. Therefore, as a renewable source of various functional cells in the human body, ESCs hold great promise for human cell therapy. During the rapid proliferation of ESCs in culture, DNA damage, such as DNA double-stranded breaks, will occur in ESCs. Therefore, to realize the potential of ESCs in human cell therapy, it is critical to understand the mechanisms how ESCs activate DNA damage response and DNA repair to maintain genomic stability, which is a prerequisite for their use in human therapy. In this context, it has been shown that ESCs harbor much fewer spontaneous mutations than somatic cells. Consistent with the finding that ESCs are genetically more stable than somatic cells, recent studies have indicated that ESCs can mount more robust DNA damage responses and DNA repair than somatic cells to ensure their genomic integrity. 相似文献
18.
S. Moskalewski A. Gołaszewska T. Książek 《Cellular and molecular life sciences : CMLS》1980,36(11):1294-1295
Summary Multiplication of chondrocytes during growth of rabbit auricular cartilage was estimated on the basis of total DNA determination and compared with the population doubling level reached by these chondrocytes in vitro. The results indicate that the in situ aging of auricular chondrocytes is caused by factors other than the intrinsic depletion of their growth potential. 相似文献
19.
Fibrocytes: a unique cell population implicated in wound healing 总被引:8,自引:0,他引:8
Metz CN 《Cellular and molecular life sciences : CMLS》2003,60(7):1342-1350
Following tissue damage, host wound healing ensues. This process requires an elaborate
interplay between numerous cell types which orchestrate a series of regulated and overlapping events.
These events include the initiation of an antigen-specific host immune response, blood vessel
formation, as well as the production of critical extracellular matrix molecules, cytokines and
growth factors which mediate tissue repair and wound closure. Connective tissue fibroblasts are
considered essential for successful wound healing; however, their origin remains a mystery.
A unique cell population, known as fibrocytes, has been identified and characterized. One
of the unique features of these blood-borne cells is their ability to home to sites of tissue damage.
This article reviews the identification and characterization of fibrocytes, summarizes the potential
role of fibrocytes in the numerous steps of the wound-healing process and highlights the potential
role of fibrocytes in fibrotic disease pathogenesis.Received 25 November 2002; received after revision 31 December 2002; accepted 16 January 2003 相似文献
20.
Daniel Umlauf Svetlana Frank Thomas Pap Jessica Bertrand 《Cellular and molecular life sciences : CMLS》2010,67(24):4197-4211
Osteoarthritis is one of the most common forms of musculoskeletal disease and the most prominent type of arthritis encountered in all countries. Although great efforts have been made to investigate cartilage biology and osteoarthritis pathology, the treatment has lagged behind that of other arthritides, as there is a lack of effective disease-modifying therapies. Numerous approaches for dealing with cartilage degradation have been tried, but enjoyed very little success to develop approved OA treatments with not only symptomatic improvement but also structure-modifying effect. In this review we discuss the most recent findings regarding the regulation of cartilage biology and pathology and highlight their potential therapeutic values. 相似文献