Cartilage: A non-vascular form of connective tissue composed of CHONDROCYTES embedded in a matrix that includes CHONDROITIN SULFATE and various types of FIBRILLAR COLLAGEN. There are three major types: HYALINE CARTILAGE; FIBROCARTILAGE; and ELASTIC CARTILAGE.Cartilage, Articular: A protective layer of firm, flexible cartilage over the articulating ends of bones. It provides a smooth surface for joint movement, protecting the ends of long bones from wear at points of contact.Cartilage Diseases: Pathological processes involving the chondral tissue (CARTILAGE).Chondrocytes: Polymorphic cells that form cartilage.Nasal Cartilages: Hyaline cartilages in the nose. There are five major nasal cartilages including two lateral, two alar, and one septal.Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans.Ear Cartilage: Cartilage of the EAR AURICLE and the EXTERNAL EAR CANAL.Laryngeal Cartilages: The nine cartilages of the larynx, including the cricoid, thyroid and epiglottic, and two each of arytenoid, corniculate and cuneiform.Hyaline Cartilage: A type of CARTILAGE characterized by a homogenous amorphous matrix containing predominately TYPE II COLLAGEN and ground substance. Hyaline cartilage is found in ARTICULAR CARTILAGE; COSTAL CARTILAGE; LARYNGEAL CARTILAGES; and the NASAL SEPTUM.Knee Joint: A synovial hinge connection formed between the bones of the FEMUR; TIBIA; and PATELLA.Proteoglycans: Glycoproteins which have a very high polysaccharide content.Cartilage Oligomeric Matrix Protein: Major component of chondrocyte EXTRACELLULAR MATRIX of various tissues including bone, tendon, ligament, SYNOVIUM and blood vessels. It binds MATRILIN PROTEINS and is associated with development of cartilage and bone.Osteoarthritis, Knee: Noninflammatory degenerative disease of the knee joint consisting of three large categories: conditions that block normal synchronous movement, conditions that produce abnormal pathways of motion, and conditions that cause stress concentration resulting in changes to articular cartilage. (Crenshaw, Campbell's Operative Orthopaedics, 8th ed, p2019)Aggrecans: Large HYALURONAN-containing proteoglycans found in articular cartilage (CARTILAGE, ARTICULAR). They form into aggregates that provide tissues with the capacity to resist high compressive and tensile forces.Collagen Type II: A fibrillar collagen found predominantly in CARTILAGE and vitreous humor. It consists of three identical alpha1(II) chains.Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or N-acetylgalactosamine.Matrilin Proteins: PROTEOGLYCANS-associated proteins that are major components of EXTRACELLULAR MATRIX of various tissues including CARTILAGE; and INTERVERTEBRAL DISC structures. They bind COLLAGEN fibers and contain protein domains that enable oligomer formation and interaction with other extracellular matrix proteins such as CARTILAGE OLIGOMERIC MATRIX PROTEIN.Chondrogenesis: The formation of cartilage. This process is directed by CHONDROCYTES which continually divide and lay down matrix during development. It is sometimes a precursor to OSTEOGENESIS.Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., COLLAGEN; ELASTIN; FIBRONECTINS; and LAMININ).Growth Plate: The area between the EPIPHYSIS and the DIAPHYSIS within which bone growth occurs.Fractures, Cartilage: Breaks in CARTILAGE.Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of SKIN; CONNECTIVE TISSUE; and the organic substance of bones (BONE AND BONES) and teeth (TOOTH).Stifle: In horses, cattle, and other quadrupeds, the joint between the femur and the tibia, corresponding to the human knee.Patella: The flat, triangular bone situated at the anterior part of the KNEE.Tibia: The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the FIBULA laterally, the TALUS distally, and the FEMUR proximally.Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee.Menisci, Tibial: The interarticular fibrocartilages of the superior surface of the tibia.Nasal Septum: The partition separating the two NASAL CAVITIES in the midplane. It is formed by the SEPTAL NASAL CARTILAGE, parts of skull bones (ETHMOID BONE; VOMER), and membranous parts.Epiphyses: The head of a long bone that is separated from the shaft by the epiphyseal plate until bone growth stops. At that time, the plate disappears and the head and shaft are united.Arytenoid Cartilage: One of a pair of small pyramidal cartilages that articulate with the lamina of the CRICOID CARTILAGE. The corresponding VOCAL LIGAMENT and several muscles are attached to it.Cricoid Cartilage: The small thick cartilage that forms the lower and posterior parts of the laryngeal wall.Cattle: Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.Thyroid Cartilage: The largest cartilage of the larynx consisting of two laminae fusing anteriorly at an acute angle in the midline of the neck. The point of fusion forms a subcutaneous projection known as the Adam's apple.Osteochondritis: Inflammation of a bone and its overlaying CARTILAGE.Matrix Metalloproteinase 13: A secreted matrix metalloproteinase that plays a physiological role in the degradation of extracellular matrix found in skeletal tissues. It is synthesized as an inactive precursor that is activated by the proteolytic cleavage of its N-terminal propeptide.Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot.Joints: Also known as articulations, these are points of connection between the ends of certain separate bones, or where the borders of other bones are juxtaposed.Tissue Engineering: Generating tissue in vitro for clinical applications, such as replacing wounded tissues or impaired organs. The use of TISSUE SCAFFOLDING enables the generation of complex multi-layered tissues and tissue structures.Compressive Strength: The maximum compression a material can withstand without failure. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed, p427)Bone and Bones: A specialized CONNECTIVE TISSUE that is the main constituent of the SKELETON. The principle cellular component of bone is comprised of OSTEOBLASTS; OSTEOCYTES; and OSTEOCLASTS, while FIBRILLAR COLLAGENS and hydroxyapatite crystals form the BONE MATRIX.Hyaluronic Acid: A natural high-viscosity mucopolysaccharide with alternating beta (1-3) glucuronide and beta (1-4) glucosaminidic bonds. It is found in the UMBILICAL CORD, in VITREOUS BODY and in SYNOVIAL FLUID. A high urinary level is found in PROGERIA.Femur Head: The hemispheric articular surface at the upper extremity of the thigh bone. (Stedman, 26th ed)Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes SYNOVIAL FLUID.Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere.Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques.Synovial Fluid: The clear, viscous fluid secreted by the SYNOVIAL MEMBRANE. It contains mucin, albumin, fat, and mineral salts and serves to lubricate joints.Stress, Mechanical: A purely physical condition which exists within any material because of strain or deformation by external forces or by non-uniform thermal expansion; expressed quantitatively in units of force per unit area.Chondroitin Sulfates: Derivatives of chondroitin which have a sulfate moiety esterified to the galactosamine moiety of chondroitin. Chondroitin sulfate A, or chondroitin 4-sulfate, and chondroitin sulfate C, or chondroitin 6-sulfate, have the sulfate esterified in the 4- and 6-positions, respectively. Chondroitin sulfate B (beta heparin; DERMATAN SULFATE) is a misnomer and this compound is not a true chondroitin sulfate.Biomechanical Phenomena: The properties, processes, and behavior of biological systems under the action of mechanical forces.Knee Injuries: Injuries to the knee or the knee joint.Mandibular Condyle: The posterior process on the ramus of the mandible composed of two parts: a superior part, the articular portion, and an inferior part, the condylar neck.Arthritis, Experimental: ARTHRITIS that is induced in experimental animals. Immunological methods and infectious agents can be used to develop experimental arthritis models. These methods include injections of stimulators of the immune response, such as an adjuvant (ADJUVANTS, IMMUNOLOGIC) or COLLAGEN.Lubrication: The application of LUBRICANTS to diminish FRICTION between two surfaces.SOX9 Transcription Factor: A SOXE transcription factor that plays a critical role in regulating CHONDROGENESIS; OSTEOGENESIS; and male sex determination. Loss of function of the SOX9 transcription factor due to genetic mutations is a cause of CAMPOMELIC DYSPLASIA.Procollagen N-Endopeptidase: An extracellular endopeptidase which excises a block of peptides at the amino terminal, nonhelical region of the procollagen molecule with the formation of collagen. Absence or deficiency of the enzyme causes accumulation of procollagen which results in the inherited connective tissue disorder--dermatosparaxis. EC Acids: Acids derived from monosaccharides by the oxidation of the terminal (-CH2OH) group farthest removed from the carbonyl group to a (-COOH) group. (From Stedmans, 26th ed)Anterior Cruciate Ligament: A strong ligament of the knee that originates from the posteromedial portion of the lateral condyle of the femur, passes anteriorly and inferiorly between the condyles, and attaches to the depression in front of the intercondylar eminence of the tibia.Arthroplasty, Subchondral: Surgical techniques used to correct or augment healing of chondral defects in the joints (CARTILAGE, ARTICULAR). These include abrasion, drilling, and microfracture of the subchondral bone to enhance chondral resurfacing via autografts, allografts, or cell transplantation.Matrix Metalloproteinase 3: An extracellular endopeptidase of vertebrate tissues similar to MATRIX METALLOPROTEINASE 1. It digests PROTEOGLYCAN; FIBRONECTIN; COLLAGEN types III, IV, V, and IX, and activates procollagenase. (Enzyme Nomenclature, 1992)Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Microscopy, Polarization: Microscopy using polarized light in which phenomena due to the preferential orientation of optical properties with respect to the vibration plane of the polarized light are made visible and correlated parameters are made measurable.Tissue Culture Techniques: A technique for maintaining or growing TISSUE in vitro, usually by DIFFUSION, perifusion, or PERFUSION. The tissue is cultured directly after removal from the host without being dispersed for cell culture.Injections, Intra-Articular: Methods of delivering drugs into a joint space.Collagen Type IX: A fibril-associated collagen usually found crosslinked to the surface of COLLAGEN TYPE II fibrils. It is a heterotrimer containing alpha1(IX), alpha2(IX) and alpha3(IX) subunits.Ribs: A set of twelve curved bones which connect to the vertebral column posteriorly, and terminate anteriorly as costal cartilage. Together, they form a protective cage around the internal thoracic organs.Chondroitin: A mucopolysaccharide constituent of chondrin. (Grant & Hackh's Chemical Dictionary, 5th ed)Collagenases: Enzymes that catalyze the degradation of collagen by acting on the peptide bonds.Lectins, C-Type: A class of animal lectins that bind to carbohydrate in a calcium-dependent manner. They share a common carbohydrate-binding domain that is structurally distinct from other classes of lectins.Bone Development: The growth and development of bones from fetus to adult. It includes two principal mechanisms of bone growth: growth in length of long bones at the epiphyseal cartilages and growth in thickness by depositing new bone (OSTEOGENESIS) with the actions of OSTEOBLASTS and OSTEOCLASTS.Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact.Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Collagen Type X: A non-fibrillar collagen found primarily in terminally differentiated hypertrophic CHONDROCYTES. It is a homotrimer of three identical alpha1(X) subunits.Humerus: Bone in humans and primates extending from the SHOULDER JOINT to the ELBOW JOINT.Arthroscopy: Endoscopic examination, therapy and surgery of the joint.Osteochondrodysplasias: Abnormal development of cartilage and bone.Rhinoplasty: A plastic surgical operation on the nose, either reconstructive, restorative, or cosmetic. (Dorland, 28th ed)Chick Embryo: The developmental entity of a fertilized chicken egg (ZYGOTE). The developmental process begins about 24 h before the egg is laid at the BLASTODISC, a small whitish spot on the surface of the EGG YOLK. After 21 days of incubation, the embryo is fully developed before hatching.Osteogenesis: The process of bone formation. Histogenesis of bone including ossification.Tissue Scaffolds: Cell growth support structures composed of BIOCOMPATIBLE MATERIALS. They are specially designed solid support matrices for cell attachment in TISSUE ENGINEERING and GUIDED TISSUE REGENERATION uses.Calcification, Physiologic: Process by which organic tissue becomes hardened by the physiologic deposit of calcium salts.Collagen Type XI: A fibrillar collagen found primarily in interstitial CARTILAGE. Collagen type XI is heterotrimer containing alpha1(XI), alpha2(XI) and alpha3(XI) subunits.Joint DiseasesIoxaglic Acid: A low-osmolar, ionic contrast medium used in various radiographic procedures.Periosteum: Thin outer membrane that surrounds a bone. It contains CONNECTIVE TISSUE, CAPILLARIES, nerves, and a number of cell types.Hindlimb: Either of two extremities of four-footed non-primate land animals. It usually consists of a FEMUR; TIBIA; and FIBULA; tarsals; METATARSALS; and TOES. (From Storer et al., General Zoology, 6th ed, p73)ArthritisElastic Cartilage: A type of CARTILAGE whose matrix contains ELASTIC FIBERS and elastic lamellae, in addition to the normal components of HYALINE CARTILAGE matrix. Elastic cartilage is found in the EXTERNAL EAR; EUSTACHIAN TUBE; EPIGLOTTIS; and LARYNX.Chondroitin Sulfate Proteoglycans: Proteoglycans consisting of proteins linked to one or more CHONDROITIN SULFATE-containing oligosaccharide chains.Chondrosarcoma: A slowly growing malignant neoplasm derived from cartilage cells, occurring most frequently in pelvic bones or near the ends of long bones, in middle-aged and old people. Most chondrosarcomas arise de novo, but some may develop in a preexisting benign cartilaginous lesion or in patients with ENCHONDROMATOSIS. (Stedman, 25th ed)Matrix Metalloproteinases: A family of zinc-dependent metalloendopeptidases that is involved in the degradation of EXTRACELLULAR MATRIX components.Interleukin-1: A soluble factor produced by MONOCYTES; MACROPHAGES, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, INTERLEUKIN-1ALPHA and INTERLEUKIN-1BETA. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation.Glycoproteins: Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins.Carpus, Animal: The region corresponding to the human WRIST in non-human ANIMALS.Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents.Temporomandibular Joint: An articulation between the condyle of the mandible and the articular tubercle of the temporal bone.Culture Techniques: Methods of maintaining or growing biological materials in controlled laboratory conditions. These include the cultures of CELLS; TISSUES; organs; or embryo in vitro. Both animal and plant tissues may be cultured by a variety of methods. Cultures may derive from normal or abnormal tissues, and consist of a single cell type or mixed cell types.Alcian Blue: A copper-containing dye used as a gelling agent for lubricants, for staining of bacteria and for the dyeing of histiocytes and fibroblasts in vivo.Sulfates: Inorganic salts of sulfuric acid.Synovitis: Inflammation of a synovial membrane. It is usually painful, particularly on motion, and is characterized by a fluctuating swelling due to effusion within a synovial sac. (Dorland, 27th ed)Bone Morphogenetic Proteins: Bone-growth regulatory factors that are members of the transforming growth factor-beta superfamily of proteins. They are synthesized as large precursor molecules which are cleaved by proteolytic enzymes. The active form can consist of a dimer of two identical proteins or a heterodimer of two related bone morphogenetic proteins.Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.Regeneration: The physiological renewal, repair, or replacement of tissue.Hyalin: A clear, homogenous, structureless, eosinophilic substance occurring in pathological degeneration of tissues.Arthritis, Rheumatoid: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.Tensile Strength: The maximum stress a material subjected to a stretching load can withstand without tearing. (McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed, p2001)ADAM Proteins: A family of membrane-anchored glycoproteins that contain a disintegrin and metalloprotease domain. They are responsible for the proteolytic cleavage of many transmembrane proteins and the release of their extracellular domain.Disease Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Talus: The second largest of the TARSAL BONES. It articulates with the TIBIA and FIBULA to form the ANKLE JOINT.Osteophyte: Bony outgrowth usually found around joints and often seen in conditions such as ARTHRITIS.Fibrocartilage: A type of CARTILAGE whose matrix contains large bundles of COLLAGEN TYPE I. Fibrocartilage is typically found in the INTERVERTEBRAL DISK; PUBIC SYMPHYSIS; TIBIAL MENISCI; and articular disks in synovial JOINTS. (From Ross et. al., Histology, 3rd ed., p132,136)Skull: The SKELETON of the HEAD including the FACIAL BONES and the bones enclosing the BRAIN.Organ Culture Techniques: A technique for maintenance or growth of animal organs in vitro. It refers to three-dimensional cultures of undisaggregated tissue retaining some or all of the histological features of the tissue in vivo. (Freshney, Culture of Animal Cells, 3d ed, p1)Fibrillar Collagens: A family of structurally related collagens that form the characteristic collagen fibril bundles seen in CONNECTIVE TISSUE.Osteochondritis Dissecans: A type of osteochondritis in which articular cartilage and associated bone becomes partially or totally detached to form joint loose bodies. Affects mainly the knee, ankle, and elbow joints.Wound Healing: Restoration of integrity to traumatized tissue.Osteoarthritis, Hip: Noninflammatory degenerative disease of the hip joint which usually appears in late middle or old age. It is characterized by growth or maturational disturbances in the femoral neck and head, as well as acetabular dysplasia. A dominant symptom is pain on weight-bearing or motion.Swine: Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA).Cadaver: A dead body, usually a human body.In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes.Bone Morphogenetic Protein 2: A potent osteoinductive protein that plays a critical role in the differentiation of osteoprogenitor cells into OSTEOBLASTS.Sharks: A group of elongate elasmobranchs. Sharks are mostly marine fish, with certain species large and voracious.Mesenchymal Stromal Cells: Bone-marrow-derived, non-hematopoietic cells that support HEMATOPOETIC STEM CELLS. They have also been isolated from other organs and tissues such as UMBILICAL CORD BLOOD, umbilical vein subendothelium, and WHARTON JELLY. These cells are considered to be a source of multipotent stem cells because they include subpopulations of mesenchymal stem cells.Horses: Large, hoofed mammals of the family EQUIDAE. Horses are active day and night with most of the day spent seeking and consuming food. Feeding peaks occur in the early morning and late afternoon, and there are several daily periods of rest.Osteochondrosis: Any of a group of bone disorders involving one or more ossification centers (EPIPHYSES). It is characterized by degeneration or NECROSIS followed by revascularization and reossification. Osteochondrosis often occurs in children causing varying degrees of discomfort or pain. There are many eponymic types for specific affected areas, such as tarsal navicular (Kohler disease) and tibial tuberosity (Osgood-Schlatter disease).Ankle Joint: The joint that is formed by the inferior articular and malleolar articular surfaces of the TIBIA; the malleolar articular surface of the FIBULA; and the medial malleolar, lateral malleolar, and superior surfaces of the TALUS.Metacarpophalangeal Joint: The articulation between a metacarpal bone and a phalanx.Aging: The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.Chondroitinases and Chondroitin Lyases: Enzymes which catalyze the elimination of glucuronate residues from chondroitin A,B, and C or which catalyze the hydrolysis of sulfate groups of the 2-acetamido-2-deoxy-D-galactose 6-sulfate units of chondroitin sulfate. EC 4.2.2.-.Hydrogels: Water swollen, rigid, 3-dimensional network of cross-linked, hydrophilic macromolecules, 20-95% water. They are used in paints, printing inks, foodstuffs, pharmaceuticals, and cosmetics. (Grant & Hackh's Chemical Dictionary, 5th ed)Chondroma: A benign neoplasm derived from mesodermal cells that form cartilage. It may remain within the substance of a cartilage or bone (true chondroma or enchondroma) or may develop on the surface of a cartilage (ecchondroma or ecchondrosis). (Dorland, 27th ed; Stedman, 25th ed)Elastic Modulus: Numerical expression indicating the measure of stiffness in a material. It is defined by the ratio of stress in a unit area of substance to the resulting deformation (strain). This allows the behavior of a material under load (such as bone) to be calculated.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Hip Joint: The joint that is formed by the articulation of the head of FEMUR and the ACETABULUM of the PELVIS.Tissue Transplantation: Transference of tissue within an individual, between individuals of the same species, or between individuals of different species.Bone Matrix: Extracellular substance of bone tissue consisting of COLLAGEN fibers, ground substance, and inorganic crystalline minerals and salts.Chondrocalcinosis: Presence of calcium salts, especially calcium pyrophosphate, in the cartilaginous structures of one or more joints. When accompanied by attacks of goutlike symptoms, it is called pseudogout. (Dorland, 27th ed)Growth Differentiation Factor 5: A growth differentiation factor that plays a role in early CHONDROGENESIS and joint formation.Achondroplasia: An autosomal dominant disorder that is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, GENU VARUM, and trident hand. (Online Mendelian Inheritance in Man,, MIM#100800, April 20, 2001)Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc.Hydrogel: A network of cross-linked hydrophilic macromolecules used in biomedical applications.Extremities: The farthest or outermost projections of the body, such as the HAND and FOOT.Interleukin-1beta: An interleukin-1 subtype that is synthesized as an inactive membrane-bound pro-protein. Proteolytic processing of the precursor form by CASPASE 1 results in release of the active form of interleukin-1beta from the membrane.Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.Matrix Metalloproteinase 1: A member of the metalloproteinase family of enzymes that is principally responsible for cleaving FIBRILLAR COLLAGEN. It can degrade interstitial collagens, types I, II and III.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ASCORBIC ACID can result in impaired hydroxyproline formation.Interleukin-1alpha: An interleukin-1 subtype that occurs as a membrane-bound pro-protein form that is cleaved by proteases to form a secreted mature form. Unlike INTERLEUKIN-1BETA both membrane-bound and secreted forms of interleukin-1alpha are biologically active.Bone Morphogenetic Protein 7: A bone morphogenetic protein that is widely expressed during EMBRYONIC DEVELOPMENT. It is both a potent osteogenic factor and a specific regulator of nephrogenesis.Microscopy, Electron, Scanning: Microscopy in which the object is examined directly by an electron beam scanning the specimen point-by-point. The image is constructed by detecting the products of specimen interactions that are projected above the plane of the sample, such as backscattered electrons. Although SCANNING TRANSMISSION ELECTRON MICROSCOPY also scans the specimen point by point with the electron beam, the image is constructed by detecting the electrons, or their interaction products that are transmitted through the sample plane, so that is a form of TRANSMISSION ELECTRON MICROSCOPY.Microscopy, Electron: Microscopy using an electron beam, instead of light, to visualize the sample, thereby allowing much greater magnification. The interactions of ELECTRONS with specimens are used to provide information about the fine structure of that specimen. In TRANSMISSION ELECTRON MICROSCOPY the reactions of the electrons that are transmitted through the specimen are imaged. In SCANNING ELECTRON MICROSCOPY an electron beam falls at a non-normal angle on the specimen and the image is derived from the reactions occurring above the plane of the specimen.GlucosamineModels, Animal: Non-human animals, selected because of specific characteristics, for use in experimental research, teaching, or testing.Polychondritis, Relapsing: An acquired disease of unknown etiology, chronic course, and tendency to recur. It is characterized by inflammation and degeneration of cartilage and can result in deformities such as floppy ear and saddle nose. Loss of cartilage in the respiratory tract can lead to respiratory obstruction.Elasticity: Resistance and recovery from distortion of shape.Oncostatin M: A cytokine with both pro- and anti-inflammatory actions that depend upon the cellular microenvironment. Oncostatin M is a 28 kDa monomeric glycoprotein that is similar in structure to LEUKEMIA INHIBITORY FACTOR. Its name derives from the the observation that it inhibited the growth of tumor cells and augmented the growth of normal fibroblasts.Arthrography: Roentgenography of a joint, usually after injection of either positive or negative contrast medium.Collagen Type I: The most common form of fibrillar collagen. It is a major constituent of bone (BONE AND BONES) and SKIN and consists of a heterotrimer of two alpha1(I) and one alpha2(I) chains.Reproducibility of Results: The statistical reproducibility of measurements (often in a clinical context), including the testing of instrumentation or techniques to obtain reproducible results. The concept includes reproducibility of physiological measurements, which may be used to develop rules to assess probability or prognosis, or response to a stimulus; reproducibility of occurrence of a condition; and reproducibility of experimental results.Metalloproteases: Proteases which use a metal, normally ZINC, in the catalytic mechanism. This group of enzymes is inactivated by metal CHELATORS.Branchial Region: A region, of SOMITE development period, that contains a number of paired arches, each with a mesodermal core lined by ectoderm and endoderm on the two sides. In lower aquatic vertebrates, branchial arches develop into GILLS. In higher vertebrates, the arches forms outpouchings and develop into structures of the head and neck. Separating the arches are the branchial clefts or grooves.Guided Tissue Regeneration: Procedures for enhancing and directing tissue repair and renewal processes, such as BONE REGENERATION; NERVE REGENERATION; etc. They involve surgically implanting growth conducive tracks or conduits (TISSUE SCAFFOLDING) at the damaged site to stimulate and control the location of cell repopulation. The tracks or conduits are made from synthetic and/or natural materials and may include support cells and induction factors for CELL GROWTH PROCESSES; or CELL MIGRATION.Ear, External: The outer part of the hearing system of the body. It includes the shell-like EAR AURICLE which collects sound, and the EXTERNAL EAR CANAL, the TYMPANIC MEMBRANE, and the EXTERNAL EAR CARTILAGES.Metalloendopeptidases: ENDOPEPTIDASES which use a metal such as ZINC in the catalytic mechanism.SOXD Transcription Factors: A subclass of closely-related SOX transcription factors. In addition to a conserved HMG-BOX DOMAIN, members of this group contain a leucine zipper motif which mediates protein DIMERIZATION.HexosaminesMandible: The largest and strongest bone of the FACE constituting the lower jaw. It supports the lower teeth.Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins.Tarsal Joints: The articulations between the various TARSAL BONES. This does not include the ANKLE JOINT which consists of the articulations between the TIBIA; FIBULA; and TALUS.Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis.Aminopropionitrile: Reagent used as an intermediate in the manufacture of beta-alanine and pantothenic acid.Histocytochemistry: Study of intracellular distribution of chemicals, reaction sites, enzymes, etc., by means of staining reactions, radioactive isotope uptake, selective metal distribution in electron microscopy, or other methods.Patellofemoral Joint: The articulation between the articular surface of the PATELLA and the patellar surface of the FEMUR.Imaging, Three-Dimensional: The process of generating three-dimensional images by electronic, photographic, or other methods. For example, three-dimensional images can be generated by assembling multiple tomographic images with the aid of a computer, while photographic 3-D images (HOLOGRAPHY) can be made by exposing film to the interference pattern created when two laser light sources shine on an object.Sternum: A long, narrow, and flat bone commonly known as BREASTBONE occurring in the midsection of the anterior thoracic segment or chest region, which stabilizes the rib cage and serves as the point of origin for several muscles that move the arms, head, and neck.Hypertrophy: General increase in bulk of a part or organ due to CELL ENLARGEMENT and accumulation of FLUIDS AND SECRETIONS, not due to tumor formation, nor to an increase in the number of cells (HYPERPLASIA).Hyaluronoglucosaminidase: An enzyme that catalyzes the random hydrolysis of 1,4-linkages between N-acetyl-beta-D-glucosamine and D-glucuronate residues in hyaluronate. (From Enzyme Nomenclature, 1992) There has been use as ANTINEOPLASTIC AGENTS to limit NEOPLASM METASTASIS.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Sulfur Radioisotopes: Unstable isotopes of sulfur that decay or disintegrate spontaneously emitting radiation. S 29-31, 35, 37, and 38 are radioactive sulfur isotopes.Papain: A proteolytic enzyme obtained from Carica papaya. It is also the name used for a purified mixture of papain and CHYMOPAPAIN that is used as a topical enzymatic debriding agent. EC Growth Factor beta3: A TGF-beta subtype that plays role in regulating epithelial-mesenchymal interaction during embryonic development. It is synthesized as a precursor molecule that is cleaved to form mature TGF-beta3 and TGF-beta3 latency-associated peptide. The association of the cleavage products results in the formation a latent protein which must be activated to bind its receptor.Collagen Type VI: A non-fibrillar collagen that forms a network of MICROFIBRILS within the EXTRACELLULAR MATRIX of CONNECTIVE TISSUE. The alpha subunits of collagen type VI assemble into antiparallel, overlapping dimers which then align to form tetramers.Chondroitin Lyases: Enzymes which catalyze the elimination of delta-4,5-D-glucuronate residues from polysaccharides containing 1,4-beta-hexosaminyl and 1,3-beta-D-glucuronosyl or 1,3-alpha-L-iduronosyl linkages thereby bringing about depolymerization. EC acts on chondroitin sulfate A and C as well as on dermatan sulfate and slowly on hyaluronate. EC acts on chondroitin sulfate A and C.Endopeptidases: A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC A region of the lower extremity immediately surrounding and including the KNEE JOINT.Cell Culture Techniques: Methods for maintaining or growing CELLS in vitro.Bone Remodeling: The continuous turnover of BONE MATRIX and mineral that involves first an increase in BONE RESORPTION (osteoclastic activity) and later, reactive BONE FORMATION (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium HOMEOSTASIS. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as OSTEOPOROSIS.Ossification, Heterotopic: The development of bony substance in normally soft structures.Tarsus, Animal: The region in the hindlimb of a quadruped, corresponding to the human ANKLE.Finite Element Analysis: A computer based method of simulating or analyzing the behavior of structures or components.Dogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)SepharoseBony Callus: The bony deposit formed between and around the broken ends of BONE FRACTURES during normal healing.Hemarthrosis: Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia.Skeleton: The rigid framework of connected bones that gives form to the body, protects and supports its soft organs and tissues, and provides attachments for MUSCLES.Bone Marrow DiseasesMetatarsal Bones: The five long bones of the METATARSUS, articulating with the TARSAL BONES proximally and the PHALANGES OF TOES distally.Gene Expression Regulation, Developmental: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action during the developmental stages of an organism.Bone Diseases, DevelopmentalTympanoplasty: Surgical reconstruction of the hearing mechanism of the middle ear, with restoration of the drum membrane to protect the round window from sound pressure, and establishment of ossicular continuity between the tympanic membrane and the oval window. (Dorland, 28th ed.)

Inhibition of transforming growth factor beta production by nitric oxide-treated chondrocytes: implications for matrix synthesis. (1/4540)

OBJECTIVE: Nitric oxide (NO) is generated copiously by articular chondrocytes activated by interleukin-1beta (IL-1beta). If NO production is blocked, much of the IL-1beta inhibition of proteoglycan synthesis is prevented. We tested the hypothesis that this inhibitory effect of NO on proteoglycan synthesis is secondary to changes in chondrocyte transforming growth factor beta (TGFbeta). METHODS: Monolayer, primary cultures of lapine articular chondrocytes and cartilage slices were studied. NO production was determined as nitrite accumulation in the medium. TGFbeta bioactivity in chondrocyte- and cartilage-conditioned medium (CM) was measured with the mink lung epithelial cell bioassay. Proteoglycan synthesis was measured as the incorporation of 35S-sodium sulfate into macromolecules separated from unincorporated label by gel filtration on PD-10 columns. RESULTS: IL-1beta increased active TGFbeta in chondrocyte CM by 12 hours; by 24 hours, significant increases in both active and latent TGFbeta were detectable. NG-monomethyl-L-arginine (L-NMA) potentiated the increase in total TGFbeta without affecting the early TGFbeta activation. IL-1beta stimulated a NO-independent, transient increase in TGFbeta3 at 24 hours; however, TGFbeta1 was not changed. When NO synthesis was inhibited with L-NMA, IL-1beta increased CM concentrations of TGFbeta1 from 24-72 hours of culture. L-arginine (10 mM) reversed the inhibitory effect of L-NMA on NO production and blocked the increases in TGFbeta1. Anti-TGFbeta1 antibody prevented the restoration of proteoglycan synthesis by chondrocytes exposed to IL-1beta + L-NMA, confirming that NO inhibition of TGFbeta1 in IL-1beta-treated chondrocytes effected, in part, the decreased proteoglycan synthesis. Furthermore, the increase in TGFbeta and proteoglycan synthesis seen with L-NMA was reversed by the NO donor S-nitroso-N-acetylpenicillamide. Similar results were seen with cartilage slices in organ culture. The autocrine increase in CM TGFbeta1 levels following prior exposure to TGFbeta1 was also blocked by NO. CONCLUSION: NO can modulate proteoglycan synthesis indirectly by decreasing the production of TGFbeta1 by chondrocytes exposed to IL-1beta. It prevents autocrine-stimulated increases in TGFbeta1, thus potentially diminishing the anabolic effects of this cytokine in chondrocytes.  (+info)

Expression of both P1 and P2 purine receptor genes by human articular chondrocytes and profile of ligand-mediated prostaglandin E2 release. (2/4540)

OBJECTIVE: To assess the expression and function of purine receptors in articular chondrocytes. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to screen human chondrocyte RNA for expression of P1 and P2 purine receptor subtypes. Purine-stimulated prostaglandin E2 (PGE2) release from chondrocytes, untreated or treated with recombinant human interleukin-1alpha (rHuIL-1alpha), was assessed by radioimmunoassay. RESULTS: RT-PCR demonstrated that human articular chondrocytes transcribe messenger RNA for the P1 receptor subtypes A2a and A2b and the P2 receptor subtype P2Y2, but not for the P1 receptor subtypes A1 and A3. The P1 receptor agonists adenosine and 5'-N-ethylcarboxamidoadenosine did not change PGE2 release from chondrocytes. The P2Y2 agonists ATP and UTP stimulated a small release of PGE2 that was potentiated after pretreatment with rHuIL-1alpha. PGE2 release in response to ATP and UTP cotreatment was not additive, but release in response to coaddition of ATP and bradykinin (BK) or UTP and BK was additive, consistent with ATP and UTP competition for the same receptor site. The potentiation of PGE2 release in response to ATP and UTP after rHuIL-1alpha pretreatment was mimicked by phorbol myristate acetate. CONCLUSION: Human chondrocytes express both P1 and P2 purine receptor subtypes. The function of the P1 receptor subtype is not yet known, but stimulation of the P2Y2 receptor increases IL-1-mediated PGE2 release.  (+info)

Destruction of hyaline cartilage in the sigmoid notch of the human ulna. (3/4540)

In an ulna from an adolescent a fossa nudata divided the articular surface of the sigmoid notch into olecranon and coronoid areas. In the floor of the fossa a layer of loose avascular pannus covered a thin layer of articular cartilage. The pannus appeared to have been formed by removal of chondroitin from the cartilage, freeing the cells and unmasking the fibres. Probably the change followed loss of contact between the articular cartilages of the sigmoid notch and trochlea during postnatal growth.  (+info)

Transport of solutes through cartilage: permeability to large molecules. (4/4540)

A review of the transport of solutes through articular cartilage is given, with special reference to the effect of variations in matrix composition. Some physiological implications of our findings are discussed. Also, results of an experimental study of the permeability of articular cartilage to large globular proteins are presented. Because of the very low partition coefficients of large solutes between cartilage and an external solution new experimental techniques had to be devised, particularly for the study of diffusion. The partition coefficients of solutes were found to decrease very steeply with increase in size, up to serum albumin. There was, however, no further decrease for IGG. The diffusion coefficient of serum albumin in cartilage was relatively high (one quarter of the value in aqueous solution). These two facts taken together suggest that there may be a very small fraction of relatively large pores in cartilage through which the transport of large molecules is taking place. The permeability of cartilage to large molecules is extremely sensitive to variations in the glycosaminoglycan content: for a threefold increase in the latter there is a hundredfold decrease in the partition coefficient. For cartilage of fixed charge density around 0-19 m-equiv/g, there is no penetration at all of globular proteins of size equal to or larger than serum albumin.  (+info)

Association of the aggrecan keratan sulfate-rich region with collagen in bovine articular cartilage. (5/4540)

Aggrecan, the predominant large proteoglycan of cartilage, is a multidomain macromolecule with each domain contributing specific functional properties. One of the domains contains the majority of the keratan sulfate (KS) chain substituents and a protein segment with a proline-rich hexapeptide repeat sequence. The function of this domain is unknown but the primary structure suggests a potential for binding to collagen fibrils. We have examined binding of aggrecan fragments encompassing the KS-rich region in a solid-phase assay. A moderate affinity (apparent Kd = 1.1 microM) for isolated collagen II, as well as collagen I, was demonstrated. Enzymatic digestion of the KS chains did not alter the capacity of the peptide to bind to collagen, whereas cleavage of the protein core abolished the interaction. The distribution of the aggrecan KS-rich region in bovine tarsometatarsal joint cartilage was investigated using immunoelectron microscopy. Immunoreactivity was relatively low in the superficial zone and higher in the intermediate and deep zones of the uncalcified cartilage. Within the pericellular and territorial matrix compartments the epitopes representing the aggrecan KS-rich region were detected preferentially near or at collagen fibrils. Along the fibrils, epitope reactivity was non-randomly distributed, showing preference for the gap region within the D-period. Our data suggest that collagen fibrils interact with the KS-rich regions of several aggrecan monomers aligned within a proteoglycan aggregate. The fibril could therefore serve as a backbone in at least some of the aggrecan complexes.  (+info)

Distribution of chondroitin sulfate in cartilage proteoglycans under associative conditions. (6/4540)

Proteoglycan aggregates and proteoglycan subunits were extracted from bovine articular cartilage with guanidine-HC1 folowed by fractionation by equilibrium centrifugation in cesium chloride density gradients. The distribution of chondroitin sulfates (CS) in the cartilage proteoglycans was studied at the disaccharide level by digestion with chondroitinases. In the proteoglycan aggregate fraction, it was observed that the proportion of 4-sulfated disaccharide units to total CS increased from the bottom to the top fractions, whereas that of 6-sulfated disaccharide units was in the reverse order. Thus, the ratio of 4-sulfated disaccharide units to 6-sulfated disaccharide units increased significantly with decreasing density. The proportion of non-sulfated disaccharide units to total CS tended to increase with increasing density. These data indicate a polydisperse distribution of CS chains, under the conditions used here, in proteoglycan aggregates from bovine articular cartilage.  (+info)

Effect of anti-inflammatory drugs on sulphated glycosaminoglycan synthesis in aged human articular cartilage. (7/4540)

The anti-inflammatory drugs, sodium salicylate, indomethacin, hydrocortisone, ibuprofen, and flurbiprofen, were examined for their effects on sulphated glycosaminoglycan synthesis in aged human cartilage in vitro. Cartilage was obtained from femoral heads removed during surgery and drug effects were found to vary significantly from one head to another. Statistical analysis of the results showed that sodium salicylate exhibits concentration-dependent inhibition of glycosaminoglycan synthesis over the concentration range used. Indomethacin, hydrocortisone, and ibuprofen, at concentrations comparable to those attained in man, caused a statistically significant depression of sulphated glycosaminoglycan synthesis in cartilage from some femoral heads but not others, reflecting the variable response of human articular cartilage to anti-inflammatory drugs. Sodium salicylate and indomethacin at higher doses produced significant (Pless than 0-005) inhibition of sulphated glycosaminoglycan synthesis in all femoral heads studied. The results for flurbiprofen were less conclusive; this compound appears not to inhibit glycosaminoglycan synthesis over the concentration range used.  (+info)

Uridine diphosphate xylosyltransferase activity in cartilage from manganese-deficient chicks. (8/4540)

The glycosaminoglycan content of cartilage is decreased in manganese deficiency in the chick (perosis). The activity of xylosyltransferase, the first enzyme in the biosynthetic pathway of sulphated glycosaminoglycans, was studied in the epiphysial cartilage of 4-week-old chicks which had been maintained since hatching on a manganese-deficient diet. Enzymic activity was measured by the incorporation of [14C]xylose from UDP-[14C]xylose into trichloroacetic acid precipitates. Optimal conditions for the xylosyltransferase assay were established and shown to be the same for both control and manganese-deficient cartilage. Assay of the enzyme by using an exogenous xylose acceptor showed no difference in xylosyltransferase activity between control and manganese-deficient tissue. Further, the extent of xylose incorporation was greater in manganese-deficient than in control cartilage preparations, suggesting an increase in xylose-acceptor sites on the endogenous acceptor protein in the deficient cartilage. 35S turnover in the manganese-deficient cartilage was also increased. The data suggest that the decreased glycosaminoglycan content in manganese-deficient cartilage is due to decreased xylosylation of the acceptor protein plus increased degradation of glycosaminoglycan.  (+info)

  • A simplified 2D axisymmetric representation of the human knee joint, including cartilage layers, meniscus and underlying bones, was developed. (
  • Patients with a symptomatic ACL-deficient knee and an associated tear of the medial meniscus are at high risk of having a lesion of the articular surface of the weight bearing area of the knee. (
  • Imaging now plays a critical role not only in clinical practice and therapeutic decisions but also in the basic research probing our understanding of cartilage physiology and biomechanics. (
  • Since biomechanical factors are known to play an essential role in osteoarthritis (OA) initiation and progression, we investigated if excessive mechanical compression can alter TGF-beta signaling in cartilage shifting it from ALK5/Smad2/3P to ALK1/Smad1/5/8P pathway, favoring terminal differentiation of chondrocytes. (
  • This book covers the latest research and advancements related to articular cartilage in biology, development, pathology, clinical applications and tissue engineering. (
  • The demonstration that interactions between these genetic engineering and tissue engineering technologies promote repair by articular chondrocytes would lend insight into the mechanisms that regulate cell-based therapies and provide a key step in the translation of these therapies to human articular cartilage diseases. (
  • The inclusion criterion of the samples in this study was based on the presence of lesions characterized in H&E stain as fibroplasia, neovascularization, collagenolysis, chondroid metaplasia in tendons and ligaments and fibrillation and cartilaginous eburnation lesions in the articular cartilage samples. (
  • Runx1 was also expressed in chondrocytes found at the periphery of OA lesions in the articular cartilage of mice that underwent an OA-inducing surgery. (
  • CONCLUSIONS: In patients with more advanced degenerative changes, the time from injury to arthroscopy was significantly longer than in patients with lesser articular surface abnormalities, and the presence of a meniscal tear was associated with a greater degree of articular cartilage damage. (
  • In both the surface layer of normal articular cartilage, and in OA cartilage, Runx1 expression by IF co-localized with markers of mesenchymal progenitor cells, as well as markers of proliferation Ki-67 and PCNA. (
  • However, it is not known if the PG molecule is citrullinated in vivo in human cartilage, and if so, whether citrulline-containing neoepitopes of PG (CitPG) can contribute to autoimmunity in RA. (