Inflammation, the fundamental pathologic process in rheumatic diseases, may disrupt the anatomy and function of any structure or tissue. Those structures primarily affected in rheumatic diseases are the connective tissues, muscles, and blood vessels. Abnormalities that occur secondary to damage to these structures may be widespread. This chapter is intended as a brief overview of selected aspects of the anatomy and biology of tissues relevant to the basic understanding of rheumatic diseases of childhood and as a stimulus for further study.
The Skeleton
The adult skeleton consists of 206 individual bones. It is the scaffold on which muscles, connective tissue structures, blood vessels, and skin are supported; it protects the vital organs; permits movement through articulations and attachment of muscles and tendons; it is a repository of minerals such as calcium, and other ions and hormones; and is the location of hematopoiesis. Many of these functions may be disturbed in the rheumatic diseases.
Bones
Classification of Bones
Bones can be classified as membranous or endochondral , depending on the manner of their ossification. Bones of the skull, face, and the clavicle are membranous bones, and ossification takes place within mesenchymal tissue condensations. The cortex of tubular bones is also influenced by membranous (subperiosteal) bone formation. Bones of the remainder of the skeleton ossify within a cartilaginous matrix (endochondral ossification).
Structure of Bones
Bones consist of cortical bone, which forms the external surface, and trabecular bone, which lies beneath the cortex. Trabecular bone predominates in the vertebral bodies and the flat bones of the pelvis and skull, whereas tubular bones of the appendicular skeleton have prominent cortical bone, which provides strength.
Long bones of the appendicular skeleton have four parts: the epiphysis, which is separated from the metaphysis by the physis, and the diaphysis, which joins the two metaphyses and provides length. Apophyses, such as the tibial tuberosity, are like epiphyses in that they are the site of new bone formation, but they do not contribute to bone length; instead, they lay down new bone in response to traction.
Cortical bone comprises tightly packed osteons (Haversian systems) that consist of osteocytes in lacunae and bone matrix arranged in a lamellar pattern, surrounding a central Haversian canal containing blood vessels and nerves. The osteons communicate with each other via canaliculi. Trabecular bone is much less organized and consists of interconnecting trabeculae, larger blood vessels, and bone marrow.
With the exception of articular surfaces, bones are covered by periosteum. The fibrous outer layer is the site of attachment of muscles, whereas the inner layer contains osteoblasts that generate new bone.
Growth of Bones
Linear growth of bone occurs at the physis, or growth plate. Circumferential growth is accounted for by periosteal deposition of new bone. Hyaline cartilage cells are arranged in columns in the metaphysis subjacent to the physis. Proliferation of these cells results in elongation of the long bone. The relative contributions to growth at the major physes of the limbs are shown in Table 2-1 . Growth of the appendicular skeleton ceases at the time of completion of ossification of the iliac apophyses, although the height of the vertebral bodies may continue to increase and contribute to overall height until the third decade of life. Skeletal bone age can be determined by radiographic identification of the onset of secondary ossification in the long bones and by physeal closure. In general, ossification centers appear earlier, and physes fuse earlier in girls than in boys. Joint inflammation accelerates the development of bone. Factors that influence growth at the physis include thyroxine, growth hormone, and testosterone. Growth hormone and insulin-like growth factor 1 (IGF-1) act together to facilitate the achievement of peak bone mass during puberty. Testosterone stimulates the physis to undergo rapid cell division, with resultant physeal widening during the growth spurt (the anabolic effect). Estrogens suppress the growth rate by increasing calcification of the matrix, a prerequisite to epiphyseal closure. A vast array of genetic abnormalities result in abnormalities of the structure of bones, some of which, such as pseudorheumatoid dysplasia, may mimic inflammatory joint disease.
| CONTRIBUTION TO TOTAL GROWTH (%) | |||
|---|---|---|---|
| GROWTH AREA | OF BONE | OF LIMB | |
| Humerus | Proximal | 80 | 40 |
| Distal | 20 | 10 | |
| Radius/Ulna | Proximal | 20 | 10 |
| Distal | 80 | 40 | |
| Femur | Proximal | 30 | 15 |
| Distal | 70 | 40 | |
| Tibia/Fibula | Proximal | 55 | 27 |
| Distal | 45 | 18 | |
Vascular Supply
The arterial supply to the diaphysis and metaphysis of a long bone arises from a nutrient artery that penetrates the diaphysis and terminates in the child in end arteries at the epiphyseal plate. Epiphyses are supplied by juxtaarticular arteries, which also supply the synovium via a complex network of arterial and arteriovenous anastomoses and capillary beds. Not until growth has ceased and the epiphyseal plate has ossified does arterial communication begin between the metaphyseal and epiphyseal-synovial circulations.
Joints
Classification of Joints
Joints may be classified as fibrous, cartilaginous , or synovial ( Table 2-2 ). Fibrous joints (synarthroses) are those in which little or no motion occurs, and the bones are separated by fibrous connective tissue. Cartilaginous joints (amphiarthroses) are those in which little or no motion occurs, but the bones are separated by cartilage. Synovial (diarthrodial) joints are those in which considerable motion occurs, and a joint space lined with a synovial membrane is present between the bones. The synovial joint is the site of inflammation in most of the chronic arthritides of childhood. Diarthrodial joints may be further classified according to their shape ( Table 2-3 ).
| Fibrous | Bones separated by fibrous connection |
| Suture | Bones of the skull |
| Syndesmosis | Bones united by interosseous ligament |
| Sacroiliac interosseous ligament | |
| Distal tibiofibular and radioulnar interosseous membranes | |
| Cartilaginous | Bones separated by cartilage and allowing minimal movement |
| Symphysis | Bones separated by cartilaginous disk |
| Symphysis pubis | |
| Sternomanubrial joint | |
| Intervertebral disk | |
| Synchondrosis | Temporary joints in fetal life; bones separated by hyaline cartilage |
| Growth plate (physis) | |
| Synovial | Bones covered by hyaline cartilage are separated by joint “space” lined with synovial membrane producing synovial fluid (SF), surrounded by a joint capsule, allowing free movement |
| Plane joints | Intercarpal, intertarsal |
| Spheroidal | Hip, shoulder |
| Cotylic | Metacarpophalangeal |
| Hinge | Interphalangeal |
| Condylar | Knee, temporomandibular joint |
| Trochoid or pivot | Radioulnar, atlanto-odontoid |
| Sellar | Carpometacarpal joint |
Development of Synovial Joints
Within the mesenchyme of the limb buds, cells destined to become chondrocytes are surrounded by the perichondrium (the source of new chondrocytes). Between the developing bones, the perichondrium is called the interzone . Cavitation occurs in this location, resulting in the formation of a joint “space.” Whether this results from enzymatic action or apoptosis is not certain. It is thought that differential growth rates result in slight negative pressure in the more slowly growing interzone, thereby facilitating separation of the interzone from the underlying cartilage and, together with a high concentration of hyaluronan at the site, the attraction of water into the newly forming joint space. The most important signals for joint morphogenesis are provided by the cartilage-derived morphogenetic protein 1 (CDMP1) and the bone morphogenetic proteins (BMPs). The joint “cavity” is occupied at first by hyaluronic acid–rich joint fluid secreted by fibroblast-like cells lining the synovial membrane. Continued development of the diarthrodial joint depends on fetal movement, which induces formation of cartilage and synovial membrane and without which the “cavity” regresses and becomes filled with fibrous tissue, as occurs in arthrogryposis. The synovial lining forms from the interzone subsequent to cavitation, and the development of other structures, such as bursae, intraarticular fat, tendons, muscle, and capsule, quickly ensues. The whole process takes place between the fourth and seventh weeks of gestation, except for the temporomandibular joint and the sacroiliac joint, which develop several weeks later.
Anatomy of Synovial Joints
The bones of the articular surfaces of diarthrodial (synovial) joints are usually covered by hyaline cartilage. The synovial membrane attaches at the cartilage–bone junction so that the entire joint “space” is surrounded by either hyaline cartilage or synovium. The temporomandibular joint is unusual in that the surface of the condyle is covered by fibrocartilage (fibroblasts and type I collagen). In the sacroiliac joint, the sacral side is covered by thicker hyaline cartilage, whereas the iliac side of the joint is covered by fibrocartilage. In some synovial joints, intraarticular fibrocartilaginous structures are present. A disk (or meniscus) separates the temporomandibular joint into two spaces; the knee joint contains two menisci that separate the articular surfaces of the tibia and femur; and the triangular fibrocartilage of the wrist joins the distal radioulnar surfaces. Other intraarticular structures include the anterior and posterior cruciate ligaments of the knee, the interosseous ligaments of the talocalcaneal joint, and the triangular ligament of the femoral head. These structures are actually extrasynovial, although they cross through the joint space.
Articular Cartilage
The hyaline cartilage (principally type II collagen) covers subchondral bone, facilitates relatively frictionless motion and absorbs the compressive forces generated by weight-bearing. In children, hyaline cartilage is somewhat compressible. The cartilage is firmly fixed to subchondral bone in adults by collagen fibrils, although there is little collagen at the osteochondral interface in the growing child. The cartilage’s margins blend with the synovial membrane and the periosteum of the metaphysis of the bone. It is composed of chondrocytes within an extracellular matrix (ECM) and becomes progressively less cellular throughout the period of growth; the cell volume in adult articular cartilage is less than 2%. The matrix consists of collagen fibers, which contribute to tensile strength, and ground substance composed of water and proteoglycan, which contributes resistance to compression.
Cartilage Zones
Articular hyaline cartilage is organized into four zones ( Fig. 2-1 ). Zones 1, 2, and 3 represent a continuum from the most superficial area of zone 1, in which the long axes of the chondrocytes and collagen fibers are parallel to the surface; through zone 2, in which the chondrocytes become rounder and the collagen fibers are oblique; to zone 3, in which the chondrocytes tend to be arranged in columns perpendicular to the surface. This organization is markedly disturbed in the chronic infantile neurocutaneous and articular syndrome (CINCA) (also called neonatal onset multisystem inflammatory disorder [NOMID]). The tidemark , a line that stains blue with hematoxylin-eosin, separates zone 3 from zone 4 and represents the level at which calcification of the matrix begins. Chondrocytes in each of the cartilage zones differ not only in appearance but also in metabolic activity, gene expression, and response to stimuli. In the child, end capillaries proliferate in zone 4, eventually leading to replacement of this area by bone. This is probably the manner in which the chondrocytes are nourished. In the adult, however, constituent replacement through the exchange of synovial fluid with cartilage matrix may play the predominant role.
Chondrocytes
Chondrocytes are primarily mesodermal in origin and are the sole cellular constituents of normal cartilage. Their terminal differentiation determines the character of the cartilage (hyaline, fibrous, or elastic). Chondrocytes in articular cartilage persist and ordinarily do not divide after skeletal maturity is attained. Those in the epiphyseal growth plate differentiate to facilitate endochondral ossification, after which they may undergo apoptosis or become osteoblasts. Chondrocytes are responsible for the synthesis of the two major constituents of the matrix—collagen and proteoglycan—and enzymes that degrade matrix components (collagenase, neutral proteinases, and cathepsins). This dual function places the chondrocyte in the role of regulating cartilage synthesis and degradation. The pericellular region immediately surrounding the chondrocyte contains type VI collagen and the proteoglycans contain decorin and aggrecan. Chondrocytes in zone 1 produce superficial zone protein (lubricin), which is important in maintaining relatively frictionless joint motion. Synthesis of this protein is defective in the camptodactyly-arthropathy-coxa vara-pericarditis syndrome.
Extracellular Matrix
The ECM of hyaline cartilage consists of collagen fibers (which contribute tensile strength), water, diverse structural and regulatory proteins, and proteoglycans. The ECM is heterogeneous and can be subdivided into three compartments. A thin inner rim of aggrecan-rich matrix surrounds the chondrocytes and lacks cross-linked collagen. An outer rim contains fine collagen fibrils. The remainder of the ECM consists primarily of aggrecan, which binds via the link protein to hyaluronan ( Fig. 2-2 ). The endoskeleton of hyaline cartilage consists of a network of collagen fibrils, 90% of which are type II collagen, with minor components of collagen types IX and X.
Proteoglycans
Proteoglycans are macromolecules consisting of a protein core to which 50 to 100 unbranched glycosaminoglycans (chondroitin sulfate [CS] and O-linked keratan sulfate [KS]) are attached. At least five different protein cores have been defined. The principal proteoglycan of hyaline cartilage is called aggrecan. Its attachment to hyaluronan is stabilized by a link protein to form large proteoglycan aggregates with molecular weights of several million ( Fig. 2-2 ). With increasing age, the size of the proteoglycan aggregate increases, the protein and KS content increase, and the CS content decreases. CS chains also become shorter with increasing age, and the position of the sulfated moiety changes, from a combination of 4-sulfated and 6-sulfated N -acetylgalactosamine at birth to mainly 6-sulfated N -acetylgalactosamine in the adult. The significance to inflammatory joint disease, if any, of these and other age-related changes, is unknown.
Collagens
Collagens, the most abundant structural proteins of connective tissues, are trimeric ECM proteins containing a characteristic glycine-X-Y repeating triple helical structure, with a high proline and hydroxyproline content. There are at least 28 different collagen α chain trimers grouped into three major classes: fibril forming, fibril-associated collagens with interrupted triple helices (FACIT), and non-fibril-forming collagens that include network-forming and transmembrane collagens ( Table 2-4 ). Fibrillar collagen triple helices are arranged in a quarter-stagger pattern to form fibrils. Many are tough, fibrous proteins that provide structural strength to the tissues of the body. FACIT collagens are non-fibrillar collagens attached to the surface of fibrillar collagens. Type XIV is a FACIT collagen attached to type II collagen and regulates fiber diameter. Network-forming collagens (types IV, VI, VIII, and X) form networks that are often three-dimensional. Transmembrane collagens (types XIII, XVII, XXIII, and XXV) have both an intracellular and an extracellular domain. Types I, II, and III are among the most common proteins in humans. Type II collagen, the principal constituent that accounts for more than half the dry weight of cartilage, is a trimer of three identical α-helical chains. Collagen types III, VI, IX, X, XI, XII, and XIV are all present in minute quantities in the mature cartilage matrix. The content of types IX and XI collagen is greater in young animals (20%) than in mature animals (3%).
| SUBCLASS AND TYPE | COMPOSITION | TISSUE DISTRIBUTION |
|---|---|---|
| Fibril-Forming Collagens | ||
| Type I | α1(I), α2(I) | Most connective tissues; abundant in bone, skin, and tendons |
| Type II | α1(II) | Cartilage, intervertebral disk, vitreous humor |
| Type III | α1(III) | Most connective tissues, particularly skin, lung, and blood vessels |
| Type V | α1(V), α2(V), α3(V) | Tissues containing type I collagen, quantitatively minor component |
| Type XI | α1(XI), α2(XI), α3(XI) | Cartilage, intervertebral disk, vitreous humor |
| Type XXIV | α1(XXIV) | Fetal skeleton |
| Type XXVII | α1(XXVII) | Fetal skeleton |
| Type XXVIII | α1(XXVIII) | Surrounds peripheral glial cells |
| FACIT Collagens | ||
| Type IX | α1(IX), α2(IX), α3(IX) | Cartilage, intervertebral disk, vitreous humor |
| Type XII | α1(XII) | Tissues containing type I collagen |
| Type XIV | α1(XIV) | Tissues containing type I collagen |
| Type XVI | α1(XVI) | Several tissues |
| Type XIX | α1(XIX) | Rhabdomyosarcoma cells |
| Type XX | α1(XX) | Corneal epithelium |
| Type XXI | α1(XXI) | Fetal blood vessel walls |
| Type XXII | α1(XXII) | Basement membrane myotendinous junction |
| Non-Fibril-Forming Collagens | ||
| Type IV * | α1(IV), α2(IV), α3(IV), α4(IV), α5(IV), α6(IV) | Basement membranes |
| Type VIII * | α1(VIII), α2(VIII) | Several tissues, especially endothelium |
| Type X * | α1(X) | Hypertrophic cartilage |
| Type VI * | α1(VI), α2(VI), α3(VI) | Most connective tissues |
| Type VII | α1(VII) | Skin, oral mucosa, cervix, cornea |
| Type XIII † | α1(XIII) | Endomysium, perichondrium, placenta, mucosa of the intestine, meninges |
| Type XVII † | α1(XVII) | Skin, cornea |
| Type XXIII † | α1(XXIII) | Prostate |
| Type XXV | Neurons | |
| Type XV † | α1(XV) | Skeletal and heart muscle, placenta |
| Type XVIII | α1(XVIII) | Many tissues, especially kidney, liver, and lung |
| Type XXVI | Not a FACIT collagen | Neonatal testes and ovaries |
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