Human joints comprise living tissues that change their structure in response to changing environmental or func- tional demands. Tissues require nourishment to survive and are subject to disease, injury, and aging; they can adapt to imposed demands or become injured if the adaptation fails or demands are too great. To understand joint struc- ture and function, we need to examine the forces acting at the joint and the composition of the tissues. The nervous, circulatory, and muscular systems also are integrally in- volved in overall joint function; however, this chapter focuses on the tissues that make up the actual joint struc- tures: the connective tissues.
Basic Principles
A joint (articulation) connects two or more components of a structure. The design of a joint and the materials used in its construction depend partly on the function of the joint and partly on the nature of the components. Joints that provide stability have a different design than those that provide mo- bility. The complexity of the design and composition matches the range of functional demands—the more varied the demands, the more complex the design. Human joints serve many functions, so they are usually more complex than most man-made designs.
The composition of materials used in joint construction also may influence design, and vice versa. Table legs made of particleboard would need to be larger than legs made of steel. The reverse also may be true: design requirements
Structure of Connective Tissue
Joint structures include many connective tissues—bones, bursae, capsules, cartilage, discs, fat pads, labra, menisci, plates, ligaments, and tendons. The gross anatomic
ConceptCornerstone 2-1
Relationships Among Function, Structure, and Composition
Joint function both depends on and affects:
• Structure (design)
• Composition (materials)
CASE APPLICATION
Materials (Living Tissues) Affected by the
Fracture case 2–1
The materials (tissues) likely to have been affected in George Chen’s case include bone, ligaments, blood vessels, nerves, and the joint capsule. Cartilage also may be involved, since 60 to 90% of these fractures involve an injury to the surface of the talus. Muscles and tendons, even if not directly in- jured, will be affected by immobilization. Thus, a number of structures will undergo a change in size and/or composi- tion. We will be most concerned initially with structures that have been injured (bone, ligament, cartilage), as incorrect loading may interfere with their healing.
Figure 2–3 The “flex foot” facilitates gait through its design and composition. The curved blade bends during loading and then assists with propulsion. A change in material affects how much the structure bends and how much energy it provides to subsequent forward movement.
Heel Toe
Tissue Structure-Function
Structure Function
Architecture Anatomy
Tissue Stress-Strain Force-Elongation Cell
Synthesis
Extracellular Events
Material Properties Collagen types and amounts
Crosslinking PG types and amounts
Figure 2–4 Form determines the overall structure of connec- tive tissues, but the characteristics of the tissue are affected by functional use. Collagen type, cross-links, and PG type and amount all can be affected by the type and amount of stress applied to the tissue. Alternatively, the tissue may adapt to altered function by becoming larger, longer, or shorter. The size of the tissue and its composition will determine the types of loads the tissue can bear; these loads will likewise signal the cells to synthesize the appropriate type and amount of tissue and either dictate or facilitate extracellular events (e.g., cross- linking) that enhance tissue function.
may dictate material composition. A car tire that is designed to last for more miles than is typical will require a change in material composition, rather than appearance. Changes oc- cur in joint structures in order to allow them to meet func- tional demands. Julius Wolff described the adaptation of bone to changes in demand (Wolff’s law); similar changes can occur in tendons and ligaments.6
Fibula
Talus
A
Plate
Fibula
Talus
B
Tibio-fibular syndesmosis
(ligament)
Deltoid ligament
Medial malleolus
Avulsion fracture Tibia Bending
fracture
Deltoid ligament
Screw Tibia Screws
Figure 2–5 A. The foot (and talus) moves laterally and rotates outward, spraining the anterior talofibular ligament and fractur- ing the fibula. If the movement of the foot continues, the deltoid ligament may avulse the tip of the medial malleolus and separate the syndesmosis between the tibia and fibula. B. Stability must be restored and maintained via internal fixation in order for the frac- tures and ligament injuries to heal. A plate and screws have been applied to the fibula, while the tip of the medial malleolus has been reattached with a screw.
Figure 2–6 Classes of connective tissue. Tendons and ligaments are considered to be dense regular connective tissues. Bone is consid- ered to be a highly specialized, mineralized form of connective tissue.
TISSUE CONNECTIVE
Connective proper
tissue Cartilage
Elastic Hyaline
Dense Regular Loose
Elastic Irregular
Fibrocartilage Areolar Reticular
Adipose
Spongy Compact
Bone Blood
behaviors and composition of capsules, cartilage, specific ligaments, menisci, and tendons are still being investi- gated.7–31 There are four classes of connective tissues (Fig. 2–6). Connective tissue is characterized by widely dispersed cells and a large volume of extracellular matrix.
At the microscopic level, the extracellular matrix has both interfibrillar (previously known as the ground substance) and fibrillar (fibrous) components. The function of most tissues, such as nerve and muscle, depends on cell structure and function. Connective tissue function, by contrast, is primarily determined by its extracellular components (Table 2–1).
Cells
The cells of all connective tissues derive from mesenchy- mal precursor cells that differentiate into different connec- tive tissue cells, either fixed in tissues or transient within the circulatory system (see Table 2–1). The fibroblast is the basic cell of most connective tissues; it produces the extracellular matrix. Depending on its mechanical and physiological environment, the fibroblast produces differ- ent types of connective tissue and receives a new name.
Fibroblasts may specialize to become chondroblasts (car- tilage), tenoblasts (tendon), or osteoblasts (bone); these cells are called fibrocytes, chondrocytes, and osteocytes when they mature and become less metabolically active.
The distinction between a “blast” and a “cyte” is based primarily on appearance, which reflects cell synthetic activity; the same cell can go through several cycles as a fibroblast/fibrocyte, depending on the need to produce new connective tissue matrix. Connective tissue cells can
“de-differentiate” and change the type of extracellular ma- trix they produce, given the appropriate environment and/or stimuli. For example, tendon cells can produce car- tilage-like tissue when subjected to compressive forces.37–39 Such findings suggest that connective tissue structure can be modified by changes in loading conditions and that we may be able to manipulate the mechanical environment to cause connective tissues to synthesize materials that will enhance their function.
Table 2–1 Connective Tissue Cell Types
TYPE NAME LOCATION AND FUNCTION
Fixed Fibroblast Found in tendon, ligament, skin, bone, etc.
Creates mostly type I collagen
Chondroblast Differentiated fibroblast found in cartilage Produces mostly type II collagen
Osteoblast Differentiated fibroblast found in bone Produces type I collagen and hydroxyapatite Osteoclast Monocyte-derived, found in bone
Responsible for bone resorption Mast cells Found in various connective tissues
Inflammatory mediators Adipose cells Found in adipose tissue
Produce and store fat
Mesenchyme cells Undifferentiated cells found primarily in embryos and in bone marrow Can differentiate into any connective tissue cell
Transient Lymphocytes White blood cells that have surface proteins specific for antigens Neutrophils White blood cells involved in fighting infection
Macrophages Derived from monocytes, move into specific tissues, involved in immune response Plasma cells B lymphocytes producing antibodies
Extracellular Matrix
The extracellular matrix is the part of connective tissues outside the cells. It comprises almost the entire volume of the tissue and determines the tissue’s function. The extracellular matrix contains mainly proteins and water and is organized into fibrillar components and a sur- rounding matrix.
Fibrillar Component
The fibrillar, or fibrous, component of the extracellular matrix contains two major classes of structural proteins: col- lagen and elastin.7 Collagen, the main substance of most connective tissues, is found in all multicellular organisms.
The most abundant protein in the human body, it accounts for 25% to 30% of all protein in mammals.41Collagen has a tensile strength similar to steel and is responsible for the functional integrity of connective tissue structures and their resistance to tensile forces.41–49
Many types of collagen have been identified, but the functions of many are not yet well understood.41–45 Some of the types of collagen and their distribution in joint structures are presented in Table 2–2. The Roman numerals that name each type of collagen—for example, type I, type II—reflect the order in which each type of collagen was discovered.42,43The fibril-forming collagens (types I, II, III, V, and XI) are the most common. Type I collagen, which accounts for 90% of the total collagen in the body, is found in most connective tissues, including tendons, ligaments, menisci, fibrocartilage, joint capsules, synovium, bones, labra, and skin.41–47 Type I collagen appears to be responsible for the tensile strength of tis- sues. Type II collagen is found mainly in cartilage and in- tervertebral discs.42,43 Type III collagen is found in skin, joint capsules, muscle and tendon sheaths, and in healing tissues.43,49
The basic building block of collagen is a triple helix of three polypeptide chains called the tropocollagen mole- cule. The repeating Gly-X-Y amino acid pattern of each chain causes the triple helix formation. Collagen peptide chains are synthesized in the rough endoplasmic reticulum inside the fibroblasts and then move through the cell toward the cell membrane. The tropocollagen molecules aggregate in groups of five to form microfibrils as they leave the cell;
outside the cell, the microfibrils in turn combine to form fibrils (fibers) of varying size.49 Intramolecular (between peptide chains within a collagen molecule) and intermolec- ular cross-links (between molecules of adjacent fibrils) sta- bilize and strengthen the enlarging fibrils.50 Fibrils collect to form a fascicle that is surrounded by an endotendon sheath. Fibrils enlarge as more collagen is added to them and more cross-linking occurs among neighboring mole- cules; thus, older fibrils are larger and contain more cross- links, making them stronger. Collagen fibers may be arranged in many different ways and vary in size and length.
In most relaxed tissues, the fibers have a wavy configuration called a crimp. When collagen fibers are stretched, the crimp disappears.
Elastin also is found in many connective tissues, but, unlike collagen, the molecule consists of single alpha-like strands without a triple helix.7 The alpha-like strands are cross-linked to each other to form rubber-like, elastic fibers. Each elastin molecule uncoils into a more extended formation when the fiber is stretched and recoils sponta- neously when the stretching force is removed. Elastin fibers branch freely and are found in all joint structures, as well as in skin, the tracheobronchial tree, and the walls of arteries. Elastin makes up a much smaller portion of the fibrous component in the extracellular matrix than collagen.
As one might expect, tissue that requires “give” contains more elastin. The aorta contains approximately 30% elastin and 20% collagen (percentage of the tissue dry weight), the
ligamentum nuchae has 75% elastin and 15% collagen, while the Achilles tendon contains only 4.4% elastin and 86% collagen.
Interfibrillar Component
The interfibrillar component of connective tissue contains water and proteins, primarily glycoproteins and proteogly- cans (PGs).32,33A glycoprotein is a protein with a carbohy- drate (sugar-type molecule) attached. There are thousands of glycoproteins in the body. The term glycoprotein technically includes PGs, but PGs were previously considered a separate class of compounds because their carbohydrates differ from the carbohydrates found in other glycoproteins, and because of their unique distribution: while glycoproteins are found in all tissues, PGs are found mainly in connective tissues. In the past, PGs were also called mucopolysaccharides, and the interfibrillar matrix was referred to as the ground sub- stance. The “ground substance” is really a mixture of PGs and water. An overview of some of the PGs found in connec- tive tissues is shown in Table 2–3.
The carbohydrate portion of PGs consists of long chains of repeating disaccharide units called glycosaminoglycans (GAGs).30 The GAGs are all very similar to glucose in structure and are distinguished by the number and location of attached amine and sulfate groups (Table 2–4). The major types of sulfated GAGs are chondroitin 4 and chondroitin 6 sulfate, keratan sulfate, heparin, heparan sulfate, and dermatan sulfate. Most GAGs attach to proteins to form PGs, except hyaluronic acid, which exists on its own. A PG can contain one or more (up to about 100) GAGs, which stick out from the protein core to form a shape like a bottle brush.34,35Once a GAG has been attached to the protein core of the PG by a specific trisaccharide mole- cule, more GAGs can added to the chain. Glucosamine (part of a GAG) and chondroitin sulfate are frequently used as supplements to treat osteoarthritis, though their efficacy remains unproven.51
Hyaluronan differs from the other GAGs because it is not sulfated and does not attach to a protein core. Hyaluronan exists as either a free GAG chain of variable length (e.g., in a tendon or ligament) or a core molecule to which large num- bers of PGs are attached (e.g., in cartilage). Hyaluronic acid is sometimes injected into osteoarthritic joints to relieve symptoms.
One large cartilage PG is called aggrecan. The protein portion of aggrecan, with GAGs bristling out from its length, attaches at one end, via a separate link protein, to a hyaluronan chain.34,35 Aggrecan molecules in the extracellular matrix do not exist in isolation but as proteoglycan aggregates.34 Each aggregate is composed of a central filament of hyaluronan with up to 100 aggre- can molecules radiating from it, with each interaction stabilized by a link protein (Fig. 2–7).35 These large aggregates, with their attached chondroitin sulfate and keratan sulfate chains of GAGs, are largely responsible for the water-binding that characterizes the extracellular matrix of cartilage and gives it the ability to withstand compression.
The PGs in the extracellular matrix of a structure (bone, cartilage, tendon, or ligament) affect its hydration through their attached GAGs.34The GAG chains attract water into the interfibrillar matrix, creating a tensile stress on the surrounding collagen network. The collagen fibers resist and contain the swelling, thus increasing the rigid- ity of the extracellular matrix and its ability to resist com- pressive forces as well as supporting the cells. The PGs also form a reservoir for nutrients and growth factors that attach to the PG molecules, and they may play a role in directing or limiting the size of collagen fibrils. The amount and type of PG in a tissue is another example of the form-function interaction of connective tissues.
Tissues that are subjected to high compressive forces (like cartilage) have more PG, with different GAGs, than tissues that resist tensile forces.38,39The type of GAG in the
Table 2–2 Collagen Types
CLASSIFICATION TYPE COMMON LOCATIONS
Fibrillar I Tendons, bone, ligaments, skin, anulus fibrosis, menisci, fibrocartilage, joint capsules, cornea Accounts for 90% of body collagen
II Hyaline articular cartilage, nucleus pulposus, vitreous humor III Skin, blood vessels, tendons, ligaments
V Cartilage, tendons
XI Cartilage, other tissues (associated with type V) IX Cartilage, cornea (found with type II)
Fibril-associated XII Tendons, ligaments (found with type I) XIV Fetal skin and tendons
IV Basement membrane
Network-forming X Hypertrophic cartilage
VIII Unknown
Filamentous VI Blood vessels, skin
Anchoring VII Anchoring filaments
Table 2–3 Proteoglycans
CLASSIFICATION NAME LOCATION, COMPOSITION, AND FUNCTION Large extracellular
aggregating
Small leucine-rich proteoglycans (SLRPs)
Cell-associated PGs
Basement membrane PGs
Nervous tissue PGs
CS, chondroitin sulfate; DS, dermatan sulfate; GAG, glycosaminoglycan; HS, heparan sulfate; KS, keratan sulfate; PG, proteoglycan.
Versican Aggrecan
Brevican Neurocan Decorin
Biglycan
Fibromodulin Lumican Epiphycan Serglycins Syndecans Betaglycan CD44 family Thrombomodulin Perlecan HS and CS PGs Bamacan Phosphacan Agrin NG2 PG
Found in smooth muscle cells, fibroblasts; function unknown Found in numerous chains of KS and CS
Binds to hyaluronan
Creates osmotic swelling pressure in cartilage by attracting water Found in nervous system; cell adhesion and migration
Found in nervous system; cell adhesion and migration One or two CS or DS chains
Binds and regulates growth factors, modulates cell functions, regulates collagen fibrillogenesis, interacts with collagen types I, II, III, V, VI, XII, XIV
Two GAG chains containing CS or DS Directs type VI collagen network assembly
Binds to complement and transforming growth factor beta (TGF-β‚) One KS GAG chain
Interacts with type I and II collagen, binds to growth factors Similar to fibromodulin, found in cornea, muscle, intestine, cartilage Found in epiphyseal cartilage
Protein core of heparin: PGs regulate enzyme activities in secretory granules Cell transmembrane PG containing HS acts as a receptor for heparin-binding
factors
Contains HS and CS Binds TGF-β‚
Cell surface receptor for hyaluronan Binds to thrombin
Found in all tissues; function uncertain Found in all tissues; function uncertain Found in various tissues; function uncertain Nervous tissue cell adhesion
Aggregates acetylcholine receptors Found in developing cells
Table 2–4 Glycosaminoglycans (GAGs)
GAG LOCALIZATION COMMENTS COMPOSITON
Hyaluronan Chondroitin sulfate
Heparan sulfate
Heparin
Dermatan sulfate Keratan sulfate
CT, connective tissue; PG, proteoglycan.
Synovial fluid, vitreous humor, loose CT, healing CT, cartilage Cartilage, bone, heart valves,
tendons, ligaments Basement membranes, cell
surfaces
Intracellular granules in mast cells lining arteries
Skin, blood vessels, tendons, ligaments
Cornea, bone, cartilage
Forms large PG aggregates
Most abundant GAG, increased with compression
Interacts with numerous proteins
Key structural unit is 3-glucosamine + 2-glucuronate
Increased with tensile stress Forms part of large PG aggregates in
cartilage
Glucuronate uronic acid Glucosamine
Glucuronate
Galactosamine with 4-sulfate or 6-sulfate
Glucuronate Glucosamine Variable sulfation Glucuronate, iduronate Glucosamine
Variable sulfation Iduronate Galactosamine Galactose Glucosamine
PG also may change, depending on whether the tissue is subjected to tensile or compressive forces.39 Tissues subjected to compression (like discs) have larger amounts of chondroitin sulfate and keratan sulfate, whereas tissues subjected to tension (like tendon) contain more dermatan sulfate.39
Glycoproteins such as fibronectin, laminin, chon- dronectin, osteonectin, tenascin, tenomodulin, chon- dromodulin, and entactin play an important role in fastening the various components of the extracellular matrix together, in the adhesion between collagen and in- tegrin molecules in cell membranes, and as inhibitors of angiogenesis (Table 2–5).52
Compression H2O
1 μm
Hyaluronan molecule
(GAG)
Keratan sulfate
(GAG) Chondroitin sulfate (GAG) Link proteins Core protein Proteoglycan aggregate A
C
B
Collagen II fibril Type II
collagen
Figure 2–7 The extracellular matrix (ECM) of articular cartilage contains numerous proteins, GAGs, and proteoglycans. The type II collagen fibers, with colla- gen XI embedded within them, form a meshwork that contains the proteoglycan (PG) aggregates, with water attached, preventing their escape into the joint (A).
When compression is applied to the cartilage, water is squeezed out but the PG aggregates remain trapped (B). The proteoglycans (C) contain chondroitin sulfate and keratan sulfate GAGs attached to a protein core, which in turn is attached, via link proteins, to a hyaluronic acid GAG chain. These proteoglycan aggregates form long bottle brush structures; aggrecan is one of the largest. (Adapted from Adams M, Roughley P: What Is In- tervertebral Disc Degeneration, and What Causes It? Spine 31(18):2151, 2006.)
ConceptCornerstone 2-2
Proteoglycan Characteristics
Proteoglycans:
• are distinguished by their protein core and by their attached GAGs;
• attract water through their attached GAGs;
• regulate collagen fibril size;
• may attach to hyaluronate (another GAG) to form large aggregating structures; and
• are increased in tissues subjected to alternating cycles of compression.
ConceptCornerstone 2-3
Extracellular Matrix Function and Structure
The extracellular matrix of connective tissue determines its function, and vice versa. The type and proportions of the components create the different tissues:
• Interfibrillar component: PGs (protein + GAGs), glycoproteins
• Fibrillar component: collagen (mainly type I or II), elastin