Structure and Function of the Musculoskeletal System

Chapter 43

Structure and Function of the Musculoskeletal System

Christy L. Crowther-Radulewicz

The way an individual functions in daily life, moves about, or manipulates objects physically depends on the integrity of the musculoskeletal system. The musculoskeletal system is actually composed of two systems: (1) the skeleton proper, which is composed of bones and joints; and (2) skeletal muscles. Each of the systems contributes to mobility. The skeleton supports the body and provides leverage to the skeletal muscles so that movement of various parts of the body is possible. This movement is accomplished by contraction of the skeletal muscles and bending or rotation at the joints.

Structure and Function of Bones

Bones give form to the body, support tissues, and permit movement by providing points of attachment for muscles. Many bones meet in movable joints that determine the type and extent of movement possible. Bones also protect many of the body’s vital organs. For example, the bones of the skull, thorax, and pelvis are hard exterior shields that protect the brain, heart, lungs, and reproductive and urinary organs.

Bone marrow is one of the sources of mesenchymal stem cells (MSCs) (Figure 43-1). These nonhematopoietic stem cells consist of a small proportion of the stromal cell population in the bone marrow, and can generate bone, cartilage, fat, cells that support the formation of blood, and fibrous connective tissue. Within certain bones, the marrow cavities also serve as storage site for the hematopoietic stem cells that form both blood and immune cells. In adults, blood cells originate exclusively in the marrow cavities of the skull, vertebrae, ribs, sternum, scapulae, and pelvis. Bones also have a crucial role in mineral homeostasis, and storing and releasing minerals (i.e., calcium, phosphate, carbonate, magnesium) that are essential for the proper working of many delicate cellular mechanisms.

Elements of Bone Tissue

Mature bone is a rigid yet flexible connective tissue consisting of cells, fibers, a gelatinous material termed ground substance, and large amounts of crystallized minerals, mainly calcium, that give bone its rigidity. The structural elements of bone are summarized in Table 43-1.

Bone cells enable bone to grow, repair itself, change shape, and continuously synthesize new bone tissue and resorb (dissolve or digest) old tissue. The fibers in bone are made of collagen, which gives bone its tensile strength (the ability to hold itself together). Ground substance acts as a medium for the diffusion of nutrients, oxygen, metabolic wastes, biochemicals, and minerals between bone tissue and blood vessels.

Bone formation arises during embryonic development when mesenchymal stem cells begin differentiating into either chondrocytes or preosteoblasts. Endochondral ossification and intramembranous bone formation are the two major mechanisms responsible for normal bone development.

Endochondral ossification occurs when mesenchymal (mesenchyme, or loose tissue found during embryonic development) stem cells begin differentiating into chondrocytes (see Figure 43-1), which in turn develop a mineralized cartilage scaffold that allows formation of osteoblasts. Most bone elements are formed this way. With the second mechanism, intramembranous bone formation, mesenchymal stem cells differentiate into a preosteoblast line that then forms osteoblasts without any cartilage framework.1,2

Multiple factors influence normal bone formation, maintenance, and remodeling. The superfamily of signaling factors, containing more than 40 members including bone morphogenic proteins (BMPs), is known as the transforming growth factor-beta (TGF-β) family. This group is primarily responsible for initiation, differentiation, and commitment of precursor cells into osteoblasts. TGF-β signals are transmitted across the plasma membrane, combine with certain proteins that act as transcription factors (Smads), and then form specific receptors known as R-Smads. These receptors, in turn, initiate intracellular signaling, interact with other transcription factors, and regulate other factors that are important in osteoblast formation, function, and maintenance.3 Crosstalk between signaling pathways (including TGF-β, BMPs, FGF, Wnt, Notch, MAPK, and Hedgehog) is critical in regulating osteoblasts.

BMPs have multiple crucial functions in the skeletal system. BMP activities are regulated at different molecular levels. Table 43-2 summarizes the role of several important BMPs.

Wnt genes belong to a large family of protein-signaling factors that are required for the development of body systems, including the musculoskeletal system. They play a significant role in forming bone, developing bone mass, remodeling, and fracture healing. Wnt signaling regulates production and differentiation of osteoblasts and osteoclasts, and affects bone mass and density, joint formation, fracture repair, bone remodeling, and some bone diseases. Other important elements responsible for bone formation and homeostasis are presented in Table 43-3.

TABLE 43-3


Transforming growth factor-beta (TGF-β) Superfamily of polypeptides; regulates bone formation, many other cellular processes though signaling
Platelet-derived growth factor (PDGF) Increases number of osteoblasts
Fibroblast growth factor-2 (FGF) FGF-2 increases osteoblast population, but not function; inhibits alkaline phosphatase activity, osteocalcin, type 1 collagen, and osteopontin
Insulin-like growth factor (IGF)  
 IGF-1 Increases peak bone mass during adolescence; decreases osteoblast apoptosis; maintains bone matrix
 IGF-2 Increases BMP-9–induced endochondral ossification
Smad proteins Mediate the signaling cascade of transforming growth factor-beta (TGF-β), especially in embryonic bone development; play a role in crosstalk between BMP/TGF-β and Wnt signaling pathways
Bone morphogenic proteins (BMPs) Members of transforming growth factor-beta (TGF-β) superfamily of polypeptides; have many functions outside skeletal system; stimulate endochondral bone and cartilage formation and function, promote osteoblast maturation; augment bone remodeling by affecting both osteoblasts and osteoclasts
Tumor necrosis factors (TNFs) Superfamily of cytokines; play major role in regulating bone metabolism, especially osteoclast function
Osteoprotegerin (OPG) Inhibits bone remodeling/resorption; produced by several cells, including osteoblasts; is a decoy receptor for RANKL (binds to RANKL, inhibiting RANK/RANKL interactions, suppressing osteoclast formation and bone resorption)
Receptor activator of nuclear factor κβ (RANK) Stimulates differentiation of osteoclast precursors; activates mature osteoclasts
Bone morphogenic protein antagonists Prevent BMP signaling
 Noggin Binds BMP-2 and BMP-4, reducing osteoblast function
 Gremlin Multiple effects in and out of skeletal system, but also binds BMP-2, -4, and -7; may play a role in development of osteoporosis
 Twisted gastrulation Acts as either a BMP agonist or an antagonist
 Activin (a BMP-related protein) Affects both osteoblasts and osteoclasts; may promote bone formation and fracture healing; expressed by both osteoblasts and chondrocytes; helps regulate bone mass
 Inhibin Dominant over activin and BMPs; helps regulate bone mass and strength by affecting formation of osteoblasts and osteoclasts
 Leptin Plays role in bone formation and resorption
 Wnt (a signaling pathway) Important in differentiating osteoblasts and bone formation; has overlapping effects with BMPs; helps regulate bone formation and remodeling
Wnt antagonists  
 Dickkopf family (Dkk) Disrupt Wnt signaling, leading to reduced bone mass
 Sclerostin Protein secreted by osteocytes, osteoblasts, and osteoclasts; binds to BMP-6 and BMP-7; interferes with Wnt signaling pathway, inhibiting bone formation by osteoblasts
Transcription Factors
Nuclear factor of activated κβ cells (NF-κβ) Affects embryonic osteoclastogenesis; plays a role in certain osteoclast, osteoblast, and chondroblast functions
Matrix metalloproteinases (MMPs)  
 Family of endopeptidases (enzymes) that includes collagenases, gelatinases, stromelysins, matrilysins Help maintain equilibrium of extracellular matrix (ECM); break down almost all components of ECM
 A disintegrin and metalloproteinase (ADAM) Proteolytic enzymes; also have cell-signaling functions, usually linked to cell membrane
 A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) Similar to ADAMs but are secreted into circulation, are found around cells; various subgroups affect multiple tissues
Cysteine Protease
Cathepsin K-expressed by osteoclasts; assists in bone remodeling by cleaving proteins, such as collagen type I, collagen type II, and osteonectin
MMP Inhibitors
Tetracyclines (especially doxycycline), bisphosphonates Block enzymatic function of MMPs
Tissue inhibitors of metalloproteinases (TIMPs) Balance effect of MMPs in maintaining ECM equilibrium


From Boyce GC, Zhenqiang, Zing L: Ann N Y Acad Sci 1192:367–375, 2010; Canalis E: J Cell Biol 108(4):769–777, 2009; Kim Y-S et al: J Korean Med Sci 25:985–991, 2010; Moester MJ et al: Calcif Tissue Int 87(2):99–107, 2010; Nicks KN et al: Mol Cell Endocrinol 310(1-2):11–20, 2009; Pasternak B, Aspenberg P: Acta Orthopaedica 80(6):693–703, 2009; Stewart A, Guan H, Yang K: J Cell Physiol 223(3):658–666, 2010; Tat SK et al: Keio Med J 58(1):29–40, 2009.

In mature bone the formation of new tissue begins with the production of an organic matrix by the bone cells. This bone matrix consists of ground substances, collagen, and other proteins (see Table 43-1) that take part in bone formation and maintenance.

The next step in bone formation is calcification, when minerals are deposited and crystallize. Minerals bind tightly to collagen fibers, producing tensile and compressional strength in bone, and withstand pressure and weightbearing.

Bone Cells

Bone contains three types of cells: osteoblasts, osteocytes, and osteoclasts (Figure 43-2). Osteoblasts are the bone-forming cells, whose primary function is to lay down new bone. Once this function is complete, osteoblasts become osteocytes that are imbedded in bone. Comprising 90% to 95% of bone cells, osteocytes develop dendritic processes that extend to either the bone surface or the bone’s vascular space.4 They help maintain bone by signaling osteoblasts and osteoclasts to form and resorb bone.5 Osteoclasts are the major bone-resorbing cells responsible for remodeling.


Osteoblasts are cells derived from mesenchymal stem cells. Osteoblasts produce several substances, including osteocalcin, TGF-β, macrophage colony-stimulating factor, receptor activator of nuclear factor κβ ligand (RANKL), osteoprotegerin (OPG), and bone matrix6 and osteocalcin when stimulated by 1,25-dihydroxy-vitamin D. Osteoblasts are active on the outer surface of bones, where they form a single layer of cells. They initiate the formation of new bone by their synthesis of osteoid (nonmineralized bone matrix). The mechanism of osteoblast stimulation is reported to be the production of so-called coupling factors generated during the resorption process. Osteoblasts cause the formation of new bone and the orderly mineralization of bone matrix by concentrating some of the plasma proteins (growth factors) found in the bone matrix and by facilitating the deposit and exchange of calcium and other ions at the site. Osteoblasts alter levels of RANKL and OPG; the balance of these two cytokines determines overall osteoclast formation7 (see Figure 44-11). As new bone is formed, it is shaped and remodeled through TGF-β, as well as other plasma proteins (growth factors) found in the bone marrow (Table 43-4).


An osteocyte is a transformed osteoblast that is trapped or surrounded in osteoid as it hardens from minerals that enter during ossification (see Figure 43-2, B). It is the final differentiation stage for an osteoblast. The osteocyte is within a space in the hardened bone matrix called a lacuna. Each osteocyte has a high nucleus/cytoplasm ratio with a thin layer of nonmineralized osteoid around it, similar to the egg white surrounding an egg yolk.

The cells of the osteoblastic lineage (osteoblasts and osteocytes) form a network of cells in bone that sense the shape and structure of bone (mechanoreceptors) and determine the appropriate locations for bone formation or resorption, according to Wolff ’s law (bone is shaped according to its function).

Osteocytes communicate with other bone cells and instruct both osteoblasts and osteoclasts about when and where to form and resorb bone; concentrate nutrients in the matrix; regulate bone mass and minerals (especially calcium and phosphorus); and secrete other proteins, such as sclerostin and fibroblast growth factor-23 (FGF-23), that influence mineral metabolism.3,4,8,9 Sclerostin inhibits osteoblasts, thus reducing bone formation. Additionally, osteocytes seem to function as endocrine receptors in regulating bone metabolism and are prime target cells of parathyroid hormone (PTH).911 Through exchanges between these cells, hormone catalysts, and minerals, optimal levels of calcium, phosphorus, and other minerals are maintained in blood plasma. The osteocyte also aids in modifying bone matrix through release of enzymes to dissolve the mineralized walls of the lacunae to prepare the bone for remodeling. (Remodeling is described on p. 1519.)


Osteoclasts are large, multinucleated bone cells derived from hematopoietic stem cells in the bone marrow stroma and are the major resorptive cells of bone. Considered to be the major remodelers of bone, osteoclasts contain lysosomes (digestive vacuoles) filled with hydrolytic enzymes. Fine projections, or microvilli, fan out from the osteoclast cell’s surface and are known as ruffled borders; these projections result from extensive infoldings of the cell membrane adjacent to the resorptive surface.12 Osteoclasts in regions of bone resorption lie in pits called Howship lacunae, where the infolded, ruffled borders of the osteoclasts greatly increase the surface area of the plasma membrane. The infolds end in numerous channels and vesicles in the cell cytoplasm, permitting them to resorb the bone under their ruffled, infolded borders.

Osteoclasts bind to the bone surface of cell attachment proteins called integrins.12 In contact with bone mineral, osteoclasts use adhesive structures, called podosomes, to attach themselves to the bone surface. They then seal their cytoplasm with the underlying bone and dissolve the bone and matrix while protecting the surrounding tissue.13 They effect resorption of bone by secretion of hydrochloric acid (HCl) and cathepsin K (a protease enzyme), which help dissolve bone minerals and collagenase, thereby aiding the digestion of collagen along with the action of cytokines (see Table 43-4). Matrix metalloproteinases (MMPs), a group of proteolytic enzymes, help control osteoclast-matrix interactions necessary for bone resorption. Once resorption is completed, the osteoclast disappears by degeneration, either by reverting to its parent cell or by leaving the site through the process of cell mobility, wherein the osteoclast then becomes an inactive, or “resting,” osteoclast. Overall, bone homeostasis is the result of crosstalk between osteoclasts, osteoblasts, and osteocytes.14 Recent evidence has indicated that osteoclasts also may play a role in the body’s immune system.1517

Bone Matrix

Bone matrix is made of the extracellular elements of bone tissue, composed of about 35% organic and 65% inorganic materials. The major organic components are collagen fibers, and the major inorganic components are the calcium and phosphate minerals. Other parts of the bone matrix are the proteins, carbohydrate-protein complexes, and ground substances. Water comprises 5% to 8% of the matrix. Within the matrix are small particles known as matrix vesicles that “bud” from chondrocytes, osteoblasts, and odontoblasts. These vesicles are the initial sites for calcification in skeletal tissues.18 Calcification begins as extracellular calcium enters the matrix vesicles and forms hydroxyapatite crystals.

Collagen Fibers

Collagen fibers are the major organic component of bone matrix. The fibers are approximately 90% type I collagen, are essential for bone strength, and are synthesized and secreted by osteoblasts. Once secreted, collagen molecules assemble into thin chains called α-chains, which combine in groups of 3 to form fibrils. The fibrils form a staggered pattern, overlapping nearby fibrils by approximately one fourth their length. This staggered, overlapping pattern creates regular gaps, called hole zones, into which mineral crystals are deposited.18 After mineral deposition, the fibrils link together and twist to form ropelike fibers. Collagen fibers then join to form a framework that gives bone its tensile strength and enables it to bear weight.

Collagen is the most abundant macromolecule in the body, accounting for approximately one third of all protein and providing the structural framework for nearly all tissues. Collagen is one of the extracellular components, along with proteoglycans and noncollagenous matrix proteins, of articular cartilage. To date, more than 20 types of collagen have been identified, though all their functions are not yet known. Cartilage-specific collagens include types II (the principal component), VI, IX, X, and XI. Type IX collagen is thought to be the “glue” that holds together the type II collagen scaffold of articular cartilage, helps maintain the structural integrity of cartilage, and resists tensile forces on the joint cartilage. Type XI regulates the fibril diameter of type II cartilage. Degradation of type IX collagen by proteolytic enzymes has been seen in the early stages of osteoarthritis and rheumatoid arthritis. Researchers have proposed that this degradation, or “unplugging,” may be the mechanism for the degenerative changes seen in osteoarthritic and rheumatoid cartilage. Table 43-5 gives the musculoskeletal distribution of other types of collagen.


Glycoproteins are also carbohydrate-protein complexes of bone. Glycoproteins control the collagen interactions that lead to fibril formation. They also play a role in calcification.

Some of the glycoproteins in bone matrix include bone sialoprotein, osteocalcin, osteonectin, laminin, albumin, and α-glycoprotein. Other proteins found in bone matrix are the compounds currently called bone morphogenic proteins (BMPs) (see Table 43-2). Sialoprotein (osteopontin) comprises about 8% of the noncollagenous matrix of bone and easily binds with calcium.

Osteocalcin is also a calcium-binding protein that binds preferentially to calcium that has already crystallized. The roles of osteocalcin may be to inhibit calcium phosphate precipitation and to play a part in bone resorption by recruiting osteoclasts.

Osteonectin is a bone-specific protein that binds selectively to both hydroxyapatite and collagen in the bone matrix. Laminin is an abundant bone matrix protein in humans that stabilizes basement membranes in bones and is important in neurite and axon growth.

Bone albumin is identical to serum albumin. In calcified matrix, bone albumin is permanently fixed to bone mineral crystals and remains so until the bone is resorbed. Bone albumin transports essential elements such as hormones, ions, and other metabolites to and from the bone cells and maintains the osmotic pressure of bone fluid (fluid surrounding mineral crystals and osteoblasts).

Bone Minerals

Mineralization is the final step in bone formation, after collagen synthesis and fiber formation. Mineralization has two distinct phases: (1) formation of the initial mineral deposit (initiation), and (2) proliferation or accretion of additional mineral crystals on the initial mineral deposits (growth).12 The majority of the mineral content in the body is an analog of the naturally occurring mineral hydroxyapatite.

Table 43-6 lists the sequence in which calcium and phosphate form amorphous (fluid) calcium phosphate compounds that are converted, in stages, to solid hexagonal crystals of hydroxyapatite (HAP). As the calcium and phosphorous concentrations increase in the bone matrix, the first precipitate to form is dicalcium phosphate dihydrate (DCPD). Once DCPD precipitation begins, the remaining phases of bone crystal formation proceed until insoluble HAP is produced, with approximately 80% to 90% of the HAP being incorporated into the collagen fibers. Amorphous calcium phosphate is distributed throughout the bone matrix.

Types of Bone Tissue

Bone consists of two types of bony (osseous) tissue: compact bone (cortical bone) and spongy bone (cancellous bone) (Figure 43-3). Compact bone constitutes approximately 85% of the skeleton; spongy bone comprises the remaining 15%. Both types of bone tissue contain the same structural elements, and, with a few exceptions, both compact tissue and spongy tissue are present in every bone. The major difference between the two types of tissue is the organization of the elements.

Compact bone is highly organized, solid, and extremely strong. The basic structural unit in compact bone is the haversian system (Figure 43-4). Each haversian system is made up of the following:

Each haversian system is a separate cylindrical entity that looks like a set of concentric rings. In the center of the haversian system is the haversian canal that runs through the long axis of bone and contains one or two blood vessels and nerve fibers. The blood vessels in the canal communicate with blood vessels in the periosteum (surface cover) and marrow cavity to transport nutrients and wastes to and from the osteocytes contained within the lacunae. Surrounding each haversian canal are the concentric lamellae. Between the lamellae are the lacunae, each of which contains one osteocyte. The lacunae are connected to each other and to the haversian canal by the canaliculi, which run parallel to the horizontal axis of the bone. Each canaliculus encloses a small extension (cytoplasmic process) from the osteocyte contained in the lacuna. The canaliculi transport both nourishment and molecular signals into the lacunae, a mechanism essential for osteocyte survival.

Spongy bone is less complex and lacks haversian systems. In spongy bone the lamellae are not arranged in concentric layers but in plates or bars termed trabeculae that branch and unite with one another to form an irregular meshwork. The pattern of the meshwork is determined by the direction of stress on the particular bone. The spaces between the trabeculae are filled with red bone marrow. The osteocyte-containing lacunae are distributed between the trabeculae and interconnected by canaliculi. Capillaries pass through the marrow to nourish the osteocytes.

All bones are covered with a double-layered connective tissue called the periosteum. The outer layer of the periosteum contains blood vessels and nerves, some of which penetrate to the inner structures of the bone through channels called Volkmann canals (see Figure 43-4). The inner layer of the periosteum is anchored to the bone by collagenous fibers (Sharpey fibers) that penetrate the bone. Sharpey fibers also help hold or attach tendons and ligaments to the periosteum of bones.12

Characteristics of Bone

The human skeleton consists of 206 bones that constitute the axial skeleton and the appendicular skeleton (Figure 43-5). The axial skeleton consists of 80 bones that make up the skull, vertebral column, and thorax. The appendicular skeleton consists of 126 bones that make up the upper and lower extremities, the shoulder girdle (pectoral girdle), and the pelvic girdle. The skeleton contributes about 14% of the weight of the adult body.

Bones can be classified by shape as long, flat, short (cuboidal), or irregular. Long bones are longer than they are wide and consist of a narrow tubular midportion (diaphysis) that merges into a broader neck (metaphysis) and a broad end (epiphysis) (see Figure 43-3).

The diaphysis consists of a shaft of thick, rigid compact bone that can tolerate bending forces. Contained within the diaphysis is the elongated marrow (medullary) cavity. The marrow cavity of the diaphysis contains primarily fatty tissue, which is referred to as yellow marrow. The yellow marrow assists red bone marrow in hematopoiesis only during times of stress. The yellow marrow cavity of the diaphysis is continuous with marrow cavities in the spongy bone of the metaphysis and diaphysis. The marrow contained within the epiphysis is red because it contains primarily blood-forming tissue (see Chapter 27). A layer of connective tissue, the endosteum, lines the outer surfaces of both types of marrow cavity.

The broadness of the epiphysis allows weightbearing to be distributed over a wide area. The epiphysis is made up of spongy bone covered by a very thin layer of compact bone. In a child the epiphysis is separated from the metaphysis by a cartilaginous growth plate, the epiphyseal plate. After puberty the epiphyseal plate calcifies and the epiphysis and metaphysis merge. By adulthood the line of demarcation between the epiphysis and metaphysis is undetectable.

In flat bones, such as the ribs or scapulae, two plates of compact bone are roughly parallel to each other. Between the compact bone plates is a layer of spongy bone. Short bones (cuboidal bones), such as the bones of the wrist or ankle, are often cuboidal in shape. They consist of spongy bone covered by a thin layer of compact bone.

Irregular bones, such as the vertebrae, mandibles, or other facial bones, have various shapes that include thin and thick segments. The thin part of an irregular bone consists of two plates of compact bone with spongy bone between the plates. The thick part consists of spongy bone surrounded by a layer of compact bone.

Maintenance of Bone Integrity


Clusters of bone cells, termed bone-remodeling units, are responsible for maintaining the structure of bone by remodeling, a three-phase process in which existing bone is resorbed and new bone is laid down to replace it. The bone-remodeling units are made up of bone precursor cells that differentiate into osteoclasts and osteoblasts. Precursor cells are located on the free surfaces of bones and along the vascular channels (especially the marrow cavities).

In phase 1 (activation) of the remodeling cycle, a stimulus (e.g., hormone, drug, vitamin, physical stressor) activates programmed osteocyte cell death (apoptosis). The distribution of these apoptotic osteocytes provides osteoclasts with information about where to begin resorbing damaged bone. In phase 2 (resorption), the osteoclasts form a “cutting cone,” which gradually resorbs bone, leaving behind an elongated cavity termed a resorption cavity. The resorption cavity in compact bone follows the longitudinal axis of the haversian system, and the resorption cavity in spongy bone parallels the surface of the trabeculae.

Phase 3 (formation) is the laying down of new bone, termed secondary bone, by osteoblasts lining the walls of the resorption cavity. Successive layers (lamellae) in compact bone are laid down until the resorption cavity is reduced to a narrow haversian canal around a blood vessel. In this way, old haversian systems are destroyed and new haversian systems are formed. New trabeculae are formed in spongy bone. The entire process of remodeling takes about 3 to 4 months.


The remodeling process can repair microscopic bone injuries, but gross injuries, such as fractures and surgical wounds (osteotomies), heal by the same stages as soft tissue injuries, except that new bone, instead of scar tissue, is the final result (see Chapter 7). In bone the stages of wound healing are as follows:

1. Hematoma formation: This process occurs if vessels have been damaged, causing hemorrhage. Fibrin and platelets within the hematoma form a meshwork that is the initial framework for healing with the help of hematopoietic growth factors such as platelet-derived growth factor and TGF-β (see Table 43-3).

2. Procallus formation: Fibroblasts, capillary buds, and osteoblasts move into the wound to produce granulation tissue called procallus. Cartilage is formed as a precursor of bone, and types I, II, and III collagen are formed. Enzymes and growth factors, such as insulin and insulin-like growth factors, plus bone morphogenic protein and osteogenin, aid in this stage of healing.

3. Callus formation: Osteoblasts in the procallus form membranous or woven bone (callus). Enzymes increase the phosphate content and permit the phosphate to join with calcium to be deposited as mineral to harden the callus.

4. Callus replacement: Osteoblasts continue to replace the callus with lamellar bone or trabecular bone (Figure 43-6).

FIGURE 43-6 Bone Remodeling.
All bone cells participate in bone remodeling. In the remodeling sequence bone sections are removed by bone-resorbing cells (osteoclasts) and replaced with a new section laid down by bone-forming cells (osteoblasts). Bone remodeling is necessary because it allows the skeleton to respond to mechanical loading, maintains quality control (repair and prevent microdamage), and allows the skeleton to release growth factors and minerals (calcium and phosphate) stored in bone matrix to the circulation. The cells work in response to signals generated in the environment (see F). Only the osteoclastic cells mediate the first phase of remodeling. They are activated, scoop out bone (A), and resorb it; then the work of the osteoblasts begins (B). They form new bone that replaces bone removed by the resorption process (C). The sequence takes 4 to 6 months. D, Micrograph of active bone remodeling seen in the settings of primary or secondary hyperparathyroidism. Note the active osteoblasts surmounted on red-stained osteoid. Marrow fibrosis is present. E, Bone remodeling cycle in normal bone (F). Numerous signaling factors are necessary for remodeling. Factors most important for resorption include granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukins-1 and -6 (IL-1 and IL-6), receptor activator for nuclear factor κβ ligand (RANKL), prostaglandin E2 (PGE2), and tumor necrosis factor-alpha (TNF-α). Important factors for bone formation include osteoprotegerin (OPG), transforming growth factor-beta (TGF-β), and estrogen. (Adapted from Nucleus Medical Art. D from Damjananov I, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)

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