Skeletal System Pt.

2
There are three types of cartilage: (1) hyaline cartilage, (2) fibrocartilage, and (3) elastic cartilage. Although each type
of cartilage can provide support, hyaline cartilage is most intimately associated with bone. An understanding of hyaline
cartilage structure is important because most bones in the body start out as a hyaline cartilage model. In addition,
growth in bone length and bone repair often involve making hyaline cartilage first, then replacing it with bone. Hyaline
cartilage chondroblasts secrete a matrix, which surrounds the chondroblasts. Once the matrix has surrounded the
chondroblast, it has differentiated into a chondrocyte. Chondrocytes are rounded cells that occupy a space called a
lacuna within the matrix. The matrix contains collagen, which provides strength, and proteoglycans, which make
cartilage resilient by trapping water.
Most cartilage is covered by a protective connective tissue sheath called the perichondrium. The perichondrium is a
double-layered outer layer of dense irregular connective tissue containing fibroblasts. The inner, more delicate layer has
fewer fibers and contains chondroblasts. Blood vessels and nerves penetrate the outer layer of the perichondrium but
do not enter the cartilage matrix, so nutrients must diffuse through the cartilage matrix to reach the chondrocytes.
Articular cartilage, which is hyaline cartilage that covers the ends of bones where they come together to form joints,
has no perichondrium, blood vessels, or nerves.
There are two types of cartilage growth: (1) appositional growth and (2) interstitial growth. In appositional growth,
chondroblasts in the perichondrium add new cartilage to the outside edge of the existing cartilage. In interstitial
growth, chondrocytes in the center of the tissue divide and add more matrix in between the existing cells.
Bone Matrix
By weight, mature bone matrix is normally about 35% organic and 65% inorganic material. The organic material consists
primarily of collagen and proteoglycans. The inorganic material consists primarily of a calcium phosphate crystal called
hydroxyapatite, which has the molecular formula Ca10(PO4)6(OH)2. The collagen and mineral components are
responsible for the major functional characteristics of bone.
Types of Bone Cells (Reviewer)
Origin of Bone Cells
Connective tissue develops embryologically from mesenchymal cells. Some of the mesenchymal cells become stem cells,
a number of which replicate and become more specialized cell types. Stem cells called osteochondral progenitor cells
can become osteoblasts or chondroblasts. Osteochondral progenitor cells are located in the inner layer of the
perichondrium and in layers of connective tissue that cover bone (periosteum and endosteum). From these locations,
they are a potential source of new osteoblasts or chondroblasts. Osteoblasts are derived from osteochondral progenitor
cells, and osteocytes are derived from osteoblasts. Whether or not osteocytes freed from their surrounding bone matrix
by reabsorption can
revert to become active osteoblasts is a debated issue. As discussed in the previous section, osteoclasts are not derived
from osteochondral progenitor cells but from stem cells in red bone marrow.
Woven Lamellar Spongy Compact
Structure of a Long Bone
A long bone is the traditional model for overall bone structure. The diaphysis is the center portion of the bone. It is
composed primarily of compact bone, surrounding a hollow center called the medullary cavity. Some spongy bone can
be found lining the medullary cavity. The ends of a long bone are called epiphyses. The epiphyses are mostly spongy
bone, with an outer layer of compact bone. Within joints, the end of a long bone is covered with hyaline cartilage called
articular cartilage.
During bone formation and growth, bones develop from centers of ossification. The primary ossification center is in the
diaphysis. The epiphysis develops from different centers of ossification from the diaphysis. Each long bone of the arm,
forearm, thigh, and leg has one or more epiphyses on each end of the bone. Each long bone of the hand and foot has
one epiphysis, which is located on the proximal or distal end of the bone. The epiphyseal plate, or growth plate, is
located between the epiphysis and the diaphysis. Growth in bone length occurs at the epiphyseal plate. Consequently,
growth in length of the long bones of the arm, forearm, thigh, and leg occurs at both ends of the diaphysis, whereas
growth in length of the hand and foot bones occurs at one end of the diaphysis. When bone stops growing in length, the
epiphyseal plate becomes ossified and is called the epiphyseal line.
The periosteum is a connective tissue membrane covering the outer surface of a bone. The outer fibrous layer is dense
irregular collagenous connective tissue that contains blood vessels and nerves. The inner layer is a single layer of bone
cells, including osteoblasts, osteoclasts, and osteochondral progenitor cells. Where tendons and ligaments attach to
bone, the collagen fibers of the tendon or ligament become continuous with those of the periosteum. In addition, some
of the collagen fibers of the tendons or ligaments penetrate the periosteum into the outer part of the bone. These
bundles of collagen fibers are called perforating fibers, or Sharpey fibers, and they strengthen the attachment of the
tendons or ligaments to the bone. The endosteum is a single cell layer of connective tissue that lines the internal
surfaces of all cavities within bones, such as the medullary cavity of the diaphysis and the smaller cavities in spongy and
compact bone. The endosteum includes osteoblasts, osteoclasts, and osteochondral progenitor cells.
Flat, Short, Irregular Bones

Intramembranous Ossification
Many skull bones, part of the mandible (lower jaw), and the diaphyses of the clavicles (collarbones) develop by
intramembranous ossification. Begins at approximately the eighth week of embryonic development and is completed by
approximately 2 years of age.
Thus, the end products of intramembranous bone formation are bones with outer compact bone
surfaces and spongy centers.
1. Osteoblast formation: Some embryonic mesenchymal cells in the connective tissue membrane differentiate
into osteochondral progenitor cells. The osteochondral progenitor cells then form osteoblasts. The osteoblasts
produce bone matrix. The bone matrix will surround the collagen fibers of the connective tissue membrane.
Once they are embedded in bone matrix, the osteoblasts become osteocytes. As a result of this process, many
tiny trabeculae of woven bone develop.
2. Spongy bone formation: Additional osteoblasts gather on the surfaces of the trabeculae and produce more
bone, thereby causing the trabeculae to become larger and longer. Spongy bone forms as the trabeculae join
together, resulting in an interconnected network of trabeculae separated by spaces.
3. Compact bone formation: Cells within the spaces of the spongy bone specialize to form red bone marrow, and
cells surrounding the developing bone specialize to form the periosteum. Osteoblasts from the periosteum lay
down bone matrix to form an outer surface of compact bone.
Thus, the end products of intramembranous bone formation are bones with outer compact bone surfaces and spongy
centers.
Endochondral Ossification
1. Cartilage model formation: Embryonic mesenchymal cells aggregate in regions of future bone formation. The
mesenchymal cells differentiate into osteochondral progenitor cells that become chondroblasts. The
chondroblasts produce a hyaline cartilage model having the approximate shape of the bone that will later be
formed.
2. Bone collar formation: When blood vessels invade the perichondrium surrounding the cartilage model,
osteochondral progenitor cells within the perichondrium become osteoblasts. Once the osteoblasts begin to
produce bone, the perichondrium becomes the periosteum. The osteoblasts produce compact bone on the
surface of the cartilage model, forming a bone collar. Hypertrophy. At this point, the cartilage is called calcified
cartilage. The chondrocytes in this calcified area eventually die, leaving enlarged lacunae with thin walls of
calcified matrix.
3. Primary ossification center formation: Blood vessels grow into the enlarged lacunae of the calcified cartilage.
Osteoblasts and osteoclasts migrate into the calcified cartilage area from the periosteum by way of the
connective tissue surrounding the outside of the blood vessels. The primary ossification center forms as
osteoblasts produce bone on the surface of the calcified cartilage. The osteoblasts transform the calcified
cartilage of the diaphysis into spongy bone. As bone development proceeds, the cartilage model continues to
grow, and the bone collar thickens. Remodeling converts woven bone to lamellar bone and contributes to the
final shape of the bone. Osteoclasts remove bone from the center of the diaphysis to form the medullary cavity,
and cells within the medullary cavity specialize to form red bone marrow.
4. Secondary ossification center formation: Secondary ossification centers are created in the epiphyses by
osteoblasts that migrate into the epiphysis. The events occurring at the secondary ossification centers are the
same as those at the primary ossification centers, except that the spaces in the epiphyses do not enlarge to form
a medullary cavity as in the diaphysis. Primary ossification centers appear during early fetal development,
 whereas secondary ossification centers appear in the proximal epiphysis of the femur, humerus, and tibia about
1 month before birth. After a person’s bones have stopped growing, the epiphyseal plate regresses into a “scar,”
called the epiphyseal line.
5. Adult bone: In mature bone, spongy and compact bone are fully developed, and the epiphyseal plate has
become the epiphyseal line. The only cartilage present is the articular cartilage at the ends of the bone. All the
original perichondrium that surrounded the cartilage model has become periosteum.

Epiphyseal Zone
1. Resting Zone - nearest the epiphysis and contains slowly dividing chondrocytes.
2. The chondrocytes in the zone of proliferation produce new cartilage through interstitial cartilage growth. The
chondrocytes divide and form columns resembling stacks of plates or coins.
3. In the zone of hypertrophy, the chondrocytes produced in the zone of proliferation mature and enlarge. Thus, a
maturation gradient exists in each column: The cells nearer the epiphysis are younger and actively proliferating,
whereas the cells progressively nearer the diaphysis are older and undergoing hypertrophy.
4. The zone of calcification is very thin and contains hypertrophied chondrocytes and calcified cartilage matrix. The
hypertrophied chondrocytes die, and blood vessels from the diaphysis grow into the area. The connective tissue
surrounding the blood vessels contains osteoblasts from the endosteum.
5. The osteoblasts line up on the surface of the calcified cartilage and, through appositional bone growth, deposit
new bone matrix, which is later remodeled.
Mechanical Stress
Types of Bone Fracture
Bone Repair
Hematoma formation. A hematoma is a localized mass of blood released from blood vessels but confined within an
organ or a space. When a bone is fractured, the blood vessels in the bone and surrounding periosteum are damaged and
a hematoma forms. Usually, the blood in a hematoma forms a clot, which consists of fibrous proteins that stop the
bleeding.
Callus formation. A callus is a mass of bone tissue that forms at a fracture site. An external callus encircles the break and
connects the broken ends of the bone. An internal callus forms between the ends of the broken bone, as well as in the
marrow cavity if the fracture occurs in the diaphysis of a long bone.
If formation of the internal callus is prevented by infection, bone movements, or the nature of the injury, the two ends
of the bone do not rejoin—a condition called nonunion of the bone. This condition can be treated surgically by
implanting an appropriate substrate, such as living bone from another site in the body or dead bone from a cadaver.
The external callus is a bone-cartilage collar that stabilizes the ends of the broken bone. In modern medical practice,
applying a cast or surgically implanting metal supports can help stabilize the bone.
Callus Ossification. External callus is replaced by woven spongy bone through endochondral ossification.
Bone remodeling. Filling the gap between bone fragments with an internal callus of woven bone is not the end of the
repair process because woven bone is not as structurally strong as the original lamellar bone. Repair is complete only
when the woven bone of the internal callus and the dead bone adjacent to the fracture site have been replaced by
compact bone.
Calcium Homeostasis
Calcium homeostasis is regulated by three hormones (chemical messengers delivered via the blood): (1)parathyroid
hormone (PTH); (2) calcitriol, a biologically active form of vitamin D3; and (3) calcitonin.

Parathyroid Hormone
Parathyroid hormone is secreted by cells in the parathyroid gland and is essential for the maintenance of blood Ca2+
levels within the homeostatic limits. PTH production and secretion are controlled by Ca2+- sensing receptors in the
parathyroid gland. The key signal for PTH secretion is a reduction in blood Ca2+ levels. PTH works through two general
mechanisms: (1) direct effects on bone cells and in the kidney and (2) indirect effects on the small intestine.

1. Direct Effects of PTH

a. Bone Cells
 PTH increases blood Ca2+ levels by exerting direct regulatory control of osteoblasts and osteocytes to
increase formation and activation of osteoclasts, the principal bone-reabsorbing cells.
The membranes of osteoblasts and osteocytes express a regulatory molecule called Receptor activator of
nuclear factor kappaβ ligand (RANKL). RANKL exists in two forms: (1) membrane-bound and (2) soluble;
however, it is the soluble form of RANKL that is more potent in triggering osteoclast formation. RANKL
belongs to a family of inflammatory signals called cytokines. Additionally, it has been demonstrated that
RANKL production and function are regulated by molecules called toll-like receptors (TLRs). TLRs are
membrane-bound proteins found in immune cells such as macrophages that recognize microbe-specific
molecules. Increases blood Ca2+ levels by continuing to stimulate osteoclast formation. Normally, a RANKL
decoy receptor, called osteoprotegerin, prevents osteoclast differentiation.
b. Kidney Tubules
PTH stimulates the reabsorption of Ca2+ from urine in the kidney tubules, which reduces the amount of
Ca2+ excreted in the urine.
2. Indirect Effects of PTH in the Small Intestine
PTH promotes the activation of calcitriol in the kidneys. Calcitriol increases absorption of Ca2+ in the small
intestine. Thus, PTH indirectly increases Ca2+ uptake from the small intestine via calcitriol
Calcitriol
Calcitriol increases blood Ca2+ levels. It is a steroid hormone derived from vitamin D3. PTH stimulates calcitriol
activation in the kidney, which contributes to PTH-induced increases in blood Ca2+ levels. Calcitriol and PTH work
together to increase osteoclast activity for bone reabsorption. In addition, calcitriol assists PTH in the kidney tubules by
preventing Ca2+ removal through urine. These actions of calcitriol increase blood Ca2+ levels.
Calcitonin
Calcitonin is secreted from C cells in the thyroid gland when blood Ca2+ levels are too high. Calcitonin rapidly lowers
blood Ca2+ levels by inhibiting osteoclast activity. However, the exact role of calcitonin, especially in adult bone
remodeling, is still under investigation.