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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5181_Библиотеки_им_академика_М_И_Перельмана.pdf
Contributors
xiii
MichaelW.Kessler, MD Department of Orthopedics, MedStar Georgetown
University Hospital, Washington, DC, USA
MedStar Georgetown Orthopedic Institute, Georgetown University School of
Medicine, Washington, DC, USA
AkhilJayKhanna, MD Department of Orthopedics, MedStar Georgetown
University Hospital, Washington, DC, USA
MedStar Georgetown Orthopedic Institute, Georgetown University School of
Medicine, Washington, DC, USA
Denver B. Kraft, MD Department of Orthopaedic Surgery, MedStar
Georgetown Univeristy Hospital, Washington, DC, USA
JuliaA.McCann, MD Department of Orthopedics, MedStar Georgetown
University Hospital, Washington, DC, USA
MedStar Georgetown Orthopedic Institute, Georgetown University School of
Medicine, Washington, DC, USA
EvanMichaelson, MD Georgetown University School of Medicine, Washington, DC, USA
MedStar Orthopedic Institue, MedStar Georgetown University Hospital,
Washington, DC, USA
Ryan S. Murray, MD Department of Orthopaedic Surgery, MedStar
Georgetown Univeristy Hospital, Washington, DC, USA
Kevin W. Park, MD Department of Orthopedics, MedStar Georgetown
University Hospital, Washington, DC, USA
MedStar Georgetown Orthopedic Institute, Georgetown University School of
Medicine, Washington, DC, USA
GregoryPerraut, MD Department of Orthopedics, MedStar Georgetown
University Hospital, Washington, DC, USA
MedStar Georgetown Orthopedic Institute, Georgetown University School of
Medicine, Washington, DC, USA
William F. Postma, MD Department of Orthopedic Surgery, MedStar
Georgetown University Hospital, Washington, DC, USA
Kenneth M. Vaz, MD Department of Orthopedics, MedStar Georgetown
University Hospital, Washington, DC, USA
MedStar Georgetown Orthopedic Institute, Georgetown University School of
Medicine, Washington, DC, USA
BrentWiesel, MD Georgetown University School of Medicine, Washington, DC, USA
MedStar Orthopedic Institue, MedStar Georgetown, University School of
Medicine, Washington, DC, USA
xiv
KyleW.Zittel, MD Department of Orthopedics, MedStar Georgetown University Hospital, Washington, DC, USA
MedStar Georgetown Orthopedic Institute, Georgetown University School of
Medicine, Washington, DC, USA
Contributors
Basic Science ofBone
andCartilage Metabolism
MichaelJ.Kelly andJohnN.Delahay
1
Normal Bone Growth
andDevelopment
Bone is a biphasic connective tissue consisting of
an inorganic mineral phase and an organic matrix
phase. The hardness of bone allows it to provide
several specialized mechanical functions: the
protection of internal organs, the scaffold providing points of attachment for other structural elements, and the levers needed to improve the
efciency of muscle action. In addition, bone
serves two biologic functions: a site for hematopoietic activity and a reservoir of minerals needed
for metabolic interchange.
Embryology
The major components of the musculoskeletal system originate from the mesoderm layer of the trilaminar embryo. This “middle layer” is populated
M. J. Kelly
Department of Orthopedic Surgery, Georgetown
University Medical Center, Washington, DC, USA
Department of Orthopedics, MedStar Georgetown
University Hospital, Washington, DC, USA
e-mail: michael.j.kelly@medstar.net
J. N. Delahay (*)
Department of Orthopaedic Surgery, MedStar
Georgetown Univeristy Hospital,
Washington, DC, USA
e-mail: delahayj@gunet.georgetown.edu
by mesenchymal cells that are totipotent and capable of differentiating into a number of tissues. The
sequence of events important in bone growth and
development begins with the appearance of the
limb bud at 26days after fertilization. It is at that
time that a tubular condensation of mesenchyme
develops centrally in the limb bud. Discrete areas,
called interzones, are seen between these condensations and represent the primitive joints, forming
in the sixth week of development (Fig.1.1).
The interzone cells form three lines of cells:
chondrogenic cells form articular cartilage, synovial cells form the capsule and synovium, and
central cells form the intra-articular structures.
Finally, the formation of joints requires repression of chondrogenesis through apoptosis, thus
leaving sites of articulation between two surfaces, and allowing for motion.
In the limb bud itself, incredibly complex biochemical interactions occur between the growing
tissue and regulatory transcription factors to control its growth. Growth must occur in three
planes: longitudinally (proximal to distal), anterior to posterior (ex. radial to ulnar in the hand),
and dorsal to ventral (ex. dorsum or palm of the
hand) (Fig.1.2).
Unfortunately, due to the complexity of these
developmental processes, the limbs are extremely
sensitive to anomalies, accounting for numerous
limb deformities seen in the general population.
Also during the sixth week of development,
the connective tissue, cartilage, and bone begin to
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
W. F. Postma et al. (eds.), Essentials of Orthopedic Surgery,
https://doi.org/10.1007/978-3-031-66215-7_1
1
2
Proximodistal
erating
Fig. 1.1 Appositional growth is seen at the joint
surfaces. Note the very high concentration of
chondrocyte nuclei near the joint space,
corresponding to cellular proliferation. (From
Practical Orthopedic Pathology: A Diagnostic
Approach, 2015 Elsevier, Deyrup and Siegal,
Figure1-7)
M. J. Kelly and J. N. Delahay
Fig. 1.2 Molecular
regulation of limb
growth. Through a
combination of complex
genetics and growth
factors, growth of the
limb bud mesenchymal
tissue is controlled in
three planes: (a)
proximal–distal, (b)
anterior–posterior, and
(c) dorsal–ventral.
(From Langman’s
Medical Embryology,
14e, gure 12.9)
a
RADICAL FRINGE
FGF-10
bc
Anterior–posterior Dorsoventral
mesenchyme
ZPA
SONIC HEDGEHOG
ENGRAILED-1
SER-2
AER
differentiate from the mesenchyme. The center of
the limb bud condenses with cells that foretell the
skeletal elements, called the chondrogenic core
(Fig.1.3).
With elongation of the limb bud through the
processes described above, this tissue progresses
distally. In the seventh week, this cartilage core
is penetrated by a vascular spindle, bringing a
rich vascular supply, occurring coincidentally
with the necrosis of the central cartilage cells.
Once this vascular spindle is established, nervous and muscle tissue development follows.
Finally, the central portion of the model is popu-
Undifferentiated
zone of prolif
mesenchyme
A
E
R
Differentiating
FGF-4 AND
FGF-8
WNT-7
ENGRAILED-1
LMX1
lated by osteoblasts, by which matrix is secreted
zone
and ossied, immature (woven) bone is formed.
Once the central portion of the model is ossied,
it is referred to as a primary ossication center,
residing within the shaft of the tubular bone
(Fig.1.4).
Further ossication of the skeleton occurs via
one of two mechanisms: (1) endochondral ossication and (2) intramembranous ossication.
While intramembranous ossication is the result
of bone forming directly from primitive brous
mesenchymal tissue by means of osteoblasts
(bone-forming cells), the more common mecha-
1 Basic Science ofBone andCartilage Metabolism
Fig. 1.3 Histologic study of fetus. Here, a sleeve, or collar, of bone begins to surround the outer surface of the
chondrogenic core. (From Bogumill GP. Orthopaedic
Pathology: A Synopsis with Clinical Radiographic
Correlation. Philadelphia, PA: Saunders; 1984. Reprinted
with permission)
3
nism of ossication is endochondral, which uses a
cartilage template. In endochondral ossication,
the mesenchyme does not form directly into boneforming cells but in fact produces cartilage forming cells or chondroblasts. After a cartilage model
is formed, osteoblasts are brought to the site by
blood vessels, which secrete bone matrix and
replace the cartilage with bone tissue (Fig.1.5).
Aside from the clavicle and at bones of the skull
(intramembranous ossication), all other bones of
the skeleton are formed in this way.
From the second through the sixth embryonic
months, progressive changes and remodeling
occur in the tubular bones. First, the medullary
canal (centrally) cavitates, leaving a hollow tube
of bone with a large mass of cartilage persisting
at each end (Fig.1.6).
Fig. 1.4 The primary ossication center of a phalanx at
approximately 14weeks gestation, located centrally in the
bone. Additionally, early bone marrow contents are being
developed. (From Lovell and Winter’s Pediatric
Orthopaedics—Figure 1-20A)
Within these masses of cartilage, the secondary ossication centers, or epiphyses, will form at
both ends (Fig.1.7).
A cartilage plate (the physis or growth
plate) persists between the developing epiphysis and metaphysis and is responsible for
growth in length (Fig.1.8). The covering of
the bone, the periosteum, is primarily responsible for growth in girth. In children, the periosteum has two layers—an outer fibrous layer
and an inner cambium layer, which is
osteogenic.
4
Secondary
M. J. Kelly and J. N. Delahay
Fig. 1.5 (a–d) A
schematic of
endochondral bone
formation. This process
is contrasted with
intramembranous
ossication, where bone
is formed directly from
the mesenchymal tissue
without a cartilage
intermediary. (From
Langman’s Medical
Embryology, 14e,
Figure12.5)
abcd
Mesenchyme Cartilage Osteoblasts
Proliferating
chondrocytes
ossification center
Bone
Growth
plate
Fig. 1.6 Primary ossication center, near term. There is
complete replacement of cartilage in the diaphyseal portion of the cartilage model. The remaining cartilage is
conned to both epiphyseal ends of the model. Note the
increasing thickness of the cortical portion of bone, which
is a result of conversion of periosteum to bone. (From
Bogumill GP. Orthopaedic Pathology: A Synopsis with
Clinical Radiographic Correlation. Philadelphia, PA:
Saunders; 1984. Reprinted with permission)
Fig. 1.7 Early secondary ossication center of a mature
fetus. The formation of the secondary ossication centers
in the lower tibia and upper femur coincides with fetal
maturity. The secondary center begins not in the center of
the epiphysis but near the growth plate. Expansion, therefore, is eccentric. (From Bogumill GP. Orthopaedic
Pathology: A Synopsis with Clinical Radiographic
Correlation. Philadelphia, PA: Saunders; 1984. Reprinted
with permission)
1 Basic Science ofBone andCartilage Metabolism
5
Fig. 1.8 Anatomy of
the growth plate,
illustrating the four
distinct physeal zones.
(From Rockwood and
Wilkins, Chapter 2,
Figure2-5)
Secondary
ossification
center
Ring of
LaCroix
Zone of
Ranvier
Periosteal
sleeve
Metaphyseal
artery
Epiphyseal artery
Germinal zone
Proliferative zone
Hypertrophic zone
Zone of
endochondral
ossification
Postnatal Development
The physis and the periosteum continue to function
postnatally in the growth and development of the
infantile skeleton. Numerous local and systemic
factors impact on their activity: vascular, hormonal,
and genetic effects all play important roles. In
essence, the reworking or remodeling of bone that is
already present occurs so that the bone can meet the
mechanical and biologic demands placed on it. And
this remodeling occurs throughout one’s life, with
humans displaying triphasic growth—rapid infantile growth, linear childhood growth, and rapid adolescent growth, followed by skeletal maturity.
Bone Tissue
Bone, whether it is immature or mature, consists
of cells and a biphasic blend of matrix (organic
components) and mineral (inorganic compo-
nent) that coexist in a very exact relationship.
The matrix phase consists largely of collagen
and glycosaminoglycans (GAGs), which are
dimeric disaccharides. Both are products of the
osteoblast. Calcium hydroxyapatite—
Ca10(PO4)6(OH)2 specically—is the basic mineral crystal in bone, contributing mostly to
strength in compression. The bulk of calcium in
the skeletal reservoir is bound in the crystals of
hydroxyapatite.
Osteoblasts, originating from osteoprogenitor cells, are bone-forming cells that secrete the
osteoid matrix components described. As the
osteoid matrix is ossied, the osteoblasts
become trapped in the matrix they produce and
are then referred to as osteocytes, or mature
bone cells, which are rather inert. Osteoclasts
are multinucleated cells (formed from a fusion
of multiple blood monocytes) whose primary
function is the degradation and removal of mineralized bone (Fig.1.9).
6
Fig. 1.9 Newly formed bone, composed of mesenchymal
tissue (M) containing capillaries, broblasts, osteoprogenitor cells, and matrix. The matrix consists of collagen
and the three major cell types found in bone tissue, osteoblasts (Ob), osteoclasts (Ocl), and osteocytes (Oc). (From
Junqueira’s Basic Histology, Chapter 8, Figure8-2)
M. J. Kelly and J. N. Delahay
Fig. 1.10 Lamellar bone, or compact bone, showing
osteons with concentric lamellae around central canals.
(From Junqueira’s Basic Histology, Chapter 8, Figure8-8)
Bone Organization
Microscopically, bone is generally described as
mature or immature. Mature bone has an ordered
lamellar arrangement of Haversian systems and
canalicular communications, giving it its classic
histologic appearance (Fig.1.10).
Immature bone, in contrast, has a much more
random appearance of collagen bers dispersed
in a matrix of irregularly spaced cells (Fig.1.11).
It is produced rapidly by osteoblasts and “remodeled” by the local cell population, until the mature
lamellar pattern is achieved. Immature bone is
seen in the adult skeleton only under pathologic
conditions (i.e., fracture callus, osteogenic sarcoma, myositis, etc.).
Macroscopically, the lamellar bone is congured either as dense cortical bone or as delicate
spicules called trabeculae (Fig.1.12).
Fig. 1.11 Immature bone, located within a primary ossication center, demonstrating the key features of endochondral ossication, including remnants of calcied
cartilage matrix (c) as well as woven bone (b) being
actively formed by osteoblasts (o). (From Junqueira’s
Basic Histology, Chapter 8, Figure8-15)
1 Basic Science ofBone andCartilage Metabolism
Fig. 1.12 Compact cortical bone peripherally, with a lattice of trabeculae forming cancellous bone at the bone’s
center. The small trabeculae that make up highly porous
cancellous bone serve as supportive struts, collectively
providing considerable strength, without greatly increasing the bone’s weight. (From Junqueira’s Basic Histology,
Chapter 8, Figure8-7). While cortical bone is composed
of densely packed Haversian systems, cancellous, or
spongy, bone is more loosely organized, giving it room to
house the bone marrow
Bone Metabolism
Although the tendency is to think of adult bone as
an inert tissue, nothing could be further from the
truth. Throughout adult life, there is a constant
ebb and ow of bone formation and bone resorption. These two processes are delicately balanced
and keep the skeletal mass in a state of equilibrium. A number of factors, systemic and local,
affect bone metabolism and hence impact bone
turnover and remodeling.
Perhaps the most well-dened factor is
mechanical stress, which forms the basis for the
classic Wolff’s law. Simply stated, trabecular,
and to a lesser degree cortical, bone remodels
along lines of mechanical stress. Bone forms
where it is needed to meet mechanical demands
and it is resorbed where the need is less. As a
result of the piezoelectric effect, where loaded,
that bone functions as a transducer, converting
mechanical energy from the applied load into
7
electrical energy and a voltage gradient is established. In turn, this voltage gradient, that is generated, modulates cellular differentiation (i.e.,
active osteoblasts in areas of high load, or active
osteoclasts in areas where bone is not needed).
Central to the process of bone metabolism,
and the actual system in which bone formation
and resorption occurs is called the RANK/
RANK-ligand/osteoprotegerin (OPG) pathway.
RANK (receptor activator of nuclear factor
kappa-B) is a receptor residing on the cell surface
of the immature, inactive osteoclast. RANKligand is a protein secreted by the activated osteoblast, which binds RANK and stimulates
maturation of the osteoclast, and affects bone
resorption. OPG, on the other hand, while also
produced by osteoblasts, functions as a decoy
receptor for RANK-ligand. Produced as a means
to inhibit bone resorption, OPG binds and
sequesters RANK-ligand, inhibiting activation of
osteoclasts, and “protecting bone.” Thus, as can
be inferred, osteoclast function relies on activation from osteoblasts, thus coupling these two
processes, and balancing the process of bone
metabolism (Fig.1.13).
Please see the following YouTube link (https://
www.youtube.com/watch?v=VwCkyf0lQwo&t=
231s) for video explanation of the RANK/
RANK-ligand/OPG pathway.
Clinical implications of the RANK-RANKligand-OPG system abound. Osteolytic bone
metastases, or cancer that has spread to the bones,
has been found to be mediated largely by this system, with RANK-ligand production by oncologic
cells as the presumed mechanism. In addition,
research has indicated that defects in this system
play a role in the pathogenesis of many metabolic
bone diseases, including osteoporosis (uncontrolled bone resorption), osteopetrosis (absence
of bone resorption), and Paget’s disease (excessive, coupled bone remodeling producing abnormal quality bone).
8
Osteoclast
Sclerostin Antibody
Monocyte
Fig. 1.13 The
RANK-RANKL-OPG
system. Osteoclast
function relies on
activation from
osteoblasts, thus
coupling these two
processes, and balancing
the process of bone
metabolism. (From JBJS
Current concepts
Review, A review of
osteocyte function and
the emerging importance
of sclerostin)
Denosumab
RANKL
Osteoblast
OPG
FGF 23
BMPs
M. J. Kelly and J. N. Delahay
RANKL
Osteocyte
Sclerostin
Bone Growth Factors
Much recent research has been aimed at understanding the molecular mechanisms involved in
bone growth, and many growth factors have since
been described. Bone morphogenic proteins
(BMPs), for example, are the bone-forming factors originating from the demineralized bone
products used in surgical procedures. BMPs use a
complex network of cell receptors to stimulate
differentiation of pluripotent mesenchymal stem
cells into osteoblasts, and for this reason, have
become quite popular in the eld of orthopedic
surgery. And while BMPs are the most mainstream, they are not alone in their ability to
induce osteogenic differentiation—RUNX2 and
WNT-Beta Catenin are just a few of the other
well-known growth factors affecting bone formation. SOX9, on the other hand, is a chondrogenic
growth factor, thus inducing the growth of cartilage. At this time, there remains much to learn
about the complex interplay of these growth fac-
tors and both normal growth and pathological
states of the musculoskeletal system.
Bone Circulation
Circulation of blood to the bones is critical in normal development as well as in pathological processes and healing of the musculoskeletal system
and originates from three sources: (1) nutrient artery
system, (2) periosteal system, and (3) metaphysealepiphyseal system. The nutrient artery system is
referred to as a high-pressure system, fed from
direct branches of major named arteries, and entering the medullary canal of the bone through the cortex of the diaphysis of long bones. The periosteal
system, in contrast, is a low-pressure system, supplying the outer aspect of the bone (Fig. 1.14).
Finally, the metaphyseal- epiphyseal system is a network of arteries surrounding the joints, which also
contributes circulation to the growth plate in children via the specially-named perichondral arteries.