Fracture healing is the most com-mon and recognizable form of bone regeneration, but several other examples of bone regeneration have been observed in humans, suggesting that the abil-
Trang 1Regeneration is defined as the
reconstitution or restoration of a
body part, tissue, or substance,
whether in response to injury or as
a normal bodily process Only
two tissues in humans possess
sig-nificant regenerative capacity—
bone and liver All other tissues,
when damaged, heal with the
for-mation of scar, leaving a mark of
new fibrous connective tissue that
replaces the injured structure The
limitation of scar tissue is that it
does not possess the biomechani-cal, physibiomechani-cal, and functional prop-erties of the original tissue Thus, regeneration is a specialized repair process that confers a biologic privilege on those tissues that pos-sess it
There is a large amount of infor-mation known about bone regener-ation as it occurs in fracture heal-ing, which is a normal process in all vertebrate animals Over the past several decades, methods of
controlling bone regeneration (e.g., limb-lengthening procedures and technologies) have been developed Subsequently, the cellular and mol-ecular bases for bone regeneration have been established, especially as regards the role of the bone mor-phogenetic proteins (BMPs) There
is recent evidence for the clinical efficacy of at least one of these tech-nologies The description of the pathophysiology of fibrodysplasia ossificans progressiva, a rare
genet-ic disease characterized by the spontaneous formation of hetero-topic bone, highlights the immense capacity inherent for postnatal bone formation in human connec-tive tissues
Dr Einhorn is Chairman and Professor, Department of Orthopaedic Surgery, Boston University School of Medicine, Boston, Mass.
Dr Lee is Orthopaedic Surgery Resident, Bowman-Gray School of Medicine, Winston-Salem, NC.
One or more of the authors or the departments with which they are affiliated have received something of value from a commercial or other party related directly or indirectly to the sub-ject of this article.
Reprint requests: Dr Einhorn, Doctors Office Building, Suite 808, 720 Harrison Avenue, Boston, MA 02118.
Copyright 2001 by the American Academy of Orthopaedic Surgeons.
Abstract
Bone is a biologically privileged tissue in that it has the capacity to undergo
regeneration as part of a repair process Fracture healing is the most
com-mon and recognizable form of bone regeneration, but several other examples
of bone regeneration have been observed in humans, suggesting that the
abil-ity to regulate bone regeneration as a therapeutic tool should be possible.
Historically, efforts at limb lengthening have led to procedures for
regenerat-ing bone, such as the method of Ilizarov This procedure, known as
distrac-tion osteogenesis, has applicadistrac-tions in a variety of skeletal condidistrac-tions,
includ-ing the restoration of large skeletal defects, the transport of bone in cases of
severe trauma with bone loss, and the correction of skeletal deformities.
Fibrodysplasia ossificans progressiva is an example of how an abnormal
metabolic condition can be viewed as evidence for the capacity of humans to
regenerate large amounts of bone if the cellular and molecular signaling
events are altered Elucidation of the cellular and molecular basis for bone
regeneration in humans—particularly the role of the human genome in
rela-tion to the expression of various growth factors and cytokines, such as the
bone morphogenetic proteins—offers great potential for the treatment of
orthopaedic conditions Development of specific bone morphogenetic proteins
as therapeutic substances to induce bone regeneration in patients is well
under way As methods for enhancing fracture healing, distraction
osteogen-esis, and other procedures are refined, the development of protein- and
gene-based therapies for regulating bone formation should lead to a new era of
orthopaedic practice.
J Am Acad Orthop Surg 2001;9:157-165
Bone Regeneration:
New Findings and Potential Clinical Applications
Thomas A Einhorn, MD, and Cassandra A Lee, MD
Trang 2Fracture Healing
Fracture healing is a form of bone
regeneration, in that it results in
functional bone tissue with all the
properties that were originally
pres-ent in the uninjured bone There are
four distinct tissue responses that
can occur in fracture healing These
responses are produced by the bone
marrow, the bone cortex, the
perios-teum, and the external soft tissues
Depending on the manner in which
the fracture is treated, these
re-sponses can occur singly, or two or
more can occur simultaneously
The bone marrow response begins
with a loss of its normal architecture
In the region adjacent to the fracture
hematoma, cellular components
un-dergo reorganization into regions of
high and low density In the region
of highest density, endothelial cells
transform into polymorphic cells,
which express an osteoblastic
pheno-type.1 These cells form bone within a
few days after fracture Interestingly,
the bone marrow response occurs
independent of the mechanical strain
environment or the method by which
the fracture is treated.2
The cortical response is
deter-mined by the type of fracture
heal-ing that takes place Two types
have been recognized In primary
fracture healing, the cortex attempts
to reestablish itself without the
formation of a callus This type of
healing occurs only when the
frac-ture is anatomically reduced and
stabilized by rigid internal fixation
A tunneling resorptive response
occurs, whereby new haversian
sys-tems are established to allow
pene-tration of blood vessels into the area
of the fracture Perivascular
mes-enchymal cells and endothelial cells
accompany these newly formed
vessels and differentiate into
osteo-progenitor cells.3 In contrast,
sec-ondary fracture healing results in
the formation of a callus and
in-volves the participation of the
peri-osteum and external soft tissues
The cortex is enveloped by the process but is not involved in a direct response This fracture heal-ing response is enhanced by motion and is inhibited by rigid fixation.3 During fracture healing, the se-quential events of tissue develop-ment occur, leading to the regenera-tion of funcregenera-tional osseous tissue
The immediate response to injury includes hematoma formation, in-flammation and angiogenesis, carti-lage formation with subsequent cal-cification, and cartilage removal accompanied by bone formation
After this last step, bone remodeling begins; this leads to the restoration
of the load-carrying capability of the bone
The surrounding soft tissue may also contribute to fracture healing
Rapid cellular activity and the de-velopment of an early bridging cal-lus help to stabilize the fracture fragments This process, like the periosteal response, may be affected
by mechanical factors and hindered
by rigid immobilization.3 Intramembranous ossification (the direct formation of bone from committed osteoprogenitor cells) contributes to the formation of a hard callus at the periphery of the fracture Endochondral ossification (the indirect formation of bone from uncommitted mesenchymal cells) occurs adjacent to the fracture site and contributes to the formation of
a soft callus During this process, cells differentiate to chondrocytes;
a cartilage anlage forms, undergoes calcification, and is ultimately re-placed by bone
The response to fracture injury involves disruption of the normal vasculature, infiltration of inflam-matory cells, and release of a multi-tude of cytokines and peptide signal-ing molecules The first detectable factors released during this response are platelet-derived growth factor and transforming growth factor-β (TGF-β).4 Other BMPs and their receptors that are also expressed are
likely important in this reparative response Macrophages and other inflammatory cells release proin-flammatory cytokines, such as inter-leukin-1, tumor necrosis factor-α, and interleukin-6.5 These events of bone repair form the fundamental basis by which bone regeneration can be viewed as a naturally occurring clini-cal process
Limb Lengthening and Bone Transport
The first successful attempt at thera-peutic human bone regeneration in humans was reported by Codivilla
in 1905 As part of a strategy to lengthen shortened limbs, he created
an osteotomy through the cortex of the femur and the tibia and induced tractional forces with the use of a calcaneal pin In 22 cases, the gain
in length was between 3 and 8 cm
In 1908, Magnuson reported suc-cessful human femoral lengthening, which was achieved by creating a median longitudinal step-cut osteot-omy The proximal segment was fixed, and the distal segment was attached to a pulley-weight system that accomplished 2- to 3-inch lengthenings in 5 minutes Once the desired length and alignment had been achieved, the fragments were fixed with screws
In 1913, Ombredanne was the first to use an external fixator for limb lengthening, but unfortunately complications of skin necrosis and infection arose It was not until
1927 that Abbott introduced the concept of a latency period to pro-mote formation of bone prior to dis-traction Current thinking suggests that the latency period provides time for the initial phases of bone repair to take place at the osteotomy site, resulting in a mechanically compliant callus, restoration of the blood supply by means of revascu-larization, and initiation of the bone regeneration sequence.6
Trang 3The procedure of distraction
os-teogenesis for bone regeneration
was refined by Ilizarov.6 Perhaps
more than any other development
in medical history, the Ilizarov
method shows how bone
regenera-tion is possible in humans The
so-called low-energy osteotomy of the
cortex was suggested by Ilizarov to
be critical to the success of the
pro-cedure Although it is possible to
perform the osteotomy at any site,
the metaphysis is ideal, in that it
offers good stability because of the
thin cortex and large trabecular
sur-face and is endowed with excellent
blood flow from an extensive
sys-tem of collateral vessels.6 The latency
period prior to distraction ranges
from 3 to 10 days (a shorter period
for metaphyseal osteotomies and a
longer period for diaphyseal
oste-otomies) Distraction varies with
respect to rate and rhythm, ranging
from 0.5 to 2.0 mm/day and from
one to four distractions per day
During distraction osteogenesis,
angiogenesis precedes ossification,
and bone is formed by
intramem-branous ossification Blood vessels
are abundant where new bone is
formed and sparse in regions of
ma-ture bone It has been established
that the distraction rate affects the
angiogenic response, and that a rate
of 0.7 to 1.3 mm/day leads to
opti-mal bone formation.7
Because distraction osteogenesis
involves gradual distraction with
protection of adjacent joints,
pa-tients have the ability to perform
activities of daily living while
un-dergoing extended lengthening
pro-cedures Several sites can be
length-ened simultaneously to correct
de-formities or to shorten the overall
period of distraction.8 Most
impor-tant, patients with large skeletal
defects who undergo this procedure
can be treated without the need for
bone grafting, internal fixation, or
multiple operations Although a
number of problems and
complica-tions are associated with this
proce-dure, it is exceptionally effective when used as a means of bone re-generation.8
An innovative method for the treatment of segmental defects caused by trauma, infection, or tumor resection was also devised by Ilizarov.9 In this procedure, an oste-otomy is created proximal to the de-fect, and the intervening segment of bone is transported distally (Fig 1)
To be successful, the segment to be transported must possess an ade-quate blood supply so that bone for-mation can be induced at its trailing end and healing supported at its leading end In addition, the micro-environment at the docking site must support healing With Iliza-rov’s ring fixator, a bone segment can be transported in any direction with use of a system of pulling
wires and transverse tension wires
or half-pins Multiple bone seg-ments can be transported in the same or opposite directions to facili-tate bone regeneration in the de-fect.10 In some cases, autogenous bone grafting is necessary to en-hance healing at the docking site The methods of limb lengthening and bone transport as described by Ilizarov and others have enjoyed substantial clinical success with regard to bone regeneration This success vividly demonstrates the tremendous capacity for regenera-tion inherent in the human skeleton Now that scientists possess the tools
to investigate the molecular basis for these phenomena, it should be possible to develop more refined methods to produce and control regeneration of the skeleton
Figure 1 Lateral radiographs of the leg of a patient who underwent single-level proximal-to-distal transport because of bone loss after a gunshot injury A three-ring apparatus was applied to the tibia, with a corticotomy at the proximal end and the transport ring at the dis-tal end; after transport, the transport fragment was docked with the bone on the opposite
side of the defect A, One month after osteotomy B, At 3 months after osteotomy, the transport segment tilted posteriorly as the pins bent C, At 6 months, the docking site was reduced in an open procedure, and the bone was grafted D, Radiograph obtained shortly
after removal of the apparatus at 10 months Two years after removal, the anatomic and functional results were excellent (Reproduced with permission from Paley D, Maar DC:
Ilizarov bone transport treatment for tibial defects J Orthop Trauma 2000;14:76-85.)
Trang 4Biologic Basis of Bone
Regeneration
In 1965, Urist observed that
im-plantation of demineralized bone
matrix at a heterotopic site led to
the formation of a new ossicle with
a hematopoietic marrow cavity.11
In doing so, he introduced the
con-cept of postfetal osteogenesis by a
process known as bone induction
Over the course of the next 35
years, decalcified segments of
di-aphyseal bone were implanted into
muscle pouches in rats,12ulnar
de-fects in rabbits,13lumbar sites in
dogs,14and various sites in humans
with certain skeletal disorders.15,16
The process of bone induction
be-gins with the formation of loose
fibrous connective tissue, which is
highly vascular and infiltrated with
macrophages, lymphocytes, and
fibroblasts The process of
endo-chondral ossification ensues, in
which bone formation gives way to
bone remodeling Bone
morpho-genetic proteins have been shown to
exist within the bone matrix and to
be responsible for this phenomenon
It is now known that the BMPs
com-prise a family of molecules, each
with its own function
Bone morphogenetic proteins
are members of the TGF-β
super-family of proteins but differ from
other TGF-β family members in
that some have more selective
effects on bone Bone
morphoge-netic proteins are highly conserved
from Drosophila (fruit fly) to humans
and have been shown to induce
proliferation and differentiation of
mesenchymal stem cells to both
chondrocytes and osteoblasts
Ge-netic and experimental evidence
supports an even more diverse
reg-ulatory role for BMPs in biologic
processes, ranging from cell
prolif-eration to apoptosis to
differentia-tion to morphogenesis They
in-duce de novo bone formation by
means of endochondral
ossifica-tion At high concentration, BMPs
may form bone directly by intra-membranous bone formation.17 The current concept of the role of BMPs is that they are key modula-tors of osteoprogenitor and mes-enchymal cells throughout the frac-ture healing process Levels of BMP expression, particularly that of BMP-2, decrease as precursor cells mature A transient spike in BMP expression occurs as mature chon-drocytes and osteoblasts lay down their respective extracellular matri-ces, but levels decrease during cal-lus remodeling.18 Although mature osteoblasts and chondrocytes do not normally express large amounts
of BMP, they do show increased
ex-pression later in the course of frac-ture healing
Recent studies in rats have shown that, during fracture repair, chondrocytes and osteoblasts ex-hibit “up-regulated” expression of certain BMPs Shortly after the fracture event, a small amount of those BMPs is released from the ex-tracellular matrix of bone Osteo-progenitor cells in the adjacent periosteum differentiate in re-sponse to this initial release, and BMP-4 levels transiently increase.19 Within this region, BMP-2 and BMP-4 appear to drive osteoprogeni-tor cells to mature into osteoblasts,
as evidenced by up-regulation of
Definitions of Specialized Terms
hormone function (i.e., the hormone is synthesized and released by an endocrine cell and binds to a receptor on a nearby cell
of the same type) Down-regulation Development of a state in which there is a
decrease in the number of receptors for a pharmacologic or physiologic substance on the cell surfaces in a given area, such that the cells in that area become less reactive to it
in which the effects of a hormone are restricted to the local environment (i.e., the hormone is synthesized and released by an endocrine cell and binds to a receptor on a nearby cell of a different type)
of DNA Up-regulation Development of a state in which there is
an increase in the number of receptors for
a pharmacologic or physiologic substance
on the cell surfaces in a given area, such that the cells in that area become more reactive to it
sequences on the 5' side of a gene or region
of interest
Trang 5BMP-2, BMP-4, and BMP-7 in the
mesenchymal cells that infiltrate
the fracture site.20 By 7 to 14 days
after fracture, BMP-2 and BMP-4
are at maximal levels in
chondro-cyte precursors but at minimal
lev-els in hypertrophic chondrocytes
and osteoblasts Once the fracture
heals, overall BMP expression is
re-duced
The precise mechanisms by
which BMPs induce ectopic
endo-chondral bone or even normal bone
development are still unknown It
is possible that BMPs stimulate
undifferentiated pluripotent stem
cells to follow chondrogenic and
osteogenic lineages over adipogenic
or myogenic pathways.21
Alterna-tively, BMPs may stimulate
chon-drogenic and osteogenic lineages
directly while inducing apoptosis in
adipogenic and myogenic cells.22
There is particular interest in the
potential role of BMP-2 and BMP-7
as therapeutic molecules Both have
been isolated, sequenced, and
syn-thesized by using recombinant
DNA technology, and both are
cur-rently under study in human
clini-cal trials Recombinant human
BMP-2 (rhBMP-2) and osteogenic
protein-1 (rhOP-1, which is
analo-gous to rhBMP-7) have been used
successfully to heal critical-sized
defects (i.e., osseous defects that, by
virtue of their size, will not heal
spontaneously) in both the
ap-pendicular and the
craniomaxillofa-cial skeleton in various animal
spe-cies.13,18,23 However, for the rhBMPs
to produce in vivo effects in
hu-mans, they must be implanted in an
adequate delivery system Such a
delivery system is essential to
main-tain the concentration of BMP at the
implantation site and to present the
molecule to responding cells In
combination with a demineralized
bone matrix carrier, rhBMP-2 is
capable of inducing bone formation
in a 5-mm rat femur defect in a
dose-dependent manner.23 Similar
results were obtained with the related
protein BMP-7 in 1.5-cm ulnar de-fects in rabbits.13 These reports, as well as others, have generated en-thusiasm for the use of BMPs in clinical applications in which bone regeneration is needed However,
as this field of research enters its 36th year, a reliable BMP-based ther-apy has not yet become available
Use of BMP for Bone Regeneration
The first study to demonstrate the clinical utility of a BMP in a critical-sized defect in humans tested the effectiveness of rhOP-1 combined with a type 1 collagen carrier24 (Fig 2) A randomized, double-blind
Figure 2 Top, Radiographs showing a fibular defect after implantation of type 1 collagen at
4 months, 6 months, and 1 year There was no substantial formation of new bone or
bridg-ing at any time Bottom, Radiographs showbridg-ing a fibular defect after implantation of rhOP-1.
There was substantial formation of bone with bridging at 4 months, more at 6 months, and bone formation and remodeling after 1 year (Courtesy of Stryker Biotech, Hopkinton, Mass.)
Trang 6prospective study was conducted in
24 patients who underwent high
tibial osteotomy in which a fibular
defect was created to enhance the
healing of the osteotomy and to
serve as the implantation site for
the test materials First, the
investi-gators validated the model of the
critical-sized fibular defect by using
demineralized bone matrix and
untreated control defects The
untreated defects showed no
pro-gression toward union, but in the
demineralized bone matrix group,
bone was formed in the defect from
6 weeks onward In the second
phase of the experiment, the
investi-gators compared the osteogenic
potential of rhOP-1 combined with a
type 1 collagen carrier against type 1
collagen alone There was no
forma-tion of new bone when collagen
alone was used; however, in the
rhOP-1 group, all but 1 patient
showed formation of new bone from
6 weeks onward These findings
suggest that rhOP-1 is osteogenic
and capable of regenerating bone in
humans
Use of Gene Therapy for
Bone Regeneration
Many of the diseases that
orthopae-dic surgeons treat involve the
fail-ure of molecular signals, including
those arising from growth factors
and cytokines Deficiencies,
includ-ing molecular signalinclud-ing defects, are
potentially correctable with gene
therapy Gene therapy has been
attempted in heritable genetic
dis-eases, as well as in acquired diseases
Most diseases, however, would
require changes in many genes and
gene products for expression to
occur, and thus cannot be cured by
substitution of one normal gene
To increase the efficiency of
trans-ferring a gene into a cell, the DNA
fragment encoding the therapeutic
gene is often introduced within a
delivery vehicle called a vector
Be-cause viruses have the ability to en-ter cells and manipulate the cellular machinery of the host, they have been used as vectors in gene therapy protocols To make viral vectors, vi-ruses are modified to directly deliver the genetic material without the ability to replicate The most com-mon viral vectors are retroviruses, adeno-associated viruses, adenovi-ruses, and herpes simplex viruses
The retrovirus is the best-developed viral vector It is able to accommo-date up to 8 kilobases (kb) of genetic material, but inserts it at random locations in the host chromosome
Adeno-associated viruses are able to insert at specific sites and infect nondividing cells, but are able to accommodate only 4 kb of genetic material Adenoviruses are nonin-tegrating viruses that show high ini-tial genetic expression, which rapidly tapers off These viruses can infect both dividing and nondividing cells, but are immunogenic because they produce adenoviral proteins Herpes simplex virus, unlike the other vec-tors, is able to accommodate ex-tremely large segments of genetic material It can infect nondividing cells but can be cytotoxic and can show transient gene expression.25 Successful gene therapy requires the gene to be expressed at an ap-propriate level, at the right time, and
in the right place This can be ac-complished with the help of so-called promoters Promoters are regulatory regions in the DNA, usu-ally situated upstream of the gene, that can both up-regulate and down-regulate gene expression in response
to temporal and environmental cues
The most common promoters used
in gene therapy are borrowed from cytomegalovirus and simian virus
40 However, although these pro-moters are typically strong effectors
of gene expression, they tend to shut down production quickly
Animal studies have shown that demineralized bone matrix, rhBMP-2, and rhBMP-7 can be used to repair
critical-sized segmental defects under ideal laboratory conditions However, these research models rarely mimic the clinical situation,
in which defects are often large and healing is hampered by impaired vascularity and scar tissue in the de-fect Current delivery system tech-nology is limited in that there is no control of the duration of the delivery
of BMP However, genetically ma-nipulated bone marrow cells could serve as an effective delivery vehicle Lieberman et al26tested the effi-cacy of delivery of the BMP-2 gene to
a critical-sized bone defect site by means of adenoviral transformation
of autologous bone marrow cells ex vivo Five groups of rats with critical-sized segmental femoral defects were treated with BMP-2–transformed bone marrow cells, rhBMP-2 in a demineralized bone matrix delivery vehicle, or three different types of control materials Twenty-two of 24 defects in the gene therapy group and all of the defects in the rhBMP-2 group healed after 2 months, as mea-sured by radiographic criteria However, while rhBMP-2 protein delivery and transformed bone mar-row cells showed equivalent effects
in healing of the defects, those defects treated with genetically engineered cells showed advanced callus re-modeling (Fig 3)
Genetically engineered pluripo-tent mesenchymal stem cells have also been used to deliver the BMP-2 gene to a segmental defect These cells express the transgene in the segmental defect, and the resultant protein affects responding cells in the microenvironment (paracrine effect) This strategy also induces a positive feedback signal to the cells themselves to produce more of the transgene (autocrine effect) Thus, use of cell-mediated gene transfer can induce both autocrine and paracrine activities
Using this approach, Gazit et al27 compared the effects of BMP-2– engineered mesenchymal stem cells
Trang 7with those of “wild-type” cells—
specifically, nonprogenitor cells
en-gineered to express BMP-2 and
rhBMP-2 protein Cells were
deliv-ered on a collagen sponge to 2.5-mm
radial defects in mice Both types of
cells were able to secrete the BMP-2
protein, thus exhibiting a paracrine
function However, the engineered
mesenchymal stem cells also exhibited
autocrine function by differentiating
spontaneously into osteogenic cells
In contrast, wild-type cells
differen-tiated only when exogenous rhBMP-2
was added The pure protein caused
new bone formation but did not
bridge the gap as effectively as the
BMP-2–producing cells did In this
model, engineered pluripotent
mes-enchymal stem cells were shown to
have greater therapeutic potential
than engineered nonmesenchymal
cells, nonengineered pluripotent
mesenchymal cells, or purified
rhBMP-2 protein
Lessons Learned From a Rare Disease
The abundance of information from preclinical studies suggests that ani-mals are capable of musculoskeletal tissue regeneration, particularly the formation of cartilage and bone
However, the application of this in-formation to patient care has yet to
be realized Two lines of clinical evidence suggest that the human organism is fully capable of sub-stantial bone regeneration The first
is the observation that slow, steady distraction of an osteotomy, as cre-ated with use of the method of Il-izarov, can regenerate substantial amounts of new bone The other de-rives from our growing knowledge about the rare but well-recognized metabolic disease fibrodysplasia ossificans progressiva (FOP)
In patients with FOP, musculo-skeletal tissues ossify and form
bone in orthotopic and heterotopic sites (Fig 4) For example, injury
or activation of undifferentiated mesenchymal cells in fascial planes will lead to the ossification of mus-cles; this has been observed in the biceps, iliopsoas, and other muscles
of the appendicular skeleton Shafritz et al,28in an immunohis-tochemistry study, showed that the lymphocytes of 11 of 12 patients with FOP demonstrated overex-pression of BMP-4, compared with only 2 of 26 control subjects It was shown further that BMP-4 is the only member of the BMP family that demonstrates this effect, and that lymphocytes capable of BMP-4 expression circulate in the peripheral blood of patients with FOP Thus, lymphocytes capable of expressing this morphogen may be recruited to sites of connective tissue injury, where they may release BMP pro-tein Type IV collagen, a major
Figure 3 Radiographs showing critical-sized femoral defects 2 months after treatment with five different materials: A, BMP-2–producing bone marrow cells; B, rhBMP-2; C, β-galactosidase–producing rat bone marrow cells; D, noninfected rat bone marrow cells; and E,
de-mineralized bone matrix alone Note that the rhBMP-2–treated defects show lacelike trabecular bone filling the defect Defects treated with the BMP-2–producing bone marrow cells showed a dense, coarse trabecular framework, which remodeled to form a new cortex None of the other treatment groups showed healing (Reproduced with permission from Lieberman JR, Daluiski A, Stevenson S, et al: The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral
defects in rats J Bone Joint Surg Am 1999;81:905-917.)
Trang 8ponent of the basement membrane
of endothelial and muscle cells, avidly binds BMP-4, resulting in a local increase in BMP-4 concentra-tion At high concentrations, BMP-4 acts as a morphogen and is capable
of up-regulating its own expression, which leads to the development of preosseous fibroproliferative lesions
These findings suggest that there
is a definable human response to BMP-4 expression as long as that expression is delivered to the re-sponding cell in the appropriate way—in the case of FOP, by a lym-phocyte Although the bone formed
in this disease is unwanted, the observation that cell-mediated ex-pression of a morphogen leads to substantial bone regeneration in humans is compelling
Summary
Orthopaedic surgeons tend to re-gard the use of molecular and gene treatment strategies as future
pro-tocols for regeneration of the tis-sues that they treat every day— bone, cartilage, muscle, tendon, and ligament However, the body does not naturally form tissues in
an isolated fashion Development
of the human organism,
particular-ly during embryogenesis, involves the simultaneous formation and modeling of several tissues and organs It has recently been discov-ered that various BMPs affect not only bone and cartilage develop-ment, but also the formation of the kidneys, heart, skin, eyes, and other tissues This suggests that BMPs are not entirely within the domain
of the musculoskeletal system, but rather are a linkage of that system
to others that constitute the human organism The ability to under-stand and harness this power holds unlimited potential for the treat-ment of skeletal and nonskeletal in-juries and diseases Indeed, the next generation of scientific discovery could yield substantial advances in patient care
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