EU_Musc_Nimni.qxp 1/5/08 11:38 Page 87
Cartilage
Bone Morphogenetic Protein-2, Cartilage Metabolism and Osteoarthritis
a report by
Marcel Nimni and Bo Han
Tissue Engineering Laboratory, Department of Surgery, University of Southern California
Adult Cartilage and Osteoarthritis mice.
12
Similar localisation is observed in human cartilage lesions,
13
Cartilage is a unique tissue. It is exposed to significant mechanical stress suggesting that BMP-2 is upregulated in injured areas such as those
during the lifetime of an individual, yet its component cells, the induced mechanically or by stimulation with agents such as interleukin
chondrocytes, are never replaced if injured. Following a stage of (IL)-1 or tumour necrosis factor-alpha (TNF-α).
14,15
Blocking BMP activity
hyperplasia during early development, they cease to divide. These cells after IL-1-induced cartilage damage prevented the natural reparative
are essentially permanent; mitosis is never seen except for when damage response displayed by chondrocytes. Exogenous BMP-2 supports the
occurs. It also seems as if any new cell arising after injury presents with expression of collagen type II and aggrecan in monolayer chondrocyte
an altered phenotypic expression and never integrates into the existing cultures, slowing the dedifferentiation that occurs under these
cartilage matrix. The proteoglycans, heterogeneous in nature, exhibit a circumstances.
16
BMP-2 increases proteglycan and collagen synthesis in
half-life (T
1/2
) of 3.5 years for their faster turnover components, and an healthy and damaged cartilage.
12
estimated 25 years for others.
1
Collagen, the fibrous component of the
matrix, shows an almost insignificant turnover in mature cartilage. During It has been well established that the injection of recombinant human
the early stages of the degenerative process associated with osteoarthritis BMP-2 (rhBMP-2) alone into muscle tissue is sufficient for the induction
(OA), turnover is markedly accelerated and the proteglycans are readily of ectopic bone formation.
17
On the other hand, BMP-2 has been
depleted. Even though the rates of synthesis of collagen, proteoglycans demonstrated to be a potent regulator of chondrocyte metabolism and
and hyaluronan are all increased, they do not seem to be able to differentiation.
18,19
BMP-2 is found to be upregulated in osteoarthritic
compensate for the greatly enhanced catabolic activities. These concepts chondrocytes and diseased cartilage.
13
These findings suggest that BMP-
have been discussed recently.
2
2 can act as a stimulus of anabolic activities in normal and osteoarthritic
chondrocytes. In turn, BMP-2 increases the synthesis of chondrocyte
Anabolic Effects and Bone Morphogenetic extracellular molecules, aggrecan and type II collagen.
Proteins in Cartilage
Growth and differentiation factors that regulate cartilage development are It appears to be clear that the steady-state homeostasis of cartilage
considered to be positive regulators of homeostasis of mature articular requires a balance between anabolic morphogens, such as cartilage-
cartilage due to their capacity to stimulate chondrocyte anabolic activity and, derived MPs (CDMPs) and BMPs, and cytokines such as IL-1, IL-7 and
in some cases, inhibit catabolic activity. The most well characterised anabolic TNF-α.
20
BMP-2 acts as a stimulus of anabolic activities in normal and
factors in the context of their production and action in articular cartilage osteoarthritic chondrocytes.
13
Furthermore, the pro-inflammatory
include insulin-like growth factor-1 (IGF-1) and bone morphogenetic cytokines IL1 and TNF-α, known to be present in the synovium and
proteins (BMPs). This article focuses on the potential of BMP-2 and other cartilage of patients with OA, stimulate the production of active BMP-2.
related growth factors of the transforming growth factor (TGF)-β family to This interplay may be significant in terms of tissue regeneration. The
prevent and reverse the biochemical changes that lead to cartilage expression of BMP in OA cartilage seems to be an anabolic response to
destruction in OA.
BMPs represent a series of multifunctional growth factors that belong to the
Marcel Nimni is a Professor of Surgery, Biochemistry and
Molecular Biology and Orthopaedics at the Keck School of
transforming factor-β superfamily. Such factors are necessary for cartilage Medicine, University of Southern California. His research focus
and bone formation during embryonic and skeletal development.
3–5
The lack
is on the structure and function of collagen, its biosynthesis
and its relationship to tissue repair. Recently, Dr Nimni has
of BMP signalling in mice results in a loss of cartilage.
6
BMPs and other
been working on nutrients involved in the metabolism of
anabolic factors that support cartilage matrix biosynthesis show declining connective tissues.
levels with ageing or their activities are downregulated.
7
The capacity of
E:nimni007@aol.com
BMP-6 to stimulate proteoglycan synthesis and the production of BMP-7
declines with age, and reduced TGF-βsignalling in ageing chondrocytes may
Bo Han is an Assistant Professor of Surgery and Biomedical Engineering at the Keck School of
Medicine, University of Southern California. The focus of her research is in the area of bone
contribute to a decreased cartilage repair capacity.
8,9
BMP-2, in particular, is
and cartilage metabolism, with a particular emphasis on the role of growth factors such as
required for cartilage maintenance and is able to stimulate cartilage repair in bone morphogenetic proteins and other enhancing factors. She has developed modalities to
defects filled with collagen sponges
10
and to improve the properties of such
biosynthesise novel targeted recombinant growth factors and to assay for their biological
activities in a variety of systems. Dr Han is currently working on the bioengineering of
newly synthesised cartilage.
11
implantable matrices used to repair damaged connective tissues, and evaluating the role of
macromolecules and adjuvant factors in enhancing such processes.
Levels of BMP-2 in healthy cartilage tend to be low, but it is actively E: bohan@usc.edu
expressed in areas surrounding damage or in osteoarthritic lesions in
© TOUCH BRIEFINGS 2008 87
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