Recent publications4-8are closing in on identifying the multiple genes underlying many important skeletal traits, such as bone mineral density, femoral strength, and vertebral den-sity..
Trang 1Biomechanics and Genes
As a traditionally trained mechanical engineer, I know that one of the ar-eas important to orthopaedics (al-though one I don’t completely under-stand) is the novel means that can be used to determine how multiple genes affect the size, strength, and stiffness of skeletal elements One of these means, which I expect will have a very important effect, is genome-wide quantitative trait link-age (QTL) analysis, done to deter-mine which parts of chromosomes and, ultimately, which genes regulate the measurable traits of the skeleton
QTL analysis is done to identify strains of animals (generally mice, but also dogs)1,2that have a range of some important measurable trait, such as femoral shaft diameter.3In mice, the technique is to crossbreed strains with extreme examples of the trait and to correlate trait magnitude with the genotype of the multigener-ational crosses of the two strains
At this point, my traditional edu-cation becomes a handicap because I can report only that the method of analysis relies on linkage analysis of genetic polymorphisms that recom-bine randomly during reproduction
Recent publications4-8are closing in
on identifying the multiple genes underlying many important skeletal traits, such as bone mineral density, femoral strength, and vertebral den-sity
However, the use of QTL analysis
is not limited to skeletal strength It has recently been applied to seeking
a genetic understanding of the super-healer mouse,9serum levels of alka-line phosphatase,10and susceptibility
to proteoglycan-induced rheumatoid arthritis.11Overall, I expect that ge-nome analysis of quantitative traits will result in profound changes in the
ability to understand the causes of and risk factors for skeletal diseases
David Fyhrie, PhD
When Stem Cells Talk
The term stem cell is applied to cells that have the capability to divide and be directed to make specific ma-trices based on the cell source and the environment of the stem cell In hematopoietic tissue, a single stem cell can be directed to form all of the blood elements However, muscu-loskeletal stem cells (MSCs) are more selective in their capacity to differentiate They can be found in marrow and any musculoskeletal tissue They do not have the wide differential capability of hematopoi-etic stem cells but to variable de-grees they can form fat, bone, carti-lage, and fibrous tissue As mature MSCs die, some can be replaced by stem cells that are tissue-appropriate Stem cells in adults do not have the capability to be
direct-ed to repair all tissue types; rather, their capabilities are dependent on the tissue origin of the cell and on the structural and biochemical envi-ronment
These factors are important in re-gard to the ability of MSCs to be di-rected to form musculoskeletal tis-sues different from their tissue of origin MSCs in fat and muscle can
be directed to form fat, cartilage, bone, and even ligaments An in vivo example of this is fracture healing,
in which the various tissues of en-chondral healing are derived in part from multipotential cells that arise from the surrounding muscle The relative success of maturation of fracture callus is based on the initial injury environment, stability, nutri-tion, and a host of other factors that can influence the direction of tissue and matrix development
David Fyhrie, PhD
Fred R.T Nelson, MD
Gary Gibson, PhD
Topics from the frontiers of basic
research presented by the Orthopaedic
Research Society.
J Am Acad Orthop Surg
2006;14:256-258
Copyright 2006 by the American
Academy of Orthopaedic Surgeons.
256 Journal of the American Academy of Orthopaedic Surgeons
Trang 2Recent research has been directed
at determining the growth factors
and cytokines produced by stem
cells that provide
immunosuppres-sion and that can direct the
differen-tiation and type of tissue formed by
other stem cells.12The importance
of stem cell cytokine expression has
also been studied in heart infarcts13
and cell repopulation after stroke.14
A sheep model of meniscal injury
and anterior cruciate ligament
inju-ry was used to determine the effects
of MSCs from bone marrow that
were expanded in tissue cultures
Af-ter serial passage, 10 million
autolo-gous cells were injected into the
joint 6 weeks following meniscal
and anterior cruciate resection
Me-niscal regeneration and diminished
osteophytic remodeling were seen in
the cell-injected animals versus
those that received the hyaluronic
acid vehicle only.15The importance
of this MSC research is the concept
that stem cell signaling to
neighbor-ing stem cells can create an in vivo
“tissue engineering” effect
Fred R.T Nelson, MD
RAGE Causes a Change
in Chondrocyte
Personality
Increased chondrocyte activity,
char-acterized by increased expression of
matrix proteins, degradative
en-zymes, and other genes commonly
observed in immature cartilage, is
characteristic of osteoarthritic
artic-ular cartilage and generally is
con-sidered to be a critical part of its
deg-radation Some chondrocytes in
osteoarthritic cartilage are nearly
al-ways observed to express a
pheno-type normally seen only in
hyper-trophic chondrocytes of the growth
plates Although the role that
ex-pression of the hypertrophic
pheno-type plays in cartilage degeneration
remains to be determined, it has
been reasonably suggested that
hy-pertrophic differentiation would
lead to damaging, growth plate–like
characteristics These include
inferi-or mechanical properties, cartilage mineralization, and cartilage thin-ning resulting from subchondral vas-cular invasion
A recent publication provides a surprising explanation of the mech-anism of articular chondrocyte hy-pertrophy and also links chondrocyte hypertrophy with inflammatory and aging processes Cecil et al16 have shown that stimulation of the recep-tor for advanced glycation end prod-ucts (RAGE) on the chondrocyte sur-face causes chondrocyte hypertrophic differentiation Addition of S100A11 protein, a known RAGE ligand and mild inflammatory agent, caused RAGE-dependent hypertrophic dif-ferentiation of human articular chon-drocytes in culture Expression of both RAGE and S100A11 was also shown to be increased in osteoar-thritic articular cartilage.16
As the name suggests, RAGE was first characterized as the receptor for advanced glycation end products (AGEs) AGEs are complex chemical modifications of proteins that result from prolonged exposure to glucose
or other sugars They accumulate in many tissues, including articular cartilage, in increasing amounts with chronological age and are seen
as tissue yellowing Unpublished ob-servations cited in the paper16 indi-cate that AGEs also stimulate RAGE-dependent hypertrophy
The studies show that hyper-trophic differentiation in articular cartilage is RAGE-dependent and can be caused by release of mild in-flammatory agents, such as S100A11
or AGEs Chondrocyte hypertrophic differentiation is one example of chondrocyte activation seen in os-teoarthritic cartilage The publica-tion of this paper suggests that we are one step closer to understanding the mechanisms generating chon-drocyte activation and are one step closer to designing therapeutic agents aimed at preventing or atten-uating activation of chondrocytes
Gary Gibson, PhD
References
1 Chase K, Adler FR, Miller-Stebbings
K, Lark KG: Teaching a new dog old tricks: Identifying quantitative trait loci using lessons from plants.
J Hered1999;90:43-51.
2 Chase K, Carrier DR, Adler FR, et al: Genetic basis for systems of skeletal quantitative traits: Principal compo-nent analysis of the canid skeleton.
Proc Natl Acad Sci U S A2002;99: 9930-9935.
3 Klein RF, Turner RJ, Skinner LD, et al: Mapping quantitative trait loci that influence femoral cross-sectional area
in mice J Bone Miner Res 2002;17:
1752-1760.
4 Koller DL, Schriefer J, Sun Q, et al: Genetic effects for femoral biome-chanics, structure, and density in C57BL/6J and C3H/HeJ inbred mouse
strains J Bone Miner Res 2003;18:
1758-1765.
5 Turner CH, Sun Q, Schriefer J, et al: Congenic mice reveal sex-specific ge-netic regulation of femoral structure
and strength Calcif Tissue Int 2003;
73:297-303.
6 Bouxsein ML, Uchiyama T, Rosen CJ,
et al: Mapping quantitative trait loci for vertebral trabecular bone volume fraction and microarchitecture in
mice J Bone Miner Res
2004;19:587-599.
7 Edderkaoui B, Baylink DJ, Beamer
WG, et al: Multiple genetic loci from CAST/EiJ Chromosome 1 affect vBMD either positively or negatively
in a C57BL/6J background J Bone
Miner Res2006;21:97-104.
8 Ishimori N, Li R, Walsh KA, et al: Quantitative trait loci that determine BMD in C57BL/6J and 129S1/SvImJ
inbred mice J Bone Miner Res 2006;
21:105-112.
9 Yu H, Mohan S, Masinde GL, et al: Mapping the dominant wound heal-ing and soft tissue regeneration QTL
in MRL x CAST Mamm Genome
2005;16:918-924.
10 Srivastava AK, Masinde G, Yu H, et al: Mapping quantitative trait loci that influence blood levels of alkaline phosphatase in MRL/MpJ and SJL/J
mice Bone 2004;35:1086-1094.
11 Adarichev VA, Nesterovitch AB, Bar-dos T, et al: Sex effect on clinical and immunologic quantitative trait loci
in a murine model of rheumatoid
ar-thritis Arthritis Rheum 2003;48:
1708-1720.
12 Corcione A, Benvenuto F, Ferretti E,
et al: Human mesenchymal stem cells
modulate B-cell functions Blood
2006;107:367-372.
Volume 14, Number 4, April 2006 257
Trang 313 Urbanek K, Torella D, Sheikh F, et al:
Myocardial regeneration by
activa-tion of multipotent cardiac stem cells
in ischemic heart failure Proc Natl
Acad Sci U S A2005;102:8692-8697.
14 Kawada H, Takizawa S, Takanashi T,
et al: Administration of
hematopoiet-ic cytokines in the subacute phase
af-ter cerebral infarction is effective for functional recovery facilitating prolif-eration of intrinsic neural stem/
progenitor cells and transition of bone marrow-derived neuronal cells.
Circulation2006;113:701-710.
15 Murphy JM, Fink DJ, Hunziker EB, Barry FP: Stem cell therapy in a
cap-rine model of osteoarthritis.
Arthritis Rheum2003;48:3464-3474.
16 Cecil DL, Johnson K, Rediske J, Lotz
M, Schmidt AM, Terkeltaub R: Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products.
J Immunol2005;175:8296-8302.
258 Journal of the American Academy of Orthopaedic Surgeons