Cơ chế sinh học và Gen ppsx

On the Horizon From the ORS Biomechanics 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) 1,2 that have a range of some important measurable trait, such as femoral shaft diameter. 3 In 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 publications 4-8 are 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, 9 serum levels of alka- line phosphatase, 10 and susceptibility to proteoglycan-induced rheumatoid arthritis. 11 Overall, 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 Recent 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. 12 The importance of stem cell cytokine expression has also been studied in heart infarcts 13 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 mar row 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. 15 The 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 al 16 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 paper 16 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 Hered 1999;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 SciUSA2002;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 Res 2006;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. SrivastavaAK, 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. On the Horizon from the ORS Volume 14, Number 4, April 2006 257 13. 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 SciUSA2005;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. Circulation 2006;113:701-710. 15. Murphy JM, Fink DJ, Hunziker EB, Barry FP: Stem cell therapy in a cap- rine model of osteoarthritis. Arthritis Rheum 2003;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 Immunol 2005;175:8296-8302. On the Horizon from the ORS 258 Journal of the American Academy of Orthopaedic Surgeons . 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. 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) 1,2 that have. 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