Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family.

Wolfman, Neil M.; Hattersley, Gary; Cox, Karen; Celeste, Anthony J.; Nelson, Rodney K.; Yamaji, Noboru; Dube, Jennifer L.; DiBlasio-Smith, Elizabeth A.; Nove, John; Song, Jun Tae; Wozney, John M.; Rosen, Vicki

doi:10.1172/jci119537

Cited by 510 publications

(429 citation statements)

References 28 publications

(30 reference statements)

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“…Even more promising, in vivo experiments of ectopic injection of GDF-5, -6, and -7 induces neotendon and ligament formation, suggesting GDFs act as signaling molecules during embryonic tendon and ligament formation [50]. Histologic examination of the induced tissue demonstrated organized collagen with regular periodicity, resembling neonatal tendon and ligament.…”

Section: Discussionmentioning

confidence: 99%

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The Effects of GDF-5 and Uniaxial Strain on Mesenchymal Stem Cells in 3-D Culture

Farng

Urdaneta²,

Barba³

et al. 2008

Clin Orthop Relat Res

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Recent endeavors in tissue engineering have attempted to identify the optimal parameters to create an artificial ligament. Both mechanical and biochemical stimulation have been used by others to independently modulate growth and differentiation, although few studies have explored their interactions. We applied previously described fabrication techniques to create a highly porous (90%-95% porosity, 212-300 lm), 3-D, bioabsorbable polymer scaffold (polycaprolactone). Scaffolds were coated with bovine collagen, and growth and differentiation factor 5 (GDF-5) was added to half of the scaffolds. Scaffolds were seeded with mesenchymal stem cells and cultured in a custom bioreactor under static or cyclic strain (10% strain, 0.33 Hz) conditions. After 48 hours, both mechanical stimulation and GDF-5 increased mRNA production of collagen I, II, and scleraxis compared to control; tenascin C production was not increased. Combining stimuli did not change gene expression; however, cellular metabolism was 1.7 times higher in scaffolds treated with both stimuli. We successfully grew a line of mesenchymal stem cells in 3-D culture, and our initial data indicate mechanical stimulation and GDF-5 influenced cellular activity and mRNA production; we did not, however, observe additive synergism with the mechanical and biological stimuli.

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Section: Discussionmentioning

confidence: 99%

“…Another category of promising stimuli is growth factors, including members of the TGF-B superfamily such as bone morphogenic protein (BMP) and growth and differentiation factor (GDF). GDF-5, in particular, shows great promise in ligament-and tendon-specific differentiation [44,50].…”

Section: Introductionmentioning

confidence: 99%

The Effects of GDF-5 and Uniaxial Strain on Mesenchymal Stem Cells in 3-D Culture

Farng

Urdaneta²,

Barba³

et al. 2008

Clin Orthop Relat Res

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show abstract

“…Terminal differentiation of single cells selected from a group of equivalent precursors may be random, or may be regulated by external environment/signals. Some specific microenvironments/ additional signals are essential for tenocyte differentiation and proliferation [94,114]. A recent report suggests an extracellular matrix (ECM)-rich niche, organized in part by biglycan (Bgn) and fibromodulin (Fmod), controls the self-renewal and differentiation of TSPCs [18].…”

Section: Tendon Cellsmentioning

confidence: 99%

The Basic Science of Tendinopathy

Murrell

2008

Clinical Orthopaedics &Amp; Related Research

314

254

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Tendinopathy is a common clinical problem with athletes and in many occupational settings. Tendinopathy can occur in any tendon, often near its insertion or enthesis where there is an area of stress concentration, and is directly related to the volume of repetitive load to which the tendon is exposed. Recent studies indicate tendinopathy is more likely to occur in situations that increase the ''dose'' of load to the tendon enthesis -including increased activity, weight, advancing age, and genetic factors. The cells in tendinopathic tendon are rounder, more numerous, and show evidence of oxidative damage and more apoptosis. These cells also produce a matrix that is thicker and weaker with more water, more immature and cartilage-like matrix proteins, and less organization. There is now evidence of a population of regenerating stem cells within tendon. These studies suggest prevention of tendinopathy should be directed at reducing the volume of repetitive loads to below that which induces oxidative-induced apoptosis and cartilage-like genes. The management strategies might involve agents or cells that induce tendon stem cell proliferation, repair and restoration of matrix integrity.

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“…The bone morphogenetic protein (BMP) signaling system, with its ligands, antagonists, and receptors is important for bone repair and regeneration, but its role in the healing of tendon is largely unknown. Intramuscular injections of growth differentiation factor 5 (GDF-5), -6, and -7 have been reported to induce tendon-or ligament-like tissue in rats [17], and absence of GDF-5 has been reported to affect ultrastructure, composition, and biomechanical integrity of Achilles tendons in mice [11]. GDF-5 might therefore have a role in establishment and maintenance of tendon properties [11].…”

Section: Introductionmentioning

confidence: 99%

Mechanical Load and BMP Signaling During Tendon Repair: A Role for Follistatin?

Eliasson

Fahlgren

Aspenberg

2008

Clinical Orthopaedics &Amp; Related Research

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Healing of the rat Achilles tendon is sensitive to mechanical loading, and the callus strength is reduced by 3 = 4 after 14 days, if loading is prevented. Exogenous GDFs stimulate tendon healing. This response is influenced by loading: without loading, cartilage and bone formation is initiated. This implies BMP signaling is crucial during tendon healing and influenced by mechanical loading. We therefore asked if mechanical loading influences the gene expression of the BMP signaling system in intact and healing tendons, and how the BMP signaling system changes during healing. The genes were four BMPs (OP-1/BMP-7, GDF-5/CDMP-1/BMP-14, GDF-6/CDMP-2/BMP-13, and GDF-7/CDMP-3/BMP-12), two receptors (BMPR1b and BMPR2), and the antagonists follistatin and noggin. The Achilles tendon was transected in rats and left to heal. Half of the rats had one Achilles tendon unloaded by injection of Botox in the calf muscles. Ten tendons were analyzed before transection and for each of four time points. All genes except noggin were expressed at all time points, but followed different patterns during healing. Loading strongly decreased the expression of follistatin, which could lead to increased signaling. The BMP system appears involved in tendon maintenance and healing, and may respond to mechanical loading.

show abstract

Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family.

Cited by 510 publications

References 28 publications

The Effects of GDF-5 and Uniaxial Strain on Mesenchymal Stem Cells in 3-D Culture

The Effects of GDF-5 and Uniaxial Strain on Mesenchymal Stem Cells in 3-D Culture

The Basic Science of Tendinopathy

Mechanical Load and BMP Signaling During Tendon Repair: A Role for Follistatin?

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