Transforming Growth Factor Beta: An Autocrine Regulator of Chondrocytes

Rosier, Randy N.; O’Keefe, Regis J.; Crabb, Ian D.; Puzas, J. Edward

doi:10.3109/03008208909023900

Cited by 121 publications

(66 citation statements)

References 16 publications

(2 reference statements)

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“…Message expression of TGF-was evident in cartilage RNA samples derived from horses of various ages. The autocrine and paracrine activity of TGF-in cartilage has been described (Rosier et al 1989, Ballock et al 1997, although circulating TGF-is presumed to contribute to cartilage development and homeostasis to some extent (Thompson et al 1989, Morales 1991. This study reveals an age-related TGF-expression profile in cartilage.…”

Section: Discussionmentioning

confidence: 65%

“…Despite these side-effects and given its defined role in cartilage growth and development, it seems plausible that TGF-in some form may still play a vital role in adjunctive therapy for enhanced cartilage repair in acute or chronic joint disease. The attenuation of constitutive TGF-expression by exogenous TGF-application would lessen the impact of TGF-supplementation; however, previous studies suggest that TGF-is autoinductive (van Obberghen-Schilling et al 1988, Rosier et al 1989, Ballock et al 1997. Additionally, TGF--driven autocrine or paracrine insulin-like growth factor-I (IGF-I) gene expression in articular chondrocytes has been described (Tsukazaki et al 1994).…”

Section: Introductionmentioning

confidence: 99%

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Molecular cloning of equine transforming growth factor-beta1 reveals equine-specific amino acid substitutions in the mature peptide sequence

Nixon

Brower-Toland

Sandell³

2000

Journal of Molecular Endocrinology

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This study cloned and sequenced equine transforming growth factor (TGF)-1, yielding a unique nucleotide structure which predicted amino acid substitutions not seen in other mammalian species. The nucleotide sequence homology was 89% to bovine, 91% to man, 90% to ovine, and 86% to rat. Derived amino acid sequence comparison showed that the equine protein was unique, differing by two residues from man, cow, sheep, pig, and dog, and by three residues in the rat. Subsequent use of the cDNA clones to examine the expression of the TGF-1 gene in various tissues indicated predominant expression in adult spleen and kidney, with an age-related peak in cartilage expression at 12 months, followed by a decline as the animals matured. Northern blots showed that the predominant transcript sizes were 2·5 and 1·9 kb. More sensitive mRNA detection using PCR reaction showed peak cartilage TGF-mRNA levels in horses 0·7 and 1 year of age, with declining expression in older animals (2·5 and 5·5 years of age).In conclusion, although the primary nucleotide sequence of equine TGF-was relatively homologous to that of other species, the resulting amino acid sequence was unique to the horse, differing by two residues from the majority of mammalian sequences, where the peptide structure is identical. Expression of TGF-was particularly evident in spleen and kidney, and showed an age-related increase in expression in cartilage as the animals approached maturity and then a decline with progressive aging.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Molecular cloning of equine transforming growth factor-beta1 reveals equine-specific amino acid substitutions in the mature peptide sequence

Nixon

Brower-Toland

Sandell³

2000

Journal of Molecular Endocrinology

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“…The use of the BMP/TGF-b pathway-specific superarray clarifies that CII-induced responses minimally overlap with TGF-b1-induced changes, and the patterns are cell type and condition dependent (that is, the same array shows different patterns by cell type and normal vs cancer). TGF-b and collagen are capable of promoting chondrocyte differentiation, which has been reported and attributed to independent linear pathways (Benya et al, 1978;Benya and Shaffer, 1982;Galera et al, 1992;Hill and Logan, 1992;Rosier et al, 1989;Suzuki, 1992;Thorp et al, 1992). The current results show that soluble ECM effects incorporate partial TGF-b receptor dynamics, and because collagen-induced gene expressional responses are distinct from TGF-b ligand-induced signaling, it suggests a unique role in cell-matrix interaction.…”

Section: Discussionmentioning

confidence: 93%

Extracellular matrix-induced transforming growth factor-β receptor signaling dynamics

Garamszegi

Samavarchi-Tehrani

et al. 2010

Oncogene

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Matrix remodeling, degradation, inflammation and invasion liberate peptide fragments that can subsequently interact with cells in an attachment-independent manner. Such 'soluble' matrix components, including collagens, fibronectin and laminin, induced Smad activation (termed crosstalk signaling), which follows a similar chronological sequence and R-Smad specificity as induced by transforming growth factor (TGF)-b1. Smad4 nuclear translocation occurred in response to collagen binding, indicating downstream signal propagation. TGF-b scavenging antibody affected only TGF-b1, but not crosstalk-induced responses. TGF-b type II receptor mutation (DR26D25), which is deficient in TGF-b type I receptor recruitment to the ligand, induced a heterotetramer signaling complex, and propagated Smad2 activation only through collagen induction and not TGF-b signaling. Consequentially, TGF-b ligand participation is not required for crosstalk signaling. This signaling requires a functional integrin b1 receptor as showed by RNA interference. Co-immunoprecipitation (co-IP) and fluorescent microscopy indicate the involvement of focal adhesion kinase (FAK) and Src activity in collagen-induced signal propagation, and suggest a membrane signaling complex formation that includes both TGF-b receptors and integrins. The related gene expressional responses are distinct from that evoked by TGF-b1, supporting its separate function. This signaling mechanism expands and partially explains TGFb receptor dynamics and consequential signaling diversityrelated gene expressional plasticity.

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“…TGF␤ has been proposed to serve as a coupling factor between bone formation and resorption during bone remodeling (60). Furthermore, TGF␤ has also been shown to stimulate cartilage regeneration (61). Active TGF␤ is significantly up-regulated in the synovial fluid of OA patients (62,63).…”

Section: Discussionmentioning

confidence: 99%

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

511

466

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Objective. It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation.Methods. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 g/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor ␤ (TGF␤), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF␤.Results. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dosedependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF␤, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Conclusion. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.Osteoarthritis (OA) is a degenerative joint disease characterized by pain, cartilage loss, and joint stiffness. Although OA has long been considered to be primarily a cartilage disorder associated with focal articular cartilage degradation, this disease is accompanied by well-defined changes in the subchondral and periarticular bone, including sclerosis and cyst and osteophyte formation (1). The importance of the bone changes in the initiation and progression of OA is still being debated. It has been suggested that increased subchondral bone stiffness reduces the ability to dissipate the load and distribute the strain generated within the joint. This increases peak dynamic forces in the overlying articular cartilage and can accelerate its damage over time (2). The functional integrity of the articular cartilage can therefore depend on the mechanical properties of the underlying bone. Accordingly, cartilage damage leads to full-thickness cartilage loss only upon repetitive loading over an already stiffened subchondral bone plate (3).Recent studies have demonstrated increased subchondral bone turnover accompanied by specific architectural changes in the subchondral trabecular bone in OA joints (4,5...

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Transforming Growth Factor Beta: An Autocrine Regulator of Chondrocytes

Cited by 121 publications

References 16 publications

Molecular cloning of equine transforming growth factor-beta1 reveals equine-specific amino acid substitutions in the mature peptide sequence

Molecular cloning of equine transforming growth factor-beta1 reveals equine-specific amino acid substitutions in the mature peptide sequence

Extracellular matrix-induced transforming growth factor-β receptor signaling dynamics

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

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