TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Abstract

The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

Identification of novel FBN1 variations implicated in congenital scoliosis

“…TGF-β plays critical roles in development and maintenance of the skeleton [47]. The two unrelated patients (XH73 and XH579) sharing the p.Leu871Phe variant presented CS with vertebral segmentation defects, rib anomalies, and diastematomyelia.…”

A Central Bioactive Region of LTBP-2 Stimulates the Expression of TGF-β1 in Fibroblasts via Akt and p38 Signalling Pathways

“…At face value, the results indicate that receptor(s) not signalling primarily via ARK or p38 are unlikely to be prime candidates for the unidentified LTBP-2 receptor. For example, growth factors EGF, FGF, and Platelet-Derived Growth Factor primarily use ERK pathways [ 57 , 58 ], and the TGF-β/BMP family uses the SMAD signalling cascade [ 59 ]. However, such growth factors can also use non-canonical pathways; EGF can stimulate Akt via mTORC2 [ 60 ], and TGF-β1 can use several signalling pathways involving p38, Akt, or ERK [ 59 , 61 ].…”

Tgfbr2 is required in Acan‐expressing cells for maintenance of the intervertebral and sternocostal joints

“…Previous studies using mouse models have also highlighted the importance of TGF‐β signaling in skeletal development and homeostasis . Expression of a truncated, kinase defective Tgfbr2 in mouse skeletal tissue resulted in articular chondrocyte hypertrophy and osteoarthritis of the knee joint .…”

“…13 Previous studies using mouse models have also highlighted the importance of TGF-β signaling in skeletal development and homeostasis. 19 Expression of a truncated, kinase defective Tgfbr2 in mouse skeletal tissue resulted in articular chondrocyte hypertrophy and osteoarthritis of the knee joint. 20 Furthermore, progressive skeletal degeneration was observed in these mice and vertebra of the spine were often misshapen and appeared fused.…”