Tenascin is a family of complex proteins found within the extracellular matrix (ECM), which serves as the body’s internal scaffolding and communication network between cells. The ECM is a complex web of proteins and other molecules that provides structural support, flexibility, and acts as a signaling hub, influencing cell growth, differentiation, migration, and survival. Tenascins are unique among ECM proteins due to their dynamic expression patterns in various tissues throughout development and during tissue repair.
The Tenascin Family Members
The tenascin family consists of four main members in vertebrates: Tenascin-C (TNC), Tenascin-R (TNR), Tenascin-X (TNX), and Tenascin-W (TNW). Each member possesses a common structural organization. This organization allows tenascins to interact with a diverse range of binding partners, including cell surface receptors and other ECM components, mediating a wide array of functions.
Tenascin-C (TNC) is the most extensively studied member. It is found in abundance during embryonic development, particularly in forming tissues like tendons, bones, and cartilage, and also during wound healing and in the stroma of tumors. TNC can exist in various molecular forms due to alternative splicing, which influences its interactions and functions.
Tenascin-R (TNR) is predominantly expressed in the central and peripheral nervous systems, playing a role in neuronal development and function. Tenascin-X (TNX) is widely distributed in loose connective tissues, such as the dermis, epimysium, and blood vessels, where it contributes to the stability and maintenance of the collagen network. Tenascin-W (TNW) is primarily detected in areas of bone formation, the periosteum, kidneys, smooth muscle, and in the stroma of various cancers.
Tenascin’s Functions in Tissue Development and Repair
Tenascin proteins contribute to normal physiological processes, particularly during embryonic development and tissue repair. During embryonic development, tenascins guide cell migration and play roles in neural development, skeletal formation (skeletogenesis), and blood vessel development (vasculogenesis). TNC, for instance, is involved in the differentiation of heart muscle cells (cardiomyocytes) and the formation of coronary blood vessels.
In adults, tenascins are generally present at low levels in healthy tissues, but their expression increases in response to tissue injury. During wound healing, tenascin-C is transiently re-expressed and then decreases as repair completes. It contributes to the inflammatory phase by inducing pro-inflammatory cytokines, promoting cell migration and proliferation, and influencing ECM synthesis and assembly.
Tenascin-C also influences cell behavior by modulating cell adhesion and differentiation. It can weaken cell adhesion and upregulate the activity of matrix metalloproteinases (MMPs), enzymes involved in breaking down the ECM, which is important for tissue remodeling. These proteins interact with various cell surface receptors to influence cellular programs.
Tenascin’s Involvement in Disease
Tenascin proteins are implicated in various disease states, largely due to their altered expression patterns and diverse molecular functions. Tenascin-C (TNC) is upregulated in pathological conditions like inflammation, fibrosis, and cancer, making it a potential biomarker for diagnosis and risk assessment. In cancer, TNC promotes tumor growth, spread (metastasis), the formation of new blood vessels (angiogenesis) that supply tumors, and can contribute to drug resistance. It achieves this by modulating cell migration, proliferation, and signaling pathways.
Tenascin-C is also involved in chronic inflammatory conditions and fibrotic diseases, such as organ fibrosis in the liver, lungs, and kidneys. Its presence at sites of inflammation suggests it is part of a general inflammatory response. TNC can exert both beneficial and harmful effects depending on the context, influencing cellular responses during tissue remodeling in conditions like heart failure and atherosclerosis.
Beyond TNC, other tenascin family members also contribute to disease. Tenascin-R (TNR) is implicated in neurological disorders, given its primary location in the nervous system. Tenascin-X (TNX) deficiency is linked to a form of Ehlers-Danlos syndrome (EDS), a group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and easy bruising. TNX also plays a role in regulating collagen deposition and fiber stability, and its absence can lead to issues with tissue structure.