Basic Science Tip #530

Tendon extracellular proteins: A primer on multiple roles, locations, and functions

Depending on the tendon there are wide ranges of structural physiologic properties as well as cell functions based on the relationship of the cells to the matrix. 55 to70% of the matrix is water. 60 to 85% of the dry weight is collagen, most of which is type I. The variations in non collagenous proteins and those associated with type I turnover are now being related to health and disease.

Although a small proteoglycan, decorin, has a major role in collagen fiber diameter a subset of small leucine‐rich proteoglycans (SLRPS) have been found to be important. Because of their binding with other collagens and growth factors these molecules play a role in cell adhesion and function. An example of tendon specificity for smaller extracellular matrix proteins is the variation of biglycan in tail versus patellar tendon. SLRPS also play a role in the physiologic molecular sliding and recovery in physiologic function of tendons.

Collagen propeptidases are essential in fibrillar relationships. In the formation of the triple helical collagen molecule (for type I collagen there are two α1 and one α2 units). Once assembled the C and N terminal propeptides are cleaved. On the N terminal side a disintegrin‐like and metalloprotease with thrombospondin type I motives (ADAMTS) does this cleavage. Disorders of this propeptidase are seen in skin laxity. On the other hand, a mutation in the propeptide site is found in one of the forms of Ehler Danlos syndrome where skin laxity is not a significant feature.

Collagen crosslinking is dependent on LOX and LOX like proteins as well as fibulin-4. An absence in normal LOX function has been found in decreased tendon strength and fibulin-4 a Marfan syndrome like state.

Lumacin interacts with fibromodulin in collagen fiber diameter. Deficiency in lumacin are likewise known to be associated with decreased tensile strength. Albeit fibromodulin is important in fiber size modulation defects in fibermodulin require concurrent molecular defects such as lumacin or biglycan.

Tenascin‐C is expressed in mechanically loaded tissues, such as tendon. It is virtually absent in non‐loaded tissues. A single nucleotide polymorphisms (SNPs) in tenascin‐C has been found to be associated with rotator cuff degeneration but the role of tenascin-C in tendon formation is not clear.

The pericellular matrix of tendon cells can play a role in collagen diameter as well as cell renewal and replication capacity. Albeit tenomodulin is important the binding sites are not clear. Versican and aggrecan are larger proteoglycans but abnormalities in formation or breakdown (and thus accumulation) are poorly understood. Thrombospondin is seen in a family of proteins (TSP1-4) as well as cartilage oligomeric protein (COMP). COMP is een in higher proportions in weight bearing tendons. The overriding effect of the molecules in cartilage make their role in isolated tendon disorders difficult to determine.

Both fibrillins and elastin are in the ECM. Abnormality in fibrillin-1 is associated with Marfan syndrome and fibrillin-2 with arachnodactyly. Elastin plays a role in the stretch and recoil of tendons and responsible for the toe region of the stress strain curve. Variation in tendons affected and tendon elasticity are seen with elastin disorders.

As the interrelationships of these and other extracellular matrix molecules are better understood genetic propensity for tendon aging disorders, applications in tissue engineering, and pharmacologic interventions are likely to emerge in the next decade.

Reference
Taye N, Karoulias SZ, Hubmacher D The "other" 15-40%: The Role of Non-Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon. J Orthop Res. 2020 Jan;38(1):23-35. doi: 10.1002/jor.24440. Epub 2019 Aug 26. PMID: 31410892