Control of organization and function of muscle and tendon by thrombospondin-4

Abstract

Thrombospondins (TSP) are multifunctional proteins that are deposited in the extracellular matrix where they directly affect the function of vascular and other cell types. TSP-4, one of the 5 TSP family members, is expressed abundantly in tendon and muscle. We have examined the effect of TSP-4 deficiency on tendon collagen and skeletal muscle morphology and function. In Thbs4−/− mice, tendon collagen fibrils are significantly larger than in wild-type mice, and there is no compensatory over-expression of TSP-3 and TSP-5, the two TSPs most highly homologous to TSP-4, in the deficient mice. TSP-4 is expressed in skeletal muscle, and higher levels of TSP-4 protein are associated with the microvasculature of red skeletal muscle with high oxidative metabolism. Lack of TSP-4 in Medial soleus, red skeletal muscle with predominant oxidative metabolism, is associated with decreased levels of several specific glycosaminoglycan modifications, decreased expression of a TGFβ receptor beta-glycan, decreased activity of lipoprotein lipase, which associates with vascular cell surfaces by binding to glycosaminoglycans, and decreased uptake of VLDL. The soleus muscle is smaller and hind- and fore-limb grip strength is reduced in Thbs4−/− mice compared to wild-type mice. These observations suggest that TSP-4 regulates the composition of the ECM at major sites of its deposition, tendon and muscle, and the absence of TSP-4 alters the organization, composition and physiological functions of these tissues.

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

“…These results point to a system by which the dynamics of fibril ultrastructure feedback on ECM production to modify tendon strength continuously. Tendon ECM and collagen fibrils are also continuously remodeled in response to mechanical forces, at least around the circumference of a tendon fascicle (Frolova et al, 2014;Heinemeier et al, 2012;Herchenhan et al, 2013;Kjaer, 2004;Pingel et al, 2014). TPCs in culture subjected to moderate mechanical forces show an increase in collagen fibril diameter, though diameter decreases with excessive mechanical force (De Almeida et al, 2010;Pingel et al, 2014).…”

“…This requirement for Tsp4 is at least partially conserved, as Tsp4 −/− mutant mice show defects in ECM deposition in developing tendons (Fig. 4) (Frolova et al, 2014;Subramanian and Schilling, 2014). Tsp4 and other subtype B thrombospondins form pentamers that directly bind to collagens, laminins and other ECM proteins (Hauser et al, 1995).…”

When is a thrombogenic matrix not thrombogenic?

“…Classification of both continues to evolve. 4,5 Originally described as "senile EBV-associated lymphoproliferative disorder," renamed "EBV-positive DLBCL of the elderly" for inclusion as a provisional entity in the 2008 World Health Organization classification, 6 the suggested terminology has been revised to acknowledge the occurrence in younger patients. 7 "Of the elderly" has been replaced by "not otherwise specified" (EBV 1 DLBCL, NOS).…”

“…2 The collagen fibrils in the tendons of TSP4 KO mice are significantly larger. 5 Thrombospondin-5, also known as cartilage oligomeric matrix protein, binds to collagen II and IX and aggrecan to promote collagen fibril assembly and ECM formation. 6 Mutations in TSP5 lead to premature assembly of the ECM in the endoplasmic reticulum and cause the human dwarfing condition pseudoachondroplasia.…”

“…Muscle tissue in TSP4-null mice contains lower levels of proteoglycans, including glypican and b-glycan. 5 Alternatively, proteolysis may result in the loss of vWF binding sites from the ECM. TSP2 reportedly mediates the uptake and clearance of matrix metalloproteinase 2 by cells.…”