Essential role of Mohawk for tenogenic tissue homeostasis including spinal disc and periodontal ligament

Abstract

Tendons and ligaments play essential roles in connecting muscle and bone and stabilizing the connections between bones. The damage to tendons and ligaments caused by aging, injury, and arthritis induces the dysfunction of the musculoskeletal system and reduces the quality of life. Current therapy for damaged tendons and ligaments depends on self-repair; however, it is difficult to reconstruct normal tissue. Regeneration therapy for tendons and ligaments has not been achieved, partly because the mechanism, cell biology, and pathophysiology of tendon and ligament development remain unclear. This review summarizes the role of the transcription factor, Mohawk, which controls tendon and ligament cell differentiation, in the maintenance of cell homeostasis, as well as its function in disease and the possibility of new therapeutic approaches.

Keywords: Tendon and ligament; development; homeostasis; regeneration; transcription factor.

Figure 1.. Development and regeneration research based on EMBRYS.

(A) The scheme of WISH database creation. (B) WISH image of Mkx in EMBRYS.

Figure 2.. Schematic drawing of tendon and ligament tissue.

Tenocytes synthesize collagens and proteoglycans. Collagen is organized in triple helical polypeptide chains, and collagen fibrils are formed from collagen microfibrils. Collagen fibrils are connected and wrapped with endotenon. A fiber bundle is an aggregate of collagen fibers. Aggregates of these fiber bundles are wrapped with epitenon and paratenon, and these are named tendon and ligament.

Figure 3.. Process of tendon and ligament healing.

The process is divided into three phases: inflammatory phase, cell proliferation phase, and remodeling phase. Tissues repaired by natural healing have insufficient mechanical strength when compared with uninjured tendon and ligament.

Figure 4.. Venus expression in Venus knock-in mice and representative phenotype in Mkx-knockout mice.

The figures on the left show Achilles tendon, tail tendon, back tendon, annulus fibrosus, and periodontal ligament in Venus knock-in (= Mkx+/−) mice. Venus expression is identified in tendons and ligaments. The figures on the right are comparisons between Mkx+/+ and Mkx−/− mice. The major phenotype at young age is hypoplastic tendons and ligaments. The major phenotype in adults is chondrogenic or osteogenic changes in tendons and ligaments. These images are modified from references , , and .

Figure 5.. Current summary of key transcription factor in tendon development.

The expression of Scx, Mkx, and Egr1 are induced by signaling cues and mechanical cues. Scx is first expressed, and Mkx and Egr1 are subsequently expressed. These factors activate the expression of tendon and ligament related genes.

Figure 6.. Future plan for tendon and ligament regeneration or reconstruction therapy.

We hope that further analysis of the intergenic network will make it possible to establish a differentiation system for tendon cells (Step 1), and to produce tendon tissue-like organoids (Step 2).