Tendons and Ligaments: Connecting Developmental Biology to Musculoskeletal Disease Pathogenesis

Abstract

Tendons and ligaments provide connections between muscle and bone or bone and bone to enable locomotion. Damage to tendons and ligaments caused by acute or chronic injury or associated with aging and arthritis is a prevalent cause of disability. Improvements in approaches for the treatment of these conditions depend on a better understanding of tendon and ligament development, cell biology, and pathophysiology. This review focuses on recent advances in the discovery of transcription factors that control ligament and tendon cell differentiation, how cell and extracellular matrix homeostasis are altered in disease, and how this new insight can lead to novel therapeutic approaches. © 2017 American Society for Bone and Mineral Research.

Keywords: ARTHRITIS; Egr1/2; LIGAMENT; Mkx; Scx; TENDON.

© 2017 American Society for Bone and Mineral Research.

Figures

Figure 1

(A) A schematic drawing showing the hierarchal structure of tendon/ligament tissue. Tropocollagens synthesized in tenocytes covalently bind and become collagen fibrils. The arrays of the collagen fibrils form collagen fibers. Tenocytes reside in the gaps of the fibers, connecting to one another through cellular channels. The collagen fibers are packed into fascicles that are bundled by endotenon. The fascicles are wrapped by epitenon to form the complete tendon/ligament tissue. (B) The expression period of the transcription factors and the signal input during the tendon development. Tenocytes are specified from mesenchymal progenitor cells by signaling cues, such as TGFβ or FGF, from neighboring tissues and marked by the expression of Scx. The expression of Egr1 and Mkx follow soon after and support the differentiation of tenocytes into embryonic tendon tissue. While the expression of Scx decreases after birth, the expression of Egr1 and Mkx persists throughout the post-natal maturation period and is essential for tissue maintenance during adult life. The panels are adopted from Itoh et al. PNAS 2010 and showing in situ hybridization of Mkx that indicates the embryonic tendon (left) and the tail tendon tissue from 10-week old mice (right).

Figure 2

The transition zones between tendon and muscle (MTJ) and tendon and bone (enthesis). Top panel: a schematic drawing of the muscle-tendon-bone unit. Muscle, tendon and bone are depicted in red, yellow and gray, respectively. Bottom panel, left: MTJ. Muscle and tendon are illustrated on the left and right, respectively. Muscle sarcomeres are depicted as black horizontal lines, with vertical bars indicating Z lines. Collagen fibers are indicated as yellow lines, with tenocytes (orange cells) embedded. MTJ is the ECM layer with finger-like protrusions to increase the surface area between the muscle and tendon and is shown as a blue line. Bottom panel, right: enthesis. Tendon and bone are illustrated on the left and right, respectively. The ECM contents and deposited minerals change gradually within the enthesis, resulting in the continuous shift of tissue elasticity and stiffness.

Figure 3

Mkx is relevant for both the differentiation and the identity of tenocytes. Left: During embryonic development, mesenchymal progenitor cells acquire a tendon/ligament or chondrocyte cell fate, depending on lineage-specific transcription factors, such as Mkx or Sox9. In the adult tissue, the tendon/ligament cells continue to express Mkx, which is indispensable for the maintenance of their cellular identity, in part through the repression of Sox9 transcription. Right: When Mkx is genetically deleted or decreased by aging/OA, the SOX9 expression increases in tendon/ligament cells and these cells transform into chondrocyte-like cells.

Figure 4

A. Osteoarthritis (OA)-associated changes in the anterior cruciate ligament (ACL). Histological images of ACL from human knee joints illustrating changes in the collagen fiber orientation and chondroid metaplasia, the two most frequent changes. Chondroid metaplasia represents a shift in the ligament cell phenotype towards a more chondrocytic cell morphology. In normal ACL, only fusiform (white arrow) and ovoid cells (white arrow head) are observed. In mild cases, only a few spheroid cells are seen. In moderate cases, spheroid cells are dominantly observed. In severe cases, only spheroid cells (black arrow) and pseudo-cloning (black arrow head) that suggests chondroid metaplasia is observed and associated with mucoid degeneration. These histological changes in the ACL correlate with the severity of changes in the articular cartilage. B. MKX is expressed in normal ACL ligament cells. The numbers of ligament cells expressing MKX are reduced in OA ACL. HE staining (A, C) and MKX immunohistochemistry (B, D) (modified from Nakahara et. al. Arthritis Rheum 2013).

Figure 5

A summary of the tendon/ligament biology discussed in this review. The expressions of Scx, Mkx and Egr1 are induced by signaling cues, such as TGFβ or FGFs (see also Figure 1), and promoted by mechanical cues. These transcription factors activate the transcription of tendon structural elements, such as collagens and SLRPs, which are indispensable for proper tendon and ligament tissue formation during embryonic development as well as tissue regeneration. They also play major roles in the maintenance of the tendon and ligament cell identity during aging or pathogenic processes (see also Figure 3), partly by repressing the factors, which promote other cell fates (see also Figure 4).