Growth and mechanobiology of the tendon-bone enthesis

Abstract

Tendons are cable-like connective tissues that transfer both active and passive forces generated by skeletal muscle to bone. In the mature skeleton, the tendon-bone enthesis is an interfacial zone of transitional tissue located between two mechanically dissimilar tissues: compliant, fibrous tendon to rigid, dense mineralized bone. In this review, we focus on emerging areas in enthesis development related to its structure, function, and mechanobiology, as well as highlight established and emerging signaling pathways and physiological processes that influence the formation and adaptation of this important transitional tissue.

Keywords: Enthesis; Fibrocartilage; Muscle loading; Tendon.

Figure 1.

The enthesis is a transitionally graded tissue positioned between bone and tendon. The primordial enthesis develops from bi-fated progenitor cells expressing chondrogenic and tenogenic factors (i.e., Scx, Sox9, and Gli1). Created with BioRender.com.

Figure 2.

The deltoid tuberosity is a superstructure on the humerus and is a reliable readout of tendon and enthesis development as well as muscle loading in the embryonic limb. In ScxCre-Sox9 mutant mouse embryos (top row), the deltoid tuberosity (black arrow) and triceps insertion (purple arrow) fail to initiate formation. In muscleless mouse embryos, the formation of the deltoid tuberosity is initiated at embryonic day (E) 14.5; however, without muscle contraction, the tuberosity is not maintained by E18.5. Images modified with permission from (23,27).

Figure 3.

The establishment of the postnatal enthesis depends on either (A) migratory (e.g., replacement) or (B) stationary (e.g., maintenance and differentiation) of the progenitor cells at the interface between tendon and bone. (C) Enthesis maturation results in dynamic remodeling of collagen-rich extracellular matrix, with predominantly collagen type I (Col1) in tendon, collagen type II (Col2) in the cartilage template, and deposition of collagen type X at the enthesis and in the secondary ossification center. Timelines shown are representative of mouse enthesis development; P = postnatal day. Modified from (31,46)