Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis

Abstract

Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in 'overuse' injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.

Figure 1.. The anatomy of tendons and ligaments in the peripheral and axial skeletons.

a| A macroscopic overview of tendon structure and the fibrocartilaginous synovio-entheseal complex at the bone insertion. b| A cross-sectional view of a tendon showing the hierarchal structure of the organ at tissue and molecular levels. c| The anatomy of spinal ligaments and the intervertebral disc (IVD). AF, annulus fibrosus.

Figure 2.. Mechanical forces exerted on tendons and ligaments.

The types of mechanical forces that are exerted on tendons and ligaments can be examined at the microscale, in which forces act on and between collagen fibres (a) and at the macroscale, in which forces act on the complete tendon or ligament (b). Whereas microscale mechanical forces are common to all tendons and ligaments, macroscale mechanical forces differ depending on the anatomical location (axial skeleton or peripheral skeleton) of the tendon or ligament. The relationship between normalized force placed on a tendon or ligament, and the subsequent tissue elongation, can be represented by a stress–strain curve (c). Each phase of tendon or ligament stretch is defined by physical changes to the structure of collagen fibres as they go from a resting (crimped) state to an undamaged stretched state, on to a microdamaged stretched state and finally to complete rupture. The slope of the linear elastic region represents the modulus of the tissue.

Figure 3.. Proposed tenocyte response mechanisms to mechanical stress.

The mechanical loading of collagen fibres in tendons and ligaments is sensed by tenocytes, which mount a biological response to alter the extracellular matrix (ECM) composition of the surrounding tissue. In the unloaded state (left-hand side), collagen fibres are crimped and tenocytes receive minimal internal and external mechanical stress signals. Inactive integrins do not form focal adhesion complexes, and active integrins do not initiate mechanotransduction. As a result, mechanical stress-related transcription factors are either destroyed, such as YAP and TAZ, or fail to enter the nucleus, such as Scx. The result is a catabolic programme to reduce tenocyte and tendon strength in an effort to maintain homeostatic tension. At physiological levels of mechanical stress (centre), internal and external mechanisms of mechanostransduction are engaged, resulting in increased formation and activation of focal adhesions and the buffering of internal mechanical stress by talin. Actin tension is converted to the activation of YAP and TAZ, whereas Scx is activated via post-translational modification to induce the expression of a tenocyte-defining transcriptional programme. Transforming growth factor-β (TGFβ) promotes a tenocyte phenotype and integrin activation, potentially through the proximity of integrins and TGFβ receptor, mediated by tenascin-C. Calcium might also enter the cells through stress-activated ion channels such as Piezo and transient receptor potential vanilloid 4, and might subsequently be transmitted to adjacent cells via gap junctions. Excessive mechanical stress (right-hand side) results in ECM damage and a rapid loss of mechanotransduction in the tenocyte. The result is cell death and the release of danger-associated molecular patterns (DAMPs) and inflammasome-activated cytokines such as IL-1β. These molecules can propagate cell death in adjacent tenocytes and can promote the recruitment of pro-inflammatory cells, which perpetuate the inflammatory cycle by releasing pro-inflammatory molecules such as TNF, IL-6, IL-17 and prostaglandin E₂ (PGE₂). MMPs, matrix metalloproteinases; TLRs, Toll-like receptors.

Figure 4.. The tendon and ligament tissue repair process.

Tenocyte death occurs following unloading of tendons, which happens after rupture and microdamage, causing the release of cytokines and damage-associated molecular patterns (DAMPs). This death results in the rapid activation of adjacent stromal cells and, potentially, tissue-resident immune cells, propelling the injured tissue into a state of repair. The early phase of tendon and ligament repair is an inflammatory phase, characterized by myeloid cell recruitment, the transition of monocytes to pro-inflammatory (M1) macrophages and the removal of apoptotic tenocytes and extracellular matrix (ECM) debris by phagocytosis. Tenocytes and myeloid cells work together to ensure an adequate catabolic response. The intermediate phase of tendon and ligament repair is characterized by a resolution of inflammation and an increase in pro-resolving (M2) macrophages. During this stage, tenocyte precursor cells are recruited into the lesion to assist with ECM repair through the deposition of a temporary type III collagen matrix. In the late phase, this temporary matrix is slowly remodelled to a permanent, type I collagen-dominated matrix. The recovered tissue in adult tendons and ligaments never regains its pre-injury architecture and is frequently scar-like in appearance.

Figure 5.. Proposed model of the relationship between mechanical stress and inflammatory arthritis.

Chronic inflammatory arthritis, including rheumatoid arthritis (RA) and spondyloarthritis (SpA), has defined genetic and environmental risk factors, but the relative contribution of these factors to the onset of systemic inflammation differs between diseases. Smoking is a well-recognized environmental risk factor for both SpA and RA, as are bacterial infections of barrier surfaces, albeit at different anatomical locations in RA and SpA. Genetic and environmental risk factors synergize to promote systemic inflammation that has both shared and distinct features in RA and SpA. The normal healing process that occurs after mechanical stress-induced microdamage at entheseal sites is hijacked by perturbed systemic immunity resulting in sustained entheseal inflammation and aberrant tissue healing. In RA, the result is bone erosion, probably as a result of protracted osteoclast activation in the subchondral bone adjacent to the enthesis. In SpA, subchondral bone erosion occurs coincident to entheseal fibrosis and subsequent ossification, possibly owing to persistent tenocyte activation through the IL-17–NF-κB axis. IBD, inflammatory bowel disease.