# Intermitt Dynamic Compression Conters Anabolic Effects in Articular Cartilage
###### Abstract  
(1) Background: Mechanical loading is an essential part of the function and maintenance of the joint. Despite the importance of intermittent mechanical loading, this factor is rarely considered in preclinical models of cartilage, limiting their translatability. The aim of this study was to investigate the effects of intermittent dynamic compression on the extracellular matrix during long-term culture of bovine cartilage explants. (2) Methods: Bovine articular cartilage explants were cultured for 21 days and subjected to 20 min of 1 Hz cyclic compressive loading five consecutive days each week. Cartilage remodeling was investigated in the presence of IGF-1 or TGF-\(\beta\)1, as well as a TGF-\(\beta\) receptor 1 (ALK5) kinase inhibitor and assessed with biomarkers for type II collagen formation (PRO-C2) and fibronectin degradation (FBN-C). (3) Results: Compression of cartilage explants increased the release of PRO-C2 and FBN-C to the conditioned media and, furthermore, IGF-1 and compression synergistically increased PRO-C2 release. Inhibition of ALK5 blocked PRO-C2 and FBN-C release in dynamically compressed explants. (4) Conclusions: Dynamic compression of cartilage explants increases both type II collagen formation and fibronectin degradation, and IGF-1 interacts synergistically with compression, increasing the overall impact on cartilage formation. These data show that mechanical loading is important to consider in translational cartilage models. Keywords:osteoarthritis; articular cartilage; dynamic compression; bovine explants; type II collagen; fibronectin; translational research +
Footnote †: journal: MedicalOA [16]. Presently, there are no approved disease-modifying OA drugs (DMOADs) proven effective at restoring cartilage or modifying the progression of structural damage. Various experimental models of articular cartilage have been used for investigating how compressive loading influences cartilage biology. Articular chondrocytes are mechanosensitive cells that respond to physiological loading by increasing extracellular matrix (ECM) synthesis and incorporation [17; 18; 19]. In contrast, excessive loading is related to decreased matrix synthesis and increases in the production of proteolytic collagenases and aggrecanases, causing cartilage destruction [20; 21; 22; 23]. Studies in tissue models that have examined the effects of cyclic compressive loading have generally applied a single loading protocol, lasting several hours to days of duration [18; 19; 20; 24]. The biosynthetic matrix response has, however, been demonstrated to be augmented when a physiological compression operation is performed repeatedly over several days [18; 19; 24]. Repeated loading protocols are more characteristic of loading in vivo, in which periods of cyclic loading rarely last more than 1 h and are not only interspersed with periods of partial recovery but also periods of full recovery that last at least 16 h per day [25]. Accordingly, healthy articular cartilage depends on intermittent physiological loading, in which cycles of cartilage loading and unloading maintain homeostasis [26]. Despite the importance of intermittent loading, it is rarely considered in experimental cartilage models. From a preclinical perspective, this potentially limits their translational potential, as the influence of intermittent loading may modulate the chondrocyte response to treatments. Insulin-like growth factor-1 (IGF-1) and transforming growth factor beta (TGF-\(\beta\)) are important anabolic inducers in articular cartilage. IGF-1 is a 7.5 kDa polypeptide produced by the liver that reaches the articular cartilage through the synovial fluid [27] but is also secreted locally by chondrocytes [28]. Exogenous addition of IGF-1 to monolayer- or explant cultures promotes synthesis of proteoglycans and attenuates their degradation [29; 30; 31]. IGF-1 also counteracts the effects of catabolic agents, by enhancing the recovery of proteoglycans after their depletion [32; 33].