Moderate Joint Loading Reduces Degenerative Actions of Matrix Metalloproteinases in the Articular Cartilage of Mouse Ulnae

Abstract

Joint loading is a recently developed loading modality, which can enhance bone formation and accelerate healing of bone fracture. Since mechanical stimulation alters expression of matrix metalloproteinases (MMPs) in chondrocytes, a question addressed herein was, does joint loading alter actions of MMPs in the articular cartilage? We hypothesized that expression and activity of MMPs are regulated in a load–intensity-dependent manner and that moderate load scan downregulates MMPs. To test this hypothesis, a mouse elbow-loading model was employed. In the articular cartilage of an ulna, the mRNA levels of a group of MMPs as well as their degenerative activities were determined. The result revealed that elbow loading altered the expression and activities of MMPs depending on its loading intensity. Collectively, the data in this study indicate that 0.2 and 0.5 N joint loading significantly reduced the expression of multiple MMPs, that is, MMP-1, MMP-3, MMP-8, and MMP-13, and overall activities of collagenases or gelatinases in articular cartilage, while higher loads increased the expression and activity of MMP-1 and MMP-13. Furthermore, moderate loads at 1 N elevated the mRNA level of CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), but higher loads at 4 N did not induce a detectable amount of CITED2 mRNA. Since CITED2 is known to mediate the downregulation of MMP-1 and MMP-13, the result indicates that joint loading at moderate intensity reduces MMP activities through potential induction of CITED2. MMPs such as MMP-1 and MMP-13 are predominant collagenases in the pathology of osteoarthritis. Therefore, joint loading could offer an interventional regimen for maintenance of joint tissues.

CITED2 mediates the cross‐talk between mechanical loading and IL‐4 to promote chondroprotection

“…Our previous studies revealed that CITED2 plays a critical chondroprotective role by suppressing MMP13 at the gene and protein levels . CITED2 responds to multiple stimuli, including cytokines and mechanical stress . In this study, we provided evidence that the anti‐inflammatory cytokine IL‐4 induces CITED2 expression in human chondrocytes.…”

“…We have previously demonstrated that moderate loading induces CITED2 gene expression and exerts a chondroprotective effect, at least in part, through repressing MMPs such as MMP13 in vitro and in vivo . We therefore examined the effect of mechanical loading in combination with IL‐4 on MMP13 expression in human OA primary chondrocytes in the presence of IL‐1β.…”

“…CBP/P300‐interacting transactivator 2 (CITED2, also known as MRG1) is a multiple stimuli–responsive transcriptional regulator, originally identified as an IL‐4‐inducible molecule in T lymphocytes and macrophages . It is a critical chondroprotective mediator that downregulates MMPs during moderate loading . Collectively, these findings raised the following questions: (1) Is CITED2 inducible by IL‐4 in chondrocytes?…”

Mechanical Loading

“…Although mechanotransduction pathways underlying chondroprotection are not well understood, recent studies have shown that biomechanical signals inhibit multiple steps in the IL-β-induced cascade downstream of IκB kinase activation, regulating IκB-α and IκB-β degradation and synthesis and promoting IκB-α shuttling to export nuclear NF-κB and terminate its transcriptional activity. 12 Furthermore, induced by dynamic moderate loading, such as joint motion and joint loading in the lateral/medial direction in vivo, 5,13 and by moderate fluid shear and intermittent hydrostatic pressure in vitro, 5,14 transactivated transcriptional factor CITED2 leads to the suppression of MMPs, at least in part through competition with MMP transactivator Ets-1 for binding to coactivator p300. 2,5 Moreover, transient receptor potential vanilloid 4 (TRPV4), a Ca 2+ -preferred membrane ion channel, acts as a transducer for loading-induced chondrocyte matrix biosynthesis.…”

CITED2 mediates the mechanical loading–induced suppression of adipokines in the infrapatellar fat pad

“…Previous studies suggested that moderate exercise, or mechanical loading within a physiologic range, exerts chondroprotection through, at least in part, the upregulation of the transcriptional regulator Cbp/p300 interacting transactivator with Glu/Asp‐rich carboxy‐terminal domain 2 (CITED2) in joint tissue cells such as chondrocytes and synoviocytes . These studies showed that CITED2 represses the expression of matrix metalloproteinases (MMPs) such as MMP‐13 . However, it is unknown whether CITED2 is also mechanosensitive and plays role in the regulation of adipokine expression in adipose tissues such as the IPFP.…”