Experimental-analytical approach to assessing mechanosensitive cartilage blood marker kinetics in healthy adults: dose-response relationship and interrelationship of nine candidate markers

Abstract

Purpose: To determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load. Methods: Serum samples were collected from 24 healthy volunteers before and at three time points after a 30-minute walking stress test performed on three test days. In each experimental session, one of three ambulatory loads was applied: 100% body weight (BW); 80%BW; 120%BW. Serum concentrations of COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C and IL-6 were assessed using commercial enzyme-linked immunosorbent assays. A two-stage analytical approach was used to determine the suitability of a biomarker by testing the response to the stress test (criterion I) and the dose-response relationship between ambulatory load magnitude and biomarker kinetics (criterion II). Results. COMP, MMP-3 and IL-6 at all three time points after, MMP-9 at 30 and 60 minutes after, and ADAMTS-4 and CPII at immediately after the stress test showed an average response to load or an inter-individual variation in response to load of up to 25% of pre-test levels. The relation to load magnitude on average or an inter-individual variation in this relationship was up to 8% from load level to load level. There was a positive correlation for the slopes of the change-load relationship between COMP and MMP-3, and a negative correlation for the slopes between COMP, MMP-3 and IL-6 with MMP-9, and COMP with IL6. Conclusions: COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load.

The Relationship Between Intra-articular Fracture Energy and a Patient's Inflammatory Response

“…MMP-3 has also been shown to be mechanosensitive; either a single injurious compression or cyclic supra-physiologic compression results in upregulation of MMP-3 and subsequent proteoglycan loss and cartilage degradation. [25][26][27][28] Mechanical injury with forces similar to what would be borne by the cartilage at the time of articular fracture has been shown to upregulate MMP-3 between 10-fold and 250-fold. 29,30 As such, future work is needed to better understand the mechanobiologic response to injury and the role of mechanobiologic mechanisms on PTOA progression.…”

Load-induced blood marker kinetics in patients with medial knee compartment osteoarthritis are associated with accumulated load and patient reported outcome measures

“…ADAMTS-4 was log transformed to address skewness. Because we intended to only interpret results that are in concordance with previous evidence for mechanosensitivity, 45 we refrained from applying Bonferroni corrections and set the significance level to 0.05. Statistical analysis was performed in R version 4.0.3 (The R Foundation, Vienna, Austria).…”

“…Previous evidence suggested that COMP, MMP-3, MMP-9, ADAMTS-4, CPII and IL-6 could suitable for assessing in vivo cartilage mechanosensitivity. 45 It is possible that these markers may reflect individual disease progression despite of the lack of group results. Joint load assessed during gait analysis can be considered a surrogate of the typical loading of an individual's joint.…”

“…MMP-3 consistently changes with ambulatory load and immobilization 45,[49][50][51] and is relevant for OA. 52,53 Our finding of an association between ΔMMP-3 and patient reported outcome measures supports the importance of MMP-3 in the context of cartilage mechanosensitivity.…”

“…The dose-response of load-induced changes in MMP-3 was stronger than those in COMP in healthy persons. 45 Most studies on in vivo mechanosensitivity of articular cartilage in health and disease have focused on COMP. [2][3][4][6][7][8][9][10][11][12][13][14][15] Greater ambulatory load lead to a greater load-induced increase in MMP-3 in healthy persons.…”