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Purpose: Strong observational evidence has linked changes in limb loading during walking following anterior cruciate ligament reconstruction (ACLR) to posttraumatic osteoarthritis (PTOA). It remains unknown if manipulating peak loading influences joint tissue biochemistry. Thus, the purpose of this study is to determine whether manipulating peak vertical ground reaction force (vGRF) during gait influences changes in serum cartilage oligomeric matrix protein (sCOMP) concentrations in ACLR participants., Methods: Forty ACLR individuals participated in this randomized crossover study (48% female, age = 21.0 ± 4.4 years, BMI = 24.6 ± 3.1). Participants attended four sessions, wherein they completed one of four biofeedback conditions (habitual loading (no biofeedback), high loading (5% increase in vGRF), low loading (5% decrease in vGRF), and symmetrical loading (between-limb symmetry in vGRF)) while walking on a treadmill for 3000 steps. Serum was collected before (baseline), immediately (acute post), 1 h (1 h post), and 3.5 h (3.5 h post) following each condition. A comprehensive general linear mixed model was constructed to address the differences in sCOMP across all conditions and timepoints in all participants and a subgroup of sCOMP Increasers., Results: No sCOMP differences were found across the entire cohort. In the sCOMP Increasers, a significant time × condition interaction was found (F 9,206  = 2.6, p = 0.009). sCOMP was lower during high loading than low loading (p = 0.009) acutely (acute post). At 3.5 h post, sCOMP was higher during habitual loading than symmetrical loading (p = 0.001)., Conclusion: These data suggest that manipulating lower limb loading in ACLR patients who habitually exhibit an acute increase in sCOMP following walking results in improved biochemical changes linked to cartilage health. Key Points • This study assesses the mechanistic link between lower limb load modification and joint tissue biochemistry at acute and delayed timepoints. • Real-time biofeedback provides a paradigm to experimentally assess the mechanistic link between loading and serum biomarkers. • Manipulating peak loading during gait resulted in a metabolic effect of lower sCOMP concentrations in a subgroup of ACLR individuals. • Peak loading modifications may provide an intervention strategy to mitigate the development of PTOA following ACLR., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Posttraumatic osteoarthritis (PTOA) is mostly treated via corticosteroid administration, and total joint arthroplasty continues to be the sole effective intervention in severe conditions. To assess the therapeutic potential of CCR2 targeting in PTOA, we used biodegradable microplates (µPLs) to achieve a slow and sustained intraarticular release of the CCR2 inhibitor RS504393 into injured knees and followed joint damage during disease progression. RS504393-loaded µPLs (RS-µPLs) were fabricated via a template-replica molding technique. A mixture of poly(lactic-co-glycolic acid) (PLGA) and RS504393 was deposited into 20 × 10 μm (length × height) wells in a polyvinyl alcohol (PVA) square-patterned template. After physicochemical and toxicological characterizations, the RS504393 release profile from µPL was assessed in PBS buffer. C57BL/6 J male mice were subjected to destabilization of the medial meniscus (DMM)/sham surgery, and RS-µPLs (1 mg/kg) were administered intraarticularly 1 week postsurgery. Administrations were repeated at 4 and 7 weeks post-DMM. Drug free-µPLs (DF-µPLs) and saline injections were performed as controls. Mice were euthanized at 4 and 10 weeks post-DMM, corresponding to the early and severe PTOA stages, respectively. Knees were evaluated for cartilage structure score (ACS, H&E), matrix loss (safranin O score), osteophyte formation and maturation from cartilage to bone (cartilage quantification), and subchondral plate thickness. The RS-µPL architecture ensured the sustained release of CCR2 inhibitors over several weeks, with ~ 20% of RS504393 still available at 21 days. This prolonged release improved cartilage structure and reduced bone damage and synovial hyperplasia at both PTOA stages. Extracellular matrix loss was also attenuated, although with less efficacy. The results indicate that local sustained delivery is needed to optimize CCR2-targeted therapies., (© 2022. The Author(s).)