Early ablation of Ccr2 in aggrecan-expressing cells following knee injury ameliorates joint damage and pain during post-traumatic osteoarthritis

Willcockson, Helen H.; Özkan, Hüseyin; Arbeeva, Liubov; Mucahit, Esra; Musawwir, Layla; Longobardi, Lara

doi:10.1016/j.joca.2022.08.015

Cited by 2 publications

(16 citation statements)

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“…PTOA pain in the DMM model was assessed, as we previously reported [ 10 ]. Weight-bearing measures (static spontaneous pain) were obtained by assessing the hindlimb weight distribution with an incapacitance meter, as previously reported [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

“…Histological preparations were obtained, as we previously reported [ 10 ]. Briefly, mouse knees were fixed (4% PFA), decalcified (Immunocal, StatLab, McKinney, TX, USA), embedded in paraffin and cut through the entire joint (frontal sections, 6 µm).…”

Section: Methodsmentioning

confidence: 99%

“…Semiquantitative measures of osteophyte formation were obtained, as we previously reported [ 10 ], using the method described by Little et al [ 27 ]. Briefly, osteophyte size (on a scale of 0–3) was scored by comparison with the thickness of the adjacent articular cartilage; osteophyte maturity (on a scale of 0–3) is used to define the tissue composition of the osteophyte, assigning a lower score to a cartilagineous osteophyte and a higher score to an osteophyte constituted predominantly by bone [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

“…As previously reported [ 10 ], we quantified the area of cartilaginous tissue (defined by Saf-O staining) within an osteophyte by performing histomorphometric analyses using ImageJ software and following the method of Nagira et al [ 26 ]. Measures were expressed as the ratio between the percentage of Saf-O Area/percentage of osteophyte.…”

Section: Methodsmentioning

confidence: 99%

“…Increased expression of chemokines in joint tissues is believed to be linked to OA progression; in particular, the C-C chemokine receptor-2 (CCR2) and its ligands CCL2 and CCL12 (a.k.a. MCP1 and MCP5, respectively) that are known to be involved in the recruitment of immune cells at sites of inflammation [ 1 , 2 ], have been shown to be significantly increased in both humans with OA and in rodent models of OA and to mediate OA pain [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. In addition to macrophages, CCR2, CCL2, and CCL12 are expressed on chondrocytes, osteoblasts, and tendon fibroblasts, where they influence early tissue degeneration following injury [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis

et al. 2023

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In osteoarthritis (OA), bone changes are radiological hallmarks and are considered important for disease progression. The C-C chemokine receptor-2 (CCR2) has been shown to play an important role in bone physiology. In this study, we investigated whether Ccr2 osteoblast-specific inactivation at different times during post-traumatic OA (PTOA) progression improves joint structures, bone parameters, and pain. We used a tamoxifen-inducible Ccr2 inactivation in Collagen1α-expressing cells to obtain osteoblasts lacking Ccr2 (CCR2-Col1αKO). We stimulated PTOA changes in CCR2-Col1αKO and CCR2+/+ mice using the destabilization of the meniscus model (DMM), inducing recombination before or after DMM (early- vs. late-inactivation). Joint damage was evaluated at two, four, eight, and twelve weeks post-DMM using multiple scores: articular-cartilage structure (ACS), Safranin-O, histomorphometry, osteophyte size/maturity, subchondral bone thickness and synovial hyperplasia. Spontaneous and evoked pain were assessed for up to 20 weeks. We found that early osteoblast-Ccr2 inactivation delayed articular cartilage damage and matrix degeneration compared to CCR2+/+, as well as DMM-induced bone thickness. Osteophyte formation and maturation were only minimally affected. Late Collagen1α-Ccr2 deletion led to less evident improvements. Osteoblast-Ccr2 deletion also improved static measures of pain, while evoked pain did not change. Our study demonstrates that Ccr2 expression in osteoblasts contributes to PTOA disease progression and pain by affecting both cartilage and bone tissues.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis

et al. 2023

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Harmonizing hope: navigating the osteoarthritis melody through the CCL2/CCR2 axis for innovative therapeutic avenues

Abbasifard,

Khorramdelazad

2024

Front. Immunol.

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Osteoarthritis (OA) is characterized by a complex interplay of molecular signals orchestrated by the CCL2/CCR2 axis. The pathogenesis of OA has been revealed to be influenced by a multifaceted effect of CCL2/CCR2 signaling on inflammation, cartilage degradation, and joint homeostasis. The CCL2/CCR2 axis promotes immune cell recruitment and tips the balance toward degeneration by influencing chondrocyte behavior. Insights into these intricate pathways will offer novel therapeutic approaches, paving the way for targeted interventions that may redefine OA management in the future. This review article explores the molecular symphony through the lens of the CCL2/CCR2 axis, providing a harmonious blend of current knowledge and future directions on OA treatment. Furthermore, in this study, through a meticulous review of recent research, the key players and molecular mechanisms that amplify the catabolic cascade within the joint microenvironment are identified, and therapeutic approaches to targeting the CCL2/CCR axis are discussed.

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Early ablation of Ccr2 in aggrecan-expressing cells following knee injury ameliorates joint damage and pain during post-traumatic osteoarthritis

Cited by 2 publications

References 49 publications

CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis

CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis

Harmonizing hope: navigating the osteoarthritis melody through the CCL2/CCR2 axis for innovative therapeutic avenues

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