Differential patterns of pathology in and interaction between joint tissues in long-term osteoarthritis with different initiating causes: phenotype matters

Abstract

Objective: To determine if osteoarthritis (OA) progression and joint tissueepathology associations link specific animal models to different human OA phenotypes. Design: Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA). Joint tissue histopathology was scored day-3 to week-16. Tissue-pathology associations (corrected for time and at week-16) were determined by partial correlation coefficients, and odds ratios (OR) calculated for likelihood of cartilage damage and joint inflammation by ordinal-logisticregression. Results: Despite distinct temporal patterns of progression, by week-16 joint-wide OA pathology in DMM and AIA was equivalent. Significant pathology associations common to both models included: osteophyte size and maturity (r > 0.4); subchondral bone (SCB) sclerosis and osteophyte maturity (r > 0.25); cartilage erosion and chondrocyte hypertrophy/apoptosis (r > 0.4), SCB sclerosis (r > 0.26), osteophyte size (r > 0.3), and maturity (r > 0.32). DMM-specific associations were between cartilage proteoglycan loss and structural damage (r ¼ 0.56), osteophyte maturity (r ¼ 0.49), size (r ¼ 0.45), and SCB sclerosis (r ¼ 0.28). AIA-specific associations were between SCB sclerosis and chondrocyte hypertrophy/apoptosis (r ¼ 0.40) and osteophyte size (r ¼ 0.37); and synovitis with cartilage structural damage (r ¼ 0.18). No tissueepathology associations were common to both models at week-16. Increased likelihood of cartilage structural damage was associated with: chondrocyte hypertrophy/apoptosis (OR>1.7), and osteophyte size (OR>2.3) in both models; SCB sclerosis (OR ¼ 2.0) and proteoglycan loss (OR ¼ 2.4) in DMM; and synovitis (OR ¼ 1.2) in AIA. Joint inflammation was associated positively with cartilage proteoglycan loss (OR ¼ 1.4) and inversely with osteophyte size (OR ¼ 0.21) in AIA only. Conclusion:This study highlights the importance of defining OA-models by initiating mechanisms and progression, not just end-stage joint-tissue pathology.

Animal Models of Bone Marrow Lesions in Osteoarthritis

“…(37) Follow-up studies are needed to confirm the presence of a BML in this mouse model and, if present, whether it precedes joint degeneration or is simply co-occurring. Another limitation of this line of investigation is the use of ACL transection, which causes severe changes in joint stability to initiate osteoarthritis (the ACL transection model is classified as "traumatic" in the literature (38,39) ). It is unclear if the same mechanisms identified under this severe traumatic disruption of joint biomechanics are also active in less-severe situations such as nontraumatic OA-associated BMLs.…”

Monocytes, Macrophages, and Their Potential Niches in Synovial Joints – Therapeutic Targets in Post-Traumatic Osteoarthritis?

“…One explanation is the current discrepancy between preclinical research predominantly using ptOA models and clinical studies, the majority of which investigate late-stage “primary OA” which occurs in the absence of prior trauma or disease ( 309 ). There is emerging evidence that the pathophysiologic mechanisms of structural and symptomatic OA differs depending on the key initiating factors or disease phenotype ( 310 , 311 ). How different the complex cellular inflammatory response is in different OA phenotypes remains to be resolved.…”

Clinical Manifestations, Histopathological Changes And Quality Of Life In Patients With Advanced Knee Osteoarthritis Caused By Age, Trauma, Obesity And Their Combination

“…Hence, the histopathological studies of OA phenotypes seem quite relevant. Earlier experimental study [18] revealed the relationship between initiating OA mechanisms and structural joint tissues progression in animal models, imitating the development of different human OA phenotypes.…”