Osteoarthritis: From Palliation to Prevention: AOA Critical Issues

Abstract

Osteoarthritis is a leading cause of disability. The traditional focus on late-stage osteoarthritis has not yielded effective disease-modifying treatments. Consequently, current clinical care focuses on palliation until joint replacement is indicated. A symposium format was used to examine emerging strategies that support the transformation of the clinical approach to osteoarthritis from palliation to prevention. Central to this discussion are concepts for diagnosis and treatment of pre-osteoarthritis, meaning joint conditions that increase the risk of accelerated development of osteoarthritis. The presentation of translational and clinical research on three common orthopaedic conditions-anterior cruciate ligament tear, intra-articular fracture, and hip dysplasia-were used to illustrate these ideas. New information regarding the use of novel quantitative magnetic resonance imaging (MRI) in the form of ultrashort echo time enhanced T2* (UTE-T2*) mapping to evaluate the potential for articular cartilage to heal subsurface damage in a mechanically sound environment was presented. These data indicate that improved diagnostics can both identify cartilage at risk and evaluate the effectiveness of early treatment strategies. With use of a new mouse model for intra-articular fracture, it was shown that inflammation correlated to fracture severity and that super-healer mice avoided early posttraumatic osteoarthritis in part through an enhanced ability to dampen inflammation. These findings suggest that there is a role for acute and sustained anti-inflammatory treatment in the prevention of osteoarthritis. For long-term treatment, contemporary gene-therapy approaches may offer an effective means for sustained intra-articular delivery of anti-inflammatory and other bioactive agents to restore joint homeostasis. To illustrate the potential of early treatment to prevent or delay the onset of disabling osteoarthritis, the positive clinical effects on articular cartilage and in long-term clinical follow-up after operative correction of structural abnormalities about the hip highlight the role for targeting mechanical factors in delaying the onset of osteoarthritis. Given that orthopaedic surgeons treat the full spectrum of joint problems, ranging from joint trauma to pre-osteoarthritic conditions and end-stage osteoarthritis, an awareness of the paradigm shift toward the prevention of osteoarthritis is critical to the promotion of improved clinical care and participation in clinical research involving new treatment strategies.

Fig. 1

Articular cartilage shows capacity to heal subsurface injury. Left: At the time of ACL reconstruction, the entire trochlear groove was softened to the point where probing indicated bubbling of the cartilage both medial and lateral to the raised “wrinkle.” Right: In this patient with poor vastus medialis obliquus recovery, breakdown of the overloaded lateral trochlear groove was noted ten months after the examination performed at the time of ACL reconstruction. In the mechanically privileged areas, the medial cartilage was firm and smooth to probing and the “wrinkle” had firmed into a raised ridge.

Fig. 2

Novel UTE-T2* mapping shows subsurface meniscus and articular cartilage structural changes due to injury that cannot be seen with conventional magnetic resonance imaging (MRI). Left: UTE-T2* maps of the articular cartilage deep tissue (A, arrows) and meniscus (B) of a human subject after ACL tear, showing a mottled pattern that was higher than that seen in the uninjured control. Right: UTE-T2* maps of the articular cartilage (C, arrows) and meniscus (D) of the same subject two years after anatomic anterior cruciate ligament reconstruction, showing return of the laminar pattern with low signal (mapped to red), comparable to the uninjured control. (Meniscal images shown in B and D were reproduced, with permission, from Chu CR, Williams AA, West RV, Qian Y, Fu FH, Do BH, Bruno S. Quantitative magnetic resonance imaging UTE-T2* mapping of cartilage and meniscus healing after anatomic anterior cruciate ligament reconstruction. Am J Sports Med. 2014 May 8. Epub ahead of print. DOI:10.1177/0363546514532227.)

Fig. 3

Super-healer mouse shows reduced susceptibility to posttraumatic osteoarthritis. Histologic images of the lateral compartment of the knee of C57BL/6 and MRL/MpJ mice were made at eight weeks after fracture. The C57BL/6 image (left) shows articular cartilage disruption and degeneration, and loss of (red) proteoglycan staining. The MRL/MpJ image (right) shows articular cartilage disruption and minimal loss of (red) staining. (Safranin O staining, original magnification, original magnification ×100.) Histology scale bars = 100 μm. Boxed areas show sites of histologic damage. (Reproduced from: Ward BD, Furman BD, Huebner JL, Kraus VB, Guilak F, Olson SA. Absence of posttraumatic arthritis following intra-articular fracture in the MRL/MpJ mouse. Arthritis & Rheumatism. 2008 [Mar]; 58[3]:744-53. Reproduced with permission of the original publisher, BioMed Central [open access article].)

Fig. 4

Fig. 4, A, B, and C Gene expression and serum levels of cytokines in C57BL/6 and MRL/MpJ mice following intra-articular fracture (fx). A: A greater than threefold change in expression from pre-fracture to post-fracture was considered significant. B and C: Enzyme-linked immunosorbent assay was used to assess the serum levels of IL-1α (B) and IL-1β (C) in C57BL/6 and MRL/MpJ mice following fracture. IL-1β peaks at Day 1 after injury, consistent with higher synovial levels after injury, while IL-1α levels have a delayed peak at three days after injury. (Reproduced, with modification, from: Lewis JS Jr., Furman BD, Zeitler E, Huebner JL, Kraus VB, Guilak F, Olson SA. Genetic and cellular evidence of decreased inflammation associated with reduced incidence of posttraumatic arthritis in MRL/MpJ mice. Arthritis & Rheumatism. 2013 [Mar]:65[3]:660-70. Reproduced with permission of the original publisher, BioMed Central [open access article].)