1 Det Sundhedsvidenskabelige Fakultet, SDU2 Orthopaedics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Orthopaedics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
Ming Ding, Carl C. Danielsen and Ivan Hvid
Introduction: Hyaluronan (HA) is a biologic material, and a major component of synovial fluid. HA has received increasing interest as a potential agent of therapeutic intervention in osteoarthrosis (OA). High molecular weight HA has been shown to reduce arthritic lesions in experimental animal models of articular cartilage injury. It is not known whether HA has any effect on the underlying subchondral bone tissues, e.g. three-dimensional (3-D) microarchitecture, density, collagen and mineral. The aims of the current study were to investigate the effects of high molecular weight HA (1.5x106 Daltons) intra-articular injection on subchondral bone tissues. Methods: Fifty-six male guinea pigs (6.5 months of age) were randomly divided into 5 groups studied in a short-term and a long-term experimental period (Fig. 1). In the short-term study: HA-I group received intra-articular injection of HA 0.4 mg/kg/week for 5 weeks in both knee joints; the control group received vehicle. In the long-term study: HA-II received 0.4mg/kg/week intra-articular injection for additional 5 weeks; HA-III received no more injection; and the control group received vehicle. After the injection periods the guinea pigs were left untreated until sacrifice (9 and 12 months of age), the left tibiae were harvested and micro-CT scanned to quantify 3-D microarchitecture of subchondral bone plate, cancellous bone and cortical bone, followed by mechanical testing and collagen and mineral determination. Results: The HA-treated groups had almost normal cartilage, whereas the control groups had typical OA-related cartilage degradation. In the short-term study, compared with the control group, HA-injection resulted in a significantly decreased subchondral plate volume fraction and plate thickness. HA-treated cancellous bone had significantly lower bone volume fraction, and typical rod-like structure. In the long-term study, these latter changes were more pronounced, with an additionally significant decrease in connectivity and bone surface density (Fig. 2). In the short-term study, HA-treated cortical bone had significantly greater volume fraction, and surface density. In the long-term study, both HA groups had greater volume fraction and cortical thickness. HA groups had greater bone mineral concentration and mineral density, lower collagen to mineral ratio, and preserved the mechanical properties of cancellous bone. The effects of HA on cartilage and subchondral bone were maintained when HA treatment was discontinued (Table 1). Discussion: The current study has investigated the effects of HA on the properties of subchondral bone tissues in a primary guinea pig OA model. Significant positive effects of high molecular weight HA on the articular cartilage and subchondral bone tissues were seen. HA protects against OA-related cartilage degradation to almost normal level, and effectively changes the subchondral bone tissue microarchitecture, collagen and mineral content and density without altering the mechanical properties of cancellous bone. The most striking features are the microarchitectural changes in the subchondral cancellous bone that lead to lower bone density and markedly rod-like structure, and thus reducing cartilage stress during impact loading. Still, the subchondral bone has a greater mineral concentration, and a lower collagen to mineral ratio, and thus preserves the mechanical properties of cancellous bone. Our results also suggest that short-term high molecular HA administration is sufficient to maintain the effects of HA, since there are no significant difference in the properties between the continuous and the discontinuous HA groups. These findings are in favor of Radin’s hypothesis that increased subchondral density leads to cartilage damage, and that subchondral bone sclerosis may actually precede cartilage degeneration and loss. We conclude that HA protects against cartilage degeneration through decreasing subchondral bone density and thickness, changing trabecular structure toward rod-like, as that subchondral bone becomes softer, thereby reducing cartilage stress during impact loading. Furthermore, HA preserves the mechanical properties of cancellous bone by increasing bone mineralization. The current findings highlighted above have the strong clinical implication that early HA administration is needed for intervention of OA initiation and progression.
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<strong> </strong><em>Annual Meeting</em><strong> </strong>of the <em>Orthopaedic Research Society</em> <strong/><strong/>, 2005