The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Abstract

Objective. It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation.Methods. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 g/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor ␤ (TGF␤), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF␤.Results. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dosedependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF␤, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Conclusion. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.Osteoarthritis (OA) is a degenerative joint disease characterized by pain, cartilage loss, and joint stiffness. Although OA has long been considered to be primarily a cartilage disorder associated with focal articular cartilage degradation, this disease is accompanied by well-defined changes in the subchondral and periarticular bone, including sclerosis and cyst and osteophyte formation (1). The importance of the bone changes in the initiation and progression of OA is still being debated. It has been suggested that increased subchondral bone stiffness reduces the ability to dissipate the load and distribute the strain generated within the joint. This increases peak dynamic forces in the overlying articular cartilage and can accelerate its damage over time (2). The functional integrity of the articular cartilage can therefore depend on the mechanical properties of the underlying bone. Accordingly, cartilage damage leads to full-thickness cartilage loss only upon repetitive loading over an already stiffened subchondral bone plate (3).Recent studies have demonstrated increased subchondral bone turnover accompanied by specific architectural changes in the subchondral trabecular bone in OA joints (4,5...

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

“…In a guinea pig model, bone densitometry evaluation following meniscectomy revealed typical variations in bone metabolism with early resorption of subchondral bone followed by increased bone density [18]. This concurs with findings from other animal models, such as the ACL dog and rat OA models, in which were observed, at an early stage of the disease process, increased subchondral bone resorption with trabecular thickness reduction and an increased number of osteoclasts, as well as increased production of catabolic factors including cathepsin K and matrix metalloproteinase (MMP)-13 [6][7][8][9].…”

“…Moreover, in this animal model, the severity of cartilage fibrillation and loss generally exceeds bone changes only in advanced OA. Although it has been shown in some induced OA animal models, which allow chronological analysis of the disease progression, that the subchondral bone changes precede cartilage changes [6][7][8][9], this has yet to be clarified in humans.…”

“…In the rat ACL transection model, alendronate demonstrated chondroprotective effects with osteophyte formation inhibition and reduction in cartilage degradation biomarkers [7]. However, different results were obtained with this drug in the spontaneous guinea pig model, in which alendronate increased the bone mineral content and density, which was associated with the acceleration of cartilage degradation [127].…”

Relationship between microstructure and degree of mineralization in subchondral bone of osteoarthritis: A synchrotron radiation µCT study

“…Animal studies have also indicated that bone resorption inhibitors suppress OA progression. (4,5) Several bone turnoverinhibiting drugs, such as alendronate, risedronate, and calcitonin, have been proposed as candidates for OA treatment. (6,7) Therefore, it is important to understand subchondral bone turnover to analyze OA pathophysiology and develop appropriate therapies.…”

Accelerated development of aging‐associated and instability‐induced osteoarthritis in osteopontin‐deficient mice

“…The main causes of OA are considered to be aging and excessive mechanical stress to the joints, due to joint instability or obesity (2). A number of in vivo studies using various joint instability models have clarified some aspects of the molecular mechanisms comprising the response to excessive mechanical stress to the joints (3)(4)(5)(6)(7)(8). However, the mechanisms of agingassociated development of OA have not been clearly elucidated.…”