The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage

Muehleman, Carol; Green, Jacalyn M.; Williams, James M.; Kuettner, Klaus E.; Thonar, Eugene J.‐M.A.; Sumner, Dale R.

doi:10.1053/joca.2001.0506

Cited by 77 publications

(70 citation statements)

References 33 publications

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“…Recently, zoledronate was reported to be partially chondroprotective in carrageenan-induced inflammatory arthritis (48) and chymopapain-induced cartilage damage in rabbits (28). In our ACLT model, ALN had a partial chondroprotective effect at the early stage of disease, as reflected in a lower Mankin score.…”

Section: Discussionmentioning

confidence: 59%

“…Urinary deoxypyridinoline, a bone remodeling marker, was previously reported to be increased in animal models of OA (28). At 2 weeks after surgery in the present study, the mean Ϯ SEM urinary levels of CTX-I, a specific marker of bone resorption (corrected for creatinine), were as follows: 5.20 Ϯ 1.54 g/mmole of creatinine in the shamϩV group, 2.71 Ϯ 1.09 in the shamϩH group, 7.41 Ϯ 3.43 in the ACLTϩV group, and 2.68 Ϯ 1.42 in the ACLTϩH group ( Figure 2b).…”

Section: Resultsmentioning

confidence: 98%

“…The investigators noted that the sample size was relatively small and cartilage changes were mild. Zoledronate was recently reported to reduce cartilage damage caused by intraarticular injections of chymopapain in the rabbit knee joint (28). Deoxypyridinoline, a systemic marker of the bone resorption, was also reduced, but subchondral bone remodeling and osteophyte formation were not examined.…”

Section: Discussionmentioning

confidence: 99%

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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

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

505

465

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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...

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Section: Discussionmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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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

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

505

465

View full text Add to dashboard Cite

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“…Localization of the early lesions of OA has not been clarified, but many researchers have focused on articular cartilage (1,2) and have considered that changes in subchondral bone occur subsequent to the degeneration of articular cartilage. However, a low bone mineral density (BMD), particularly in the knee joint with OA (3,4), high bone turnover (5-7), and efficacy of bone resorption inhibitors for OA (8)(9)(10)(11)(12)(13)(14) have recently been reported, suggesting that subchondral bone plays an important role in the pathogenesis of knee OA. Burr (15) reported that microdamage to subchondral bone by mechanical overload was repaired and led to bone sclerosis, by which bone turnover was enhanced and resulted in the deterioration of subchondral bone, suggesting the importance of subchondral bone and bone turnover in the progression of OA.…”

mentioning

confidence: 99%

Role of subchondral bone in osteoarthritis development: A comparative study of two strains of guinea pigs with and without spontaneously occurring osteoarthritis

Muraoka¹,

Hagino²,

Okano³

et al. 2007

Arthritis & Rheumatism

106

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Objective. To evaluate the relationships among cartilage and subchondral bone before and after the onset of cartilage degeneration in the Hartley guinea pig model of spontaneous osteoarthritis (OA) as compared with those in Weiser-Maple guinea pigs, which do not develop OA.Methods. Mice from each strain were used at ages 2, 3, 5, and 8 months (n ‫؍‬ 7 at each time point). The region observed was the medial tibial plateau. Cartilage degeneration was evaluated histologically. Subchondral bone structure was evaluated based on subchondral bone plate thickness and subchondral cancellous bone trabecular parameters calculated from the microfocal computed tomography 3-dimensional reconstruction image. The bone mineral density (BMD) of the subchondral cancellous bone as well as levels of urinary N-telopeptide of type I collagen (NTX) and serum osteocalcin (OC) were measured.Results. In Hartley guinea pigs, the number of chondrocytes in the surface layer started to decrease at 3 months. At 8 months, fibrillation expanded to the radial zone. In Weiser-Maple guinea pigs, no cartilage degeneration was noted even at 8 months. Subchondral bone plate thickness was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The subchondral bone had a rod-like and convex structure at 2 months in Hartley guinea pigs. BMD was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The serum OC level was significantly higher in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months and 3 months, whereas the urinary NTX level was significantly lower in Hartley guinea pigs at 3 months.Conclusion. Subchondral bone is fragile, and bone formation may be promoted in subchondral bone before the onset of cartilage degeneration in Hartley guinea pigs. Subchondral bone may be involved in the development of OA.Osteoarthritis (OA) is the most prevalent of joint diseases, and its pathology is characterized by the degeneration of articular cartilage, sclerosis of subchondral bone, and osteophyte formation. Localization of the early lesions of OA has not been clarified, but many researchers have focused on articular cartilage (1,2) and have considered that changes in subchondral bone occur subsequent to the degeneration of articular cartilage. However, a low bone mineral density (BMD), particularly in the knee joint with OA (3,4), high bone turnover (5-7), and efficacy of bone resorption inhibitors for OA (8)(9)(10)(11)(12)(13)(14) have recently been reported, suggesting that subchondral bone plays an important role in the pathogenesis of knee OA. Burr (15) reported that microdamage to subchondral bone by mechanical overload was repaired and led to bone sclerosis, by which bone turnover was enhanced and resulted in the deterioration of subchondral bone, suggesting the importance of subchondral bone and bone turnover in the progression of OA. Most of these clinical and experimental studies of subchondral bone were related to OA progression, but there have been fewer studies con...

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“…The results of this study proved our hypothesis and also showed compatibility with existing literature. 12,16 Aside from the well-known effects of BP on bone tissue, its effects on cartilage tissue has not previously been clearly understood. The effect of BP on cartilage tissue was explained in two ways: (1) indirectly prevents focal destruction by inhibiting subchondral bone resorption, and (2) directly decreases cartilage matrix degeneration.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic Acid Effect on Chondrocyte Apoptosis in Degenerative Osteoarthritis Model

Uysal

Özkoç

Bolat

et al. 2016

International Surgery

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Apoptosis refers to cell death without inflammatory process, and is related to degenerative changes in joints. We hypothesized that zoledronic acid (ZA) would have a positive effect on chondrocyte viability and decreases in chondrocyte loss, which are important for the progression of degeneration. This study aimed to reveal the difference in time-dependent apoptotic changes in cartilage tissue in the anterior cruciate ligament (ACL) transection model of osteoarthritis (OA) in rat knees after treatment with zoledronic acid. We randomly divided 48 male Wistar albino rats into 6 groups. The knees of all rats except those in the control group underwent the operation for ACL transection. ZA for half of the rats and saline solution for the others was injected weekly into knees. Animals were killed at 0, 3, and 6 weeks after surgery. Apoptosis of chondrocytes were analyzed using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. Comparison of groups was performed using Kruskal Wallis analysis and the Mann Whitney U test. Significant differences were observed between the groups treated with ZA and saline. ZA treatment significantly decreased the number of apoptotic cells in chondral tissue. ZA prevents time-dependent degenerative changes in chondral tissue by decreasing chondrocyte death. Intra-articular ZA may have the potential to treat and conserve chondral viability. ZA prevents chondrocyte loss and may play a therapeutic role in OA and conserving joint health. Further studies are needed to evaluate the potential of intraarticular ZA for the prevention or treatment of age-related degenerative changes.Key words: Apoptosis -Osteoarthritis -Cartilage -Zoledronic acid -Chondrocyte O steoarthritis (OA) has been considered to be, primarily, a cartilage disorder resulting from the changes in matrix composition of cartilage and the reduction of tissue cellularity. OA cartilage was initially thought to occur through loss of chondrocytes. 1 The factors that trigger the initial chondrocyte destruction still are not sufficiently apparent. OA is also associated with subchondral and periarticular bone changes.2 Increased subchondral turnover leads to changes in subchondral bone architecture.3 Apoptosis or programmed cell death represents a physiologic form of cell death that does not induce an inflammatory response. Recent studies have reported that apoptosis plays a major role in cell death in cartilage tissue. [4][5][6][7][8] In some studies, it was also suggested that osteoarthritic cartilage has shown that apoptosis has also been positively correlated with the severity of cartilage destruction and matrix depletion. [4][5][6]9 Bisphosphonates (BPs), which are the inhibitors of osteoclastic activity, show their therapeutic action by inhibition of bone remodeling. Higher rates of bone turnover is associated with progression of OA.10 BP has a protective effect against the development of osteoarthritic changes.11,12 Zoledronic acid (ZA), a third-generation BP, is the most potent form of its kind, so only smal...

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The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage

Cited by 77 publications

References 33 publications

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

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

Role of subchondral bone in osteoarthritis development: A comparative study of two strains of guinea pigs with and without spontaneously occurring osteoarthritis

Zoledronic Acid Effect on Chondrocyte Apoptosis in Degenerative Osteoarthritis Model

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