Accelerated Cartilage Resorption by Chondroclasts during Bone Fracture Healing in Osteoprotegerin-Deficient Mice

Ota, Norikazu; Takaishi, Hironari; Kosaki, Naoto; Takito, Jiro; Yoda, Masaki; Tohmonda, Takahide; Kimura, Tokuhiro; Okada, Yasunori; Yasuda, Hisataka; Kawaguchi, Hiroshi; Matsumoto, Morio; Chiba, Kazuhiro; Ikegami, Hiroyasu; Toyama, Yoshiaki

doi:10.1210/en.2009-0452

Cited by 39 publications

(37 citation statements)

References 59 publications

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“…However, we observed extracellular and tissue localization of RANKL in the lacunae of the chondrocytes that is consistent with RANKL being in a soluble form. In addition, it has been shown previously that significant amounts of sRANKL (10.9 ± 2.2 pg/ml) are produced by OPG-knockout chondrocytes in vitro, indicating that sRANKL can indeed be produced by chondrocytes in the setting of an altered RANKL/OPG ratio [23]. In human osteoarthritis of the temporomandibular joint, sRANKL levels in the synovial fluid were not increased compared to normal [24]; however, supporting our findings sRANKL is increased in the serum of patients with primary knee OA [25].…”

Section: Discussionmentioning

confidence: 75%

The expression of RANKL and OPG in the various grades of osteoarthritic cartilage

et al. 2011

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The objective of the study was to determine whether cartilage expression of the bone regulating molecules receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) varies between the different grades of osteoarthritis (OA). Cartilage samples were obtained from 30 patients undergoing total hip/knee replacement surgery. Tissue sections were stained with Safranin O and graded. Immunohistochemical staining was then performed, and levels of RANKL and OPG expression were assessed using a semi-quantitative scoring system. In addition, levels of mRNA encoding for RANKL and OPG were determined by a relative real-time reverse transcription-polymerase chain reaction technique. We found that expression of RANKL protein, mRNA expression, and the ratio of RANKL: OPG mRNA was greater in grade 2 cartilage in comparison with grade 0 cartilage (P < 0.05). Increased RANKL staining in the grade 2 cartilage was predominantly in the peri-cellular region of the middle and deep zones as well as in the matrix of the superficial zone. OPG mRNA expression was greater in grade 3 cartilage in comparison with grade 0 cartilage (P < 0.05). Cartilage and subchondral bone are in close proximity and soluble proteins produced in the cartilage are likely to move from one compartment to the other. Our finding of increased expression of RANKL in grade 2 OA cartilage might explain the increase in bone turnover reported in the subchondral bone of OA patients. The changes seen in the different grades of tissue may also indicate that this effect occurs during the early stages of OA development.

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Section: Discussionmentioning

confidence: 75%

The expression of RANKL and OPG in the various grades of osteoarthritic cartilage

et al. 2011

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“…By regulating osteoclast activity, the RANK/RANKL/OPG axis has ramifications for a wide range of physiologic and pathologic processes in bone, including osteoporosis, metastatic bone disease, rheumatoid arthritis, fracture healing, and periodontal disease [21,[25][26][27][28][36][37][38][39][40][41][42]. OPG has a well-defined bone protective effect and is able to rescue bone mass in a variety of bone catabolic conditions through its central role as an inhibitor of osteoclast differentiation and survival [43].…”

Section: Discussionmentioning

confidence: 99%

“…As such, the peak of OPG levels correlates with cartilaginous callus formation and the RANKL peak correlates with remodeling of the callus into bone tissue [37]. Also, chondroclast activity is upregulated in OPG -/-knockout mice, resulting in an increased rate of callus replacement [39]. Conversely, RANKL antibody therapy inhibits the normal sequence of callus remodeling in a mouse long bone fracture model, leading to greater callus size, mineral content, and biomechanical strength [42].…”

Section: Discussionmentioning

confidence: 99%

Local Delivery of Recombinant Osteoprotegerin Enhances Postorthodontic Tooth Stability

et al. 2012

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Relapse after orthodontic tooth movement is a significant problem in orthodontics. The purpose of this study was to examine the efficacy of the osteoclast inhibitor osteoprotegerin-Fc (OPG-Fc) for inhibiting postorthodontic relapse. Rat maxillary molars were moved mesially and allowed to relapse for 24 days. Low-dose (1 mg/kg) or high-dose (5 mg/kg) OPG-Fc or saline was injected adjacent to the molars during relapse. Tooth movement, micro-CT, histologic bone quality, and serum OPG and TRAP-5b were measured. OPG-Fc injections significantly diminished postorthodontic relapse from 63% (0.78/1.20 mm) of total movement in vehicle control rats to 31% (0.31/1.00 mm) in low-dose and 24% (0.28/1.16 mm) in high-dose OPG-Fc groups 24 days after appliance removal. Normalization of bone and periodontal tissues occurred as early as 8 and 16 days in the high- and low-dose OPG-Fc-treated groups, respectively, while the vehicle-treated group showed only partial tissue recovery 24 days following tooth movement. After 24 days of relapse, there was complete recovery to pre-tooth-movement values for bone volume fraction (BVF) and tissue mineral density (TMD) in both the low- and high-dose OPG-Fc groups, while BVF recovered only partially and TMD did not recover in the vehicle control group. Greatly elevated serum OPG levels and reduced serum TRAP-5b levels in OPG-Fc-treated animals indicated systemic exposure to locally injected drug. The profound decrease in postorthodontic relapse by local OPG-Fc administration indicates that osteoclasts are critical to bone maturation following tooth movement and points to the potential pharmacologic use of OPG-Fc or other RANKL inhibitors for orthodontic retention.

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“…Interestingly, Ota and colleagues investigated chondroclasts and found processes reminiscent of the pathogenesis of OA in the bone growth plate during fracture repair. The local OPG produced by chondrocytes controlled cartilage resorption, thereby serving as a negative regulator for chondrocyte-dependent chondroclastogenesis 133. These results begin to elucidate the interactions of chondrocytes, cartilage matrix and osteoclasts.…”

Section: The Role Of Subchondral Bone Turnover and Structure In Oamentioning

confidence: 90%

The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments?

et al. 2013

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Osteoarthritis (OA) is the most common form of arthritic disease, and a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the entire joint, affecting bone, cartilage and synovium that thereby presents multiple targets for treatment. This manuscript will summarise emerging observations from cell biology, preclinical and preliminary clinical trials that elucidate interactions between the bone and cartilage components in particular. Bone and cartilage health are tightly associated. Ample evidence has been found for bone changes during progression of OA including, but not limited to, increased turnover in the subchondral bone, undermineralisation of the trabecular structure, osteophyte formation, bone marrow lesions and sclerosis of the subchondral plate. Meanwhile, a range of investigations has shown positive effects on cartilage health when bone resorption is suppressed, or deterioration of the cartilage when resorption is increased. Known bone therapies, namely oestrogens, selective oestrogen receptor modifiers (SERMs), bisphosphonates, strontium ranelate, calcitonin and parathyroid hormone, might prove useful for treating two critical tissue components of the OA joint, the bone and the cartilage. An optimal treatment for OA likely targets at least these two tissue components. The patient subgroups for whom these therapies are most appropriate have yet to be fully defined but would likely include, at a minimum, those with high bone turnover.

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Accelerated Cartilage Resorption by Chondroclasts during Bone Fracture Healing in Osteoprotegerin-Deficient Mice

Cited by 39 publications

References 59 publications

The expression of RANKL and OPG in the various grades of osteoarthritic cartilage

The expression of RANKL and OPG in the various grades of osteoarthritic cartilage

Local Delivery of Recombinant Osteoprotegerin Enhances Postorthodontic Tooth Stability

The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments?

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