Inhibiting Periapical Lesions through AAV-RNAi Silencing of Cathepsin K

Gao, Bo; Chen, W.; Hao, Liang; Zhu, Guochun; Shan, Feng; Ci, Hongliang; Zhou, Xuedong; Stashenko, P.; Li, Y.P.

doi:10.1177/0022034512468757

Cited by 49 publications

(67 citation statements)

References 30 publications

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“…Exposure of the left and right first molar pulp was performed as described previously (10,17). In brief, mice were anesthetized with peritoneal injection of 62.5 mg/kg ketamine and 12.5 mg/kg xylazine according to body weight.…”

Section: Animalsmentioning

confidence: 99%

“…Bacterial culture and infection procedure protocols were conducted as described previously (10,17). In brief, exposed pulps were infected with a mixture of four common human endodontic pathogens, including Prevotella intermedia (ATCC 25611; American Type Culture Collection [ATCC], Manassas, VA), Fusobacterium nucleatum (ATCC 25586), Peptostreptococcus micros (ATCC 33270), and Streptococcus intermedius (ATCC 27335).…”

Section: Animalsmentioning

confidence: 99%

“…Micro-computed tomography (micro-CT) scans were evaluated for bone loss as described previously, with modifications (10,17). Briefly, the two-dimensional picture that showed the largest target root canal was selected as the baseline image.…”

Section: Animalsmentioning

confidence: 99%

“…P values of Ͻ0.05 and U values of Ͼ1.96 were considered significant. Data quantification analyses were performed using the NIH Image J program as described previously (10,17).…”

Section: Animalsmentioning

confidence: 99%

“…Recent studies demonstrated that cathepsins are required for expression of Toll-like receptor 9 in dendritic cells, which plays an essential role in innate recognition of microbial products and activation of defense responses (9). Our research led to the surprising and pivotal realization that Ctsk also has significant functions in the immune system (10,11), so we termed the Ctsk gene an "osteoimmune gene." The study of bone and the immune system, which is termed osteoimmunology, represents a new perspective which takes into account the multiple advances made in the study of biological events in bone and the immune system in recent years (12,13).…”

mentioning

confidence: 98%

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A Small Molecule, Odanacatib, Inhibits Inflammation and Bone Loss Caused by Endodontic Disease

et al. 2015

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dPeriapical disease, an inflammatory disease mainly caused by dental caries, is one of the most prevalent infectious diseases of humans, affecting both children and adults. The infection travels through the root, leading to inflammation, bone destruction, and severe pain for the patient. Therefore, the development of a new class of anti-periapical disease therapies is necessary and critical for treatment and prevention. A small molecule, odanacatib (ODN), which is a cathepsin K (Ctsk) inhibitor, was investigated to determine its ability to treat this disease in a mouse model of periapical disease. While Ctsk was originally found in osteoclasts as an osteoclast-specific lysosomal protease, we were surprised to find that ODN can suppress the bacterium-induced immune response as well as bone destruction in the lesion area. X rays and microcomputed tomography (micro-CT) showed that ODN treatment had significant bone protection effects at different time points. Immunohistochemical and immunofluorescent staining show that ODN treatment dramatically decreased F4/80؉ macrophages and CD3 ؉ T cells in the lesion areas 42 days after infection. Consistent with these findings, quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis showed low levels of proinflammatory mRNAs (for tumor necrosis factor alpha, interleukin 6, and interleukin 23␣) and corresponding cytokine expression in the ODN-treated disease group. The levels of mRNA for Toll-like receptors 4, 5, and 9 also largely decreased in the ODN-treated disease group. Our results demonstrated that ODN can inhibit endodontic disease development, bone erosion, and immune response. These results indicate that application of this small molecule offers a new opportunity to design effective therapies that could prevent periapical inflammation and revolutionize current treatment options. P eriapical lesions result from microbial infection of the dental pulp tissue by members of the autogenous oral microflora, which induce inflammation in the pulp tissue (1). This inflammatory process, much like periodontitis, increases in magnitude in the apical region of the root canal system and subsequently in the periapical area, leading to periapical bone resorption as the infection spreads throughout the canal system toward the apical foramen and into the adjacent bone (2). Furthermore, periapical lesions that present with radiographic bone lesions are preceded by necrotic pulp tissues. Unlike periodontal disease inflammation (3, 4), endodontic lesions exhibit differences in the character of the immune response (5).Despite many studies aimed at discovering ways to alleviate the effects of oral disease, there is still an urgent need to improve the health of millions with periapical disease who suffer from oralbacterial-infection-induced periapical inflammation, oral bone erosion, and the potential loss of teeth. The discovery of the critical roles of cathepsin K (Ctsk) in osteoclastic bone resorption is the fruit of decades of investigation on bone biol...

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Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

“…P values of Ͻ0.05 and U values of Ͼ1.96 were considered significant. Data quantification analyses were performed using the NIH Image J program as described previously (10,17).…”

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 98%

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A Small Molecule, Odanacatib, Inhibits Inflammation and Bone Loss Caused by Endodontic Disease

et al. 2015

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Periapical Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in Mice

Kang

Cheong

Chaichanasakul

et al. 2013

Journal of Bone and Mineral Research

103

142

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Osteonecrosis of the jaw (ONJ) is a well-recognized complication of antiresorptive medications, such as bisphosphonates (BPs). Although ONJ is most common after tooth extractions in patients receiving high dose BPs, many patients do not experience oral trauma. Animal models utilizing tooth extractions and high BP doses recapitulate several clinical, radiographic and histologic findings of ONJ. We and others have reported on rat models of ONJ utilizing experimental dental disease in the absence of tooth extraction. These models emphasize the importance of dental infection/inflammation for ONJ development. Here, we extend our original report in the rat, and present a mouse model of ONJ in the presence of dental disease. Mice were injected with high dose zoledronic acid and pulpal exposure of mandibular molars was performed to induce periapical disease. After 8 weeks, quantitative and qualitative radiographic and histologic analyses of mouse mandibles were executed. Periapical lesions were larger in vehicle- vs. BP treated mice. Importantly, radiographic features resembling clinical ONJ, including thickening of the lamina dura, periosteal bone deposition and increased trabecular density, were seen in the drilled site of BP treated animals. Histologically, osteonecrosis, periosteal thickening, periosteal bone apposition, epithelial migration and bone exposure were present in the BP treated animals in the presence of periapical disease. No difference in TRAP+ cell numbers was observed, but round, detached, and removed from the bone surface cells were present in BP animals. Although 88% of the BP animals showed areas of osteonecrosis in the dental disease site, only 33% developed bone exposure, suggesting that osteonecrosis precedes bone exposure. Our data further emphasize the importance of dental disease in ONJ development, provide qualitative and quantitative measures of ONJ, and present a novel mouse ONJ model in the absence of tooth extraction that should be useful in further exploring ONJ pathophysiological mechanisms.

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Monocyte-Specific Knockout of C/ebpα Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpα in Osteoclast Differentiation and Function

Chen

Zhu

Jules

et al. 2017

Journal of Bone and Mineral Research

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CCAAT/enhancer-binding protein α (C/ebpα) is critical for osteoclastogenesis by regulating osteoclast (OC) lineage commitment and is also important for OC differentiation and function in vitro. However, the role of C/ebpα in postnatal skeletal development has not been reported owing to lethality in C/ebpα−/− mice from hypoglycemia within 8 hours after birth. Herein, we generated conditional knockout mice by deleting the C/ebpα gene in monocyte via LysM-Cre to examine its role in OC differentiation and function. C/ebpαf/fLysM-Cre mice exhibited postnatal osteopetrosis due to impaired osteoclastogenesis, OC lineage priming defects, as well as defective OC differentiation and activity. Furthermore, our ex-vivo analysis demonstrated that C/ebpα conditional deletion significantly reduced OC differentiation, maturation, and activity while mildly repressing macrophage development. At the molecular level, C/ebpα deficiency significantly suppresses the expressions of OC genes associated with early stages of osteoclastogenesis as well as genes associated with OC differentiation and activity. We also identified numerous C/ebpα critical cis-regulatory elements on the Cathepsin K promoter which allow C/ebpα to significantly upregulate Cathepsin K expression during OC differentiation and activity. In pathologically induced mouse model of osteoporosis, C/ebpα deficiency can protect mice against ovariectomy-induced bone loss, uncovering a central role for C/ebpα in osteolytic diseases. Collectively, our findings have further established C/ebpα as a promising therapeutic target for bone loss by concurrently targeting OC lineage priming, differentiation and activity.

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Inhibiting Periapical Lesions through AAV-RNAi Silencing of Cathepsin K

Cited by 49 publications

References 30 publications

A Small Molecule, Odanacatib, Inhibits Inflammation and Bone Loss Caused by Endodontic Disease

A Small Molecule, Odanacatib, Inhibits Inflammation and Bone Loss Caused by Endodontic Disease

Periapical Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in Mice

Monocyte-Specific Knockout of C/ebpα Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpα in Osteoclast Differentiation and Function

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