Cathepsin K Knockout Mice Develop Osteopetrosis Due to a Deficit in Matrix Degradation but Not Demineralization

Gowen, Maxine; Lazner, Francesca; Dodds, Robert A.; Kapadia, Rasesh; Feild, John; Tavaria, Michael D.; Bertoncello, Ivan; Drake, Fred H.; Zavarselk, Silva; Tellis, Irene; Hertzog, Paul J.; Debouck, Christine; Kola, Ismail

doi:10.1359/jbmr.1999.14.10.1654

Cited by 442 publications

(318 citation statements)

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“…In fact, in vitro and in vivo studies suggest that the 2 types of proteases, MMP-9 and cathepsin K, are involved in bone resorption mediated by osteoclasts, performing the collagen degradation in bone (Delaisse et al, 2003;Everts et al, 1992). Votta et al (1997) found reduced bone resorption, both in vitro and in vivo, using an inhibitor of cathepsin K. Moreover, cathepsin K-deficient mice showed significant osteopetrosis (Saftig et al, 1998;Gowen et al, 1999). In periodontal area, increased levels of cathepsin K Figure 4.…”

Section: Discussionmentioning

confidence: 99%

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

et al. 2014

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The NOD-like receptors are cytoplasmic proteins that sense microbial by-products released by invasive bacteria. Although NOD1 and NOD2 are functionally expressed in cells from oral tissues and play a role triggering immune responses, the role of NOD2 receptor in the bone resorption and in the modulation of osteoclastogenesis is still unclear. We show that in an experimental model of periodontitis with Porphyromonas gingivalis W83, NOD2-/- mice showed lower bone resorption when compared to wild type. Quantitative polymerase chain reaction analysis revealed that wild-type infected mice showed an elevated RANKL/OPG ratio when compared to NOD2-/- infected mice. Moreover, the expression of 2 osteoclast activity markers—cathepsin K and matrix metalloproteinase 9—was significantly lower in gingival tissue from NOD2-/- infected mice compared to WT infected ones. The in vitro study reported an increase in the expression of the NOD2 receptor 24 hr after stimulation of hematopoietic bone marrow cells with M-CSF and RANKL. We also evaluated the effect of direct activation of NOD2 receptor on osteoclastogenesis, by the activation of this receptor in preosteoclasts culture, with different concentrations of muramyl dipeptide. The results show no difference in the number of TRAP-positive cells. Although it did not alter the osteoclasts differentiation, the activation of NOD2 receptor led to a significant increase of cathepsin K expression. We confirm that this enzyme was active, since the osteoclasts resorption capacity was enhanced by muramyl dipeptide stimulation, evaluated in osteoassay plate. These results show that the lack of NOD2 receptor impairs the bone resorption, suggesting that NOD2 receptor could contribute to the progression of bone resorption in experimental model of periodontitis. The stimulation of NOD2 by its agonist, muramyl dipeptide, did not affect osteoclastogenesis, but it does favor the bone resorption capacity identified by increased osteoclast activity.

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Section: Discussionmentioning

confidence: 99%

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

et al. 2014

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“…42 In conjunction, by inhibition of osteoclastic acidification in vivo by bafilomycin in new bone implants in a rat model, a massive increase in new bone formation was observed. 43 The cathepsin K-deficient patients (pycnodysostosis) and the cathepsin K-null mutation mice that develop osteopetrosis because of a deficit in matrix degradation, but not demineralization 14,16,44 do not display increased levels of osteoclasts. This further indicates that factors released during dissolution of the inorganic phase of the bone are playing a role in osteoclast life span.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Degradation of the organic phase of bone is for the major part mediated by the enzyme cathepsin K, which degrades collagen type I. [12][13][14][15][16] Interestingly, abrogation of degradation of the organic phase of bone does not prevent dissolution of the inorganic phase, because the lowering of …”

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confidence: 99%

“…[12][13][14][15][16] Interestingly, abrogation of degradation of the organic phase of bone does not prevent dissolution of the inorganic phase, because the lowering of Accepted for publication October 5, 2004. pH in the osteoclastic resorption compartment remains unimpaired. 14,17 In patients with impaired acidification of the resorption lacunae either because of a mutation in the osteoclastic V-ATPase a3 or in the chloride channel ClC-7, bone resorption is impaired whereas bone formation appears unaltered or even increased. 18 -22 A further interesting feature found in patients with defective acidification is the presence of increased numbers of abnormally large osteoclasts.…”

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confidence: 99%

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Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Karsdal

Henriksen

Sørensen

et al. 2005

The American Journal of Pathology

139

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Patients with defective osteoclastic acidification have increased numbers of osteoclasts, with decreased resorption, but bone formation that remains unchanged. We demonstrate that osteoclast survival is increased when acidification is impaired, and that impairment of acidification results in inhibition of bone resorption without inhibition of bone formation. We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/ NS3696), the proton pump (bafilomycin) and cathepsin K. We found that bafilomycin and NS5818 dose dependently inhibited acidification of the osteoclastic resorption compartment and bone resorption. Inhibition of bone resorption by inhibition of acidification, but not cathepsin K inhibition, augmented osteoclast survival, which resulted in a 150 to 300% increase in osteoclasts compared to controls. We investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model with twice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation evaluated by osteocalcin. We speculate that attenuated acidification inhibits dissolution of the inorganic phase of bone and results in an increased number of nonresorbing osteoclasts that are responsible for the coupling to normal bone formation. Thus, we suggest that acidification is essential for normal bone remodeling and that attenuated acidification leads to uncoupling with decreased bone resorption and unaffected bone formation. The coupling process is understood as a bone formation response that is the consequence of bone resorption, with an amount of bone formed that is equal to that resorbed. 1,2 Uncoupling occurs when the balance between formation and resorption is disturbed, which might lead to either osteopetrosis or osteoporosis. 3,4 Although it has long been appreciated that bone formation is tightly coupled to bone resorption in normal adult bone turnover, 5,6 this coupling can be dissociated in some circumstances, for example during skeletal growth and in some but not all osteopetrotic mutations.Bone consists of two phases, the organic phase, which contains proteins such as collagen type I, and the inorganic phase, which consists of crystallized calcium phosphate. Dissolution of the inorganic phase of bone under the osteoclast attached to the bone surface is a prerequisite for degradation of the organic phase, and is mediated by acidification of the resorption compartment. The decrease in pH necessary to dissolve the inorganic phase is mediated by an active transport of protons over the ruffled border membrane, which is driven by an osteoclastic Vtype H ϩ ATPase. 7,8 At the same time a passive transport of chloride through chloride channels preserves the electroneutrality, 9 and is mediated by the chloride channel ClC-7. 10,11 Degradation of the organic phase of bone is for the major part mediated b...

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“…Cathepsin K knockout mice develop osteopetrosis due to a deficit matrix degradation but not demineralization [26]. Similarly, mutations in the human cathepsin K gene have demonstrated an association with a rare skeletal dysplasia, pycnodysostosis [27,28].…”

Section: Osteoclast Physiologymentioning

confidence: 99%

Molecular Understanding of Osteoclast Differentiation and Physiology

Lee

2010

Endocrinol Metab

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Cathepsin K Knockout Mice Develop Osteopetrosis Due to a Deficit in Matrix Degradation but Not Demineralization

Cited by 442 publications

References 40 publications

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Molecular Understanding of Osteoclast Differentiation and Physiology

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