Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman Primate

Stroup, George B.; Lark, Michael W.; Veber, Daniel F.; Bhattacharyya, Amit; Blake, S; Dare, Lauren; Erhard, Karl F.; Hoffman, Sandra J.; James, Ian E.; Marquis, Robert W.; Ru, Yu; Vasko-Moser, Janice A.; Smith, Brian R.; Tomaszek, Thadeus; Gowen, Maxine

doi:10.1359/jbmr.2001.16.10.1739

Cited by 147 publications

(116 citation statements)

References 35 publications

(40 reference statements)

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“…When cathepsin K inhibitors were used in two different models of osteoporosis significant decreases in bone resorption were observed, however accompanied by secondary significant decreases in bone formation. 15,25 In our previous studies of the effect of a putative ClC-7 inhibitor in the aged rat OVX model, 28 evaluating bone resorption by CTX and formation by osteocalcin, as well as using dynamic histomorphometry indices of mineral apposition rate and mineralized surface index, we showed that by inhibition of acidification of the osteoclastic resorption lacunae, bone resorption was dose dependently inhibited without an effect on bone formation. This suggested that the signal for bone formation could be maintained despite the reduced resorption.…”

Section: Discussionmentioning

confidence: 86%

“…22 Bone formation remains to be carefully investigated in cathepsin K-deficient patients, however small molecule inhibitors of cathepsin K have been shown to cause both an inhibition of bone resorption and bone formation in various animal models. 15,25 The decrease in bone formation secondary to the decrease in bone resorption is possibly a result of the tight coupling of bone formation to bone resorption observed normally. From these combined observations, it could be speculated that acidification of the osteoclastic resorption compartment and dissolution of the inorganic phase of bone might be important for the proper coupling of bone resorption to bone formation.…”

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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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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

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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“…Representative images (c-F) of bone resorption pit formation in osteoassay plate evaluated in osteoclasts precursors cells from WT and NOD2 -/-mice cultivated with M-CSF + RANKL (control) and MDP 1 µg/mL. Bars = 100 µm (Mogi & Otogo, 2007;Garg et al, 2009) and matrix metalloproteinases (Leppilahti et al, 2014) were found in the gingival crevicular fluid of patients with periodontitis when compared to healthy patients, suggesting that the inhibition of cathepsin K may be a viable treatment for chronic diseases, such as periodontal disease (Stroup et al, 2001;Garg et al, 2009).…”

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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“…[31][32][33][34][35][36][37][38][39][40][41] In addition, in nonhuman primate models, serum markers of bone resorption were also consistent with the observed phenotype. [42][43][44][45][46] Biomarkers of bone remodeling can also be used in in vitro models. 47 These cellular models can be reliably used for enhancing preclinical evaluation of pharmacological agents in metastatic bone disease.…”

Section: Preclinical Use Of Bone Remodeling Markersmentioning

confidence: 99%

Bone remodeling markers and bone metastases: From cancer research to clinical implications

Ferreira¹,

Alho²,

Casimiro³

et al. 2015

BoneKEy Reports

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Bone metastasis is a frequent finding in the natural history of several types of cancers. However, its anticipated risk, diagnosis and response to therapy are still challenging to assess in clinical practice. Markers of bone metabolism are biochemical by-products that provide insight into the tumor-bone interaction, with potential to enhance the clinical management of patients with bone metastases. In fact, these markers had a cornerstone role in the development of bone-targeted agents; however, its translation to routine practice is still unclear, as reflected by current international guidelines. In this review, we aimed to capture several of the research and clinical translational challenges regarding the use of bone metabolism markers that we consider relevant for future research in bone metastasis.

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Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman Primate

Abstract: ABSTRACT

Cited by 147 publications

References 35 publications

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

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

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

Bone remodeling markers and bone metastases: From cancer research to clinical implications

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