A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat

Lark, Michael W.; Stroup, George B.; James, Ian E.; Dodds, Robert A.; Hwang, Shing Mei; Blake, S; Lechowska, Beata; Hoffman, Sandra J.; Smith, Brian R.; Kapadia, Rasesh; Liang, Xiaoguang; Erhard, Karl F.; Ru, Yu; Dong, Xiaoyang; Marquis, Robert W.; Veber, Daniel F.; Gowen, Maxine

doi:10.1016/s8756-3282(02)00675-0

Cited by 80 publications

(54 citation statements)

References 29 publications

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“…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 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.…”

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“…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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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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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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“…36 This was important information to support the design of potent cathepsin K inhibitors. 37 Furthermore, the specificity of cathepsin K inhibitors can be tested in situ by directly quantifying the inhibition of the actual enzyme within the osteoclast. 37,38 It has also been demonstrated that cathepsin K processing and polarization occurs when the osteoclast approaches bone, indicative that local factors in the microenvironment regulate these events.…”

Section: Discussionmentioning

confidence: 99%

“…37 Furthermore, the specificity of cathepsin K inhibitors can be tested in situ by directly quantifying the inhibition of the actual enzyme within the osteoclast. 37,38 It has also been demonstrated that cathepsin K processing and polarization occurs when the osteoclast approaches bone, indicative that local factors in the microenvironment regulate these events. 36 This cytochemical assay should prove invaluable for specifically identifying osteoclast populations at different phases of osteoclast function.…”

Section: Discussionmentioning

confidence: 99%

A cytochemical assay for osteoclast cathepsin K activity

Dodds

2003

Cell Biochemistry & Function

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Cathepsin K is a member of the papain superfamily of cysteine proteases and plays a pivotal role in osteoclast-mediated bone resorption. This enzyme is an excellent target for antiresorptive therapies for osteopenic disorders such as osteoporosis. 1 Although isolated inhibitor studies on purified enzymes is required to discover potent and selective inhibitors of cathepsin K, a quantitative cytochemical assay 2 for cathepsin K would allow inhibitors to be tested on actual osteoclasts within sections of bone. Furthermore cathepsin K activity could be used to identify and analyse osteoclasts at definitive stages of their lifespan. A cytochemical assay is described that localizes osteoclast cathepsin K activity in unfixed, undecalcified cryostat sections of animal and human bone.

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Local co‐delivery of rhBMP‐2 and cathepsin K inhibitor L006235 in poly(d,l‐lactide‐co‐glycolide) nanospheres

Fathi

Murphy

et al. 2015

J Biomed Mater Res

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Cathepsin K inhibitors (CKIs) are an emerging class of drugs that are potent antagonists of osteoclastic activity. We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so to achieve a sustained release we manufactured polymer nanoparticles encapsulating the CKI L006235 (CKI/nP). CKI/nP and the collagen matrices that were used to deliver them were characterized by electron microscopy and fluorescent confocal microscopy, and data indicated that the particles were evenly distributed throughout the collagen. Elution studies indicated a linear release of the inhibitor from the CKI/nP, with approximately 2% of the drug being released per day. In an in vivo study, mice were implanted with collagen scaffolds containing rhBMP-2 that were loaded with the CKI/nP. Measurement of bone volume (BV) by microCT showed no significant increase with CKI/nP incorporation, and other parameters similarly showed no statistical differences. Cell culture studies confirmed the activity of the drug, even at low concentrations. These data indicate that polymer nanoparticles are an effective method for sustained drug delivery of a CKI, however, this may not be readily translatable to substantively improved bone tissue engineering outcomes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 136-144, 2017.

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A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat

Cited by 80 publications

References 29 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

A cytochemical assay for osteoclast cathepsin K activity

Local co‐delivery of rhBMP‐2 and cathepsin K inhibitor L006235 in poly(d,l‐lactide‐co‐glycolide) nanospheres

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