Degradation of the Organic Phase of Bone by Osteoclasts: A Secondary Role for Lysosomal Acidification

Henriksen, Kim; Sørensen, Mette G; Nielsen, Rasmus Hjorth; Gram, Jeppe; Schaller, Sophie; Dziegiel, Morten Hanefeld; Everts, Vincent; Bollerslev, Jens; Karsdal, Morten A.

doi:10.1359/jbmr.050905

Cited by 86 publications

(63 citation statements)

References 56 publications

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“…It has been suggested that MMPs contribute to bone resorption by osteoclasts [15,16]. We found that the broad-spectrum inhibitors of MMPs, BB94, MV034388 and GM6001, had no effect on CTX-I release ( Figure 5).…”

Section: Resultsmentioning

confidence: 76%

Regulation and enzymatic basis of bone resorption by human osteoclasts

2007

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Although much has been learned recently of the mechanisms that regulate osteoclastic differentiation, much less is known of the means through which their resorptive activity is controlled. This is especially so for human osteoclasts. We have recently developed an assay that allows us to measure resorptive activity while minimizing confounding effects on differentiation by optimizing osteoclastogenesis, so that measurable resorption occurs over a short period, and by relating resorption in each culture during the test period to the resorption that had occurred in the same culture in a prior control period. In the present study, we found that RANKL (receptor activator of nuclear factor kappaB ligand) strongly stimulated the release of CTX-I (C-terminal telopeptide degradation product of type I collagen) by osteoclasts over a similar range to that over which it induces osteoclastic differentiation, consistent with a distinct action on osteoclastic function. CT (calcitonin) dose-dependently inhibited bone resorption, whereas PTH (parathyroid hormone), IL (interleukin)-1, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-8, VEGF (vascular endothelial growth factor), MCP-1 (monocyte chemoattractant protein-1), MIP-1gamma (macrophage inflammatory protein-1gamma), IFN (interferon)-gamma and dibutyryl cGMP had no significant effect. Ca(2+), cyclosporin A, IFN-beta and dibutyryl cAMP all strongly suppressed resorption. Bone resorption was also strongly suppressed by alendronate, the cysteine protease inhibitor E64 and the cathepsin K inhibitor MV061194. Inhibitors of MMPs (matrix metalloproteinases) had no effect on CTX-I release. Moreover, the release of the MMP-derived collagen fragment ICTP (C-terminal cross-linked telopeptide of type I collagen) represented less that 0.01% of the quantity of CTX-I released in our cultures. This suggests that MMPs make, at most, a very small contribution to the bone-resorptive activity of osteoclasts.

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Section: Resultsmentioning

confidence: 76%

Regulation and enzymatic basis of bone resorption by human osteoclasts

2007

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“…Compensation for lack of cathepsin K activity by MMPs is also seen in cultures of human osteoclasts challenged with the cysteine proteinase inhibitor E64 Henriksen et al 2006;Sassi et al 2000), a phenomenon also seen in cathepsin K deWcient mice (Kiviranta et al 2005). The mice have a bone phenotype that mimics the human bone phenotype to a large extent, and in vitro data from these mice parallel the data from humans (Gowen et al 1999;Saftig et al 1998).…”

Section: Cathepsin Kmentioning

confidence: 69%

“…The study of the cellular phenotype of ADOII, consistently showed that high numbers of abnormally large multinuclear TRACP-positive osteoclasts were present on the inner bone surface (Bollerslev et al 1993;Semba et al 2000), a Wnding which is due to increased survival of the osteoclasts (Henriksen et al 2006). In addition, high levels of TRACP were found in the serum of ADOII patients (Bollerslev et al 1988;Alatalo et al 2004;Bollerslev et al 2000;Gram et al 1991;Waguespack et al 2002).…”

Section: Chloride Channel 7 (Clc-7)mentioning

confidence: 98%

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Advances in osteoclast biology resulting from the study of osteopetrotic mutations

et al. 2008

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Osteopetrosis is the result of mutations affecting osteoclast function. Careful analyses of osteopetrosis have provided instrumental information on bone remodeling, including the coupling of bone formation to bone resorption. Based on a range of novel genetic mutations and the resulting osteoclast phenotypes, we discuss how osteopetrosis models have clarified the function of the coupling of bone formation to bone resorption, and the pivotal role of the osteoclast and their function in this phenomenon. We highlight the distinct possibility that osteoclast activities can be divided into two separate avenues: bone resorption and control of bone formation.

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“…In cell culture MMPs may contribute to the degradation of the bone ECM and mediate the release of the C-terminal telopeptide of type I collagen (CTX) fragment in the absence of cathepsin K activity. 45 Interestingly, mice lacking MMP13 or both MMP9…”

Section: Lysosomal Proteins Implicated In the Degradation Of The Bonementioning

confidence: 99%