Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts

Fuller, K.; Lawrence, Kevin M.; Ross, Jade L.; Grabowska, Urszula; Shiroo, Masahiro; Samuelsson, Bertil; Chambers, T.J.

doi:10.1016/j.bone.2007.09.044

Cited by 103 publications

(70 citation statements)

References 56 publications

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“…Furthermore, these studies showed that only mature osteoclasts produce the anabolic signal (76) and hence illustrated the specificity of this phenomenon, while also providing some evidence as to why bone formation appears very low or even missing in the absence of osteoclasts, as seen in the RANK-deficient patients (78). However, controversies still exist, as demonstrated recently where inhibition of bone resorption in vitro with the V-ATPase inhibitor bafilomycin blunted release of anabolic factors from the bone matrix (79). Thus, there are still discussions related to the origin of the anabolic molecules initiating and driving bone formation as a consequence of bone resorption by osteoclasts.…”

Section: Analysis Of Osteoclasts From Ado Patientsmentioning

confidence: 63%

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Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Section: Analysis Of Osteoclasts From Ado Patientsmentioning

confidence: 63%

“…molecules, such as IGF1, BMP6, and Wnt10b (76,79,80). Furthermore, there are also molecules that are still being explored in detail, such as the ephrinB2-ephB4 interaction and sphingosine-1-phosphate (76,77).…”

Section: Analysis Of Osteoclasts From Ado Patientsmentioning

confidence: 99%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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“…doi:10.1371/journal.pone.0027482.g007 increased bone formation, despite reduced bone resorption, although the effects appear to be bone type dependent [53,68,69]. One study showed that inhibition of cathepsin K in osteoclasts in vitro led to augmented release of anabolic factors from the resorption compartment, while inhibition of acid secretion by bafilomycin prevented the release of anabolic factors [70]. All these data strongly indicate that the osteoclasts possess the ability to induce an anabolic response in osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of Bone Resorption and Bone Formation in Adult Mice with a Non-Functional V-ATPase in Osteoclasts Leads to Increased Bone Strength

Henriksen¹,

Flores²,

Thomsen³

et al. 2011

BASIC - Bone, Calciotropic Hormones &Amp; Vitamin D

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Osteopetrosis caused by defective acid secretion by the osteoclast, is characterized by defective bone resorption, increased osteoclast numbers, while bone formation is normal or increased. In contrast the bones are of poor quality, despite this uncoupling of formation from resorption. To shed light on the effect of uncoupling in adult mice with respect to bone strength, we transplanted irradiated three-month old normal mice with hematopoietic stem cells from control or oc/oc mice, which have defective acid secretion, and followed them for 12 to 28 weeks. Engraftment levels were assessed by flow cytometry of peripheral blood. Serum samples were collected every six weeks for measurement of bone turnover markers. At termination bones were collected for mCT and mechanical testing. An engraftment level of 98% was obtained. From week 6 until termination bone resorption was significantly reduced, while the osteoclast number was increased when comparing oc/oc to controls. Bone formation was elevated at week 6, normalized at week 12, and reduced onwards. mCT and mechanical analyses of femurs and vertebrae showed increased bone volume and bone strength of cortical and trabecular bone. In conclusion, these data show that attenuation of acid secretion in adult mice leads to uncoupling and improves bone strength.

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“…Besides collagens, cathepsin K cleaves a variety of other bone-and cartilage resident proteins such as osteonectin, aggrecan, and IGF-1 [22,23].…”

Section: Introductionmentioning

confidence: 99%

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy

Atef¹,

Aziz²

2015

J Arthritis

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Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts

Cited by 103 publications

References 56 publications

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Dissociation of Bone Resorption and Bone Formation in Adult Mice with a Non-Functional V-ATPase in Osteoclasts Leads to Increased Bone Strength

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy

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Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts

Cited by 103 publications

References 56 publications

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Dissociation of Bone Resorption and Bone Formation in Adult Mice with a Non-Functional V-ATPase in Osteoclasts Leads to Increased Bone Strength

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy

Contact Info

Product

Resources

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Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy