Osteoclast Activity and Subtypes as a Function of Physiology and Pathology—Implications for Future Treatments of Osteoporosis

Henriksen, Kim; Bollerslev, Jens; Everts, Vincent; Karsdal, Morten A.

doi:10.1210/er.2010-0006

Cited by 197 publications

(176 citation statements)

References 355 publications

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“…This suggests the involvement of Na + -dependent HCO 3 − import mechanisms during pH recovery, which are an indirect sink of ATP. Transporters of the SLC4 family, including Na + /HCO 3 − cotransporters and Na + -dependent Cl − /HCO 3 − exchangers were widely identified as key players in this regulatory process (21,(48)(49)(50). The sea urchin PMC transcriptome contains a large number of genes coding for ion transporters including Na + /K + -ATPase (NKA), Na + /HCO 3 − cotransporters (NBC), H + -ATPases (HA), and NHEs (51).…”

Section: Chronically Elevated Seawater Pco 2 Directly Affects the Sitmentioning

confidence: 99%

Acidified seawater impacts sea urchin larvae pH regulatory systems relevant for calcification

Stumpp

Melzner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

221

217

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Calcifying echinoid larvae respond to changes in seawater carbonate chemistry with reduced growth and developmental delay. To date, no information exists on how ocean acidification acts on pH homeostasis in echinoderm larvae. Understanding acid-base regulatory capacities is important because intracellular formation and maintenance of the calcium carbonate skeleton is dependent on pH homeostasis. Using H + -selective microelectrodes and the pHsensitive fluorescent dye BCECF, we conducted in vivo measurements of extracellular and intracellular pH (pH e and pH i ) in echinoderm larvae. We exposed pluteus larvae to a range of seawater CO 2 conditions and demonstrated that the extracellular compartment surrounding the calcifying primary mesenchyme cells (PMCs) conforms to the surrounding seawater with respect to pH during exposure to elevated seawater pCO 2 . Using FITC dextran conjugates, we demonstrate that sea urchin larvae have a leaky integument. PMCs and spicules are therefore directly exposed to strong changes in pH e whenever seawater pH changes. However, measurements of pH i demonstrated that PMCs are able to fully compensate an induced intracellular acidosis. This was highly dependent on Na + and HCO 3 − , suggesting a bicarbonate buffer mechanism involving secondary active Na + -dependent membrane transport proteins. We suggest that, under ocean acidification, maintained pH i enables calcification to proceed despite decreased pH e . However, this probably causes enhanced costs. Increased costs for calcification or cellular homeostasis can be one of the main factors leading to modifications in energy partitioning, which then impacts growth and, ultimately, results in increased mortality of echinoid larvae during the pelagic life stage. pH microelectrode | Strongylocentrotus droebachiensis | acid-base regulation | Na + -HCO 3 − transport | epithelial transport S ea urchin larvae have been shown to react with particular sensitivity to CO 2 -induced reductions in seawater pH (1-4). When larvae are chronically exposed to elevated seawater pCO 2 of >0.1 kPa, e.g., as is predicted to occur during the next century in response to anthropogenic CO 2 emissions or through upwelling of low-pH deep water, this sensitivity is reflected in reduced growth and developmental rates (5, 6). Echinoderm larvae are considered to be especially vulnerable to seawater pH reduction and to the associated changes in calcium carbonate saturation state of seawater (Ω Cal ) because their internal skeleton is composed of high magnesium calcite, a highly soluble form of CaCO 3 (7, 8). However, long-term reductions in growth and development might just as well be evoked by other physiological mechanisms that are also sensitive to hypercapnia and the related acid-base disturbances. Recent studies conducted on several marine taxa including mollusks (9) and echinoderms (10) demonstrated increased metabolic rates in response to elevated seawater pCO 2 . It was concluded that reductions in somatic growth and rate of development were caused by a sh...

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Section: Chronically Elevated Seawater Pco 2 Directly Affects the Sitmentioning

confidence: 99%

Acidified seawater impacts sea urchin larvae pH regulatory systems relevant for calcification

Stumpp

Melzner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

221

217

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“…Studies of ADO patients have demonstrated the potential mode of action of a ClC-7 inhibitor, and the most intriguing finding is the apparent uncoupling between bone resorption and bone formation, a finding that clearly indicates that bone resorption can be inhibited without detrimental effects on bone formation (81,96,97).…”

Section: Clc-7 Inhibitorsmentioning

confidence: 99%

“…The possibility to have a pure anabolic response or an anti-resorptive response without the secondary reduction in bone formation associated with presently available treatments is enticing (97).…”

Section: Potential Therapeutic Aspectsmentioning

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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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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“…Many bone diseases are caused by disorders of osteoclast differentiation and function. For example, osteoporosis is induced by hyper‐activity of osteoclasts that resorb bone mass 6, 7. On the contrary, osteosclerosis is because of hypo‐activity of osteoclasts, resulting in increased bone mass 8, 9.…”

Section: Introductionmentioning

confidence: 99%

Dual effects of baicalin on osteoclast differentiation and bone resorption

Yang

et al. 2018

J Cellular Molecular Medi

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Osteoclasts (OC) are critical cells responsible for many bone diseases such as osteoporosis. It is of great interest to identify agents that can regulate the activity of OC to treat osteolytic bone diseases. In this study, we found that baicalin exerted a two‐way regulatory effect on OC in a concentration‐dependent manner in vitro and in vivo. In detail, baicalin at a low concentration (below 1 μmol/L) enhanced OC differentiation and bone resorption, but baicalin at a high concentration (above 2 μmol/L) exhibited inhibitory effects on OC. We demonstrated that baicalin at low concentrations enhanced the mitogen‐activated protein kinase (MAPK) (ERK) signalling pathway and activated c‐Fos and NFATc1 expression, and thus enhanced gene expression, OC differentiation and bone resorption. However, baicalin at higher levels not only suppressed ERK phosphorylation and c‐fos and NFATc1 expression, but also altered the expression of apoptosis‐related proteins, and therefore inhibiting OC function. This dual effect was further verified in an LPS‐induced mouse calvarial osteolysis model, evidenced by enhanced osteolysis at a lower concentration but reduced bone loss at a higher concentration. Overall, our findings indicate that baicalin exerts dose‐dependent effects on OC formation and function. Therefore, caution should be applied when using baicalin to treating OC‐related bone diseases.

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Osteoclast Activity and Subtypes as a Function of Physiology and Pathology—Implications for Future Treatments of Osteoporosis

Cited by 197 publications

References 355 publications

Acidified seawater impacts sea urchin larvae pH regulatory systems relevant for calcification

Acidified seawater impacts sea urchin larvae pH regulatory systems relevant for calcification

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

Dual effects of baicalin on osteoclast differentiation and bone resorption

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