ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion

Supanchart, Chayarop; Wartosch, Lena; Schlack, Claire; Kühnisch, Jirko; Felsenberg, Dieter; Fuhrmann, Jens C.; Vernejoul, M. C. De; Jentsch, Thomas J.; Kornak, Uwe

doi:10.1016/j.bone.2013.09.022

Cited by 9 publications

(16 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on these results, we believe that a biotechnological device containing sRANKL cell sources regulated physiologically, as demonstrated in this study for instance by PTH, could bypass the overdose problems and be more tolerated in long-term treatments. In fact, PTH, which is elevated in osteopetrosis due to the hypocalcemic condition [41,42] , could play a central role in the control of RANKL expression in osteoblasts implanted in vivo for therapeutic purposes. It could induce a burst of sRANKL release in the first phase of treatment then, being attenuated by the stabilization of calcemia, it could contribute to a more physiologic release of the cytokine according to the calcemic status of the subject.…”

Section: Discussionmentioning

confidence: 99%

Biotechnological approach for systemic delivery of membrane Receptor Activator of NF-κB Ligand (RANKL) active domain into the circulation

et al. 2015

View full text Add to dashboard Cite

Deficiency of Receptor Activator of NF-κB Ligand (RANKL) prevents osteoclast formation causing osteopetrosis. RANKL is a membrane-bound protein cleaved into active soluble (s)RANKL by metalloproteinase 14 (MMP14). We created a bio-device that harbors primary osteoblasts, cultured on 3D hydroxyapatite scaffolds carrying immobilized MMP14 catalytic domain. Scaffolds were sealed in diffusion chambers and implanted in RANKL-deficient mice. Mice received 1 or 2 diffusion chambers, once or twice and were sacrificed after 1 or 2 months from implants. A progressive increase of body weight was observed in the implanted groups. Histological sections of tibias of non-implanted mice were negative for the osteoclast marker Tartrate-Resistant Acid Phosphatase (TRAcP), consistent with the lack of osteoclasts. In contrast, tibias excised from implanted mice showed TRAcP-positive cells in the bone marrow and on the bone surface, these latter morphologically similar to mature osteoclasts. In mice implanted with 4 diffusion chambers total, we noted the highest number and size of TRAcP-positive cells, with quantifiable eroded bone surface and significant reduction of trabecular bone volume. These data demonstrate that our bio-device delivers effective sRANKL, inducing osteoclastogenesis in RANKL-deficient mice, supporting the feasibility of an innovative experimental strategy to treat systemic cytokine deficiencies.

show abstract

Section: Discussionmentioning

confidence: 99%

Biotechnological approach for systemic delivery of membrane Receptor Activator of NF-κB Ligand (RANKL) active domain into the circulation

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The ruffled border is a unique folded highly permeable membrane facing to the resorbing bone surface. To dissolve bone minerals, protons (H + ) and chloride ions (Cl − ) is released via the plasma membrane (a3 isoform) vacuolar H + -ATPase proton pump [23] and chloride ion-proton anti-porter ClC-7 [24] clustered in the ruffled border into the resorption lacunae, acidifying the resorptive lacunae to a pH of 4.5 [8]. Concomitantly, the cysteine peptidase cathepsin K [25] degrades bone matrix.…”

Section: Acidic Extracellular Microenvironment In Cancer-colonizedmentioning

confidence: 99%

“…To dissolve bone minerals, mature osteoclasts release protons (H + ) and chloride ions (Cl − ) into the resorption lacunae via the plasma membrane (a3 isoform) vacuolar H+-ATPase proton pump [23] and chloride ion-proton anti-porter ClC-7 [24], acidifying the resorption lacunae to a pH of 4.5 [7]. Concomitantly, the lysosomal cysteine peptidase cathepsin K [25] degrades bone matrix including type I collagen.…”

Section: Figurementioning

confidence: 99%

Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain

Yoneda

Hiasa

Nagata

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

Solid and hematologic cancers colonized bone produce a number of pathologies. One of the most common complications associated with bone-colonized cancer is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and mortality and diminishes the quality of life and affects survival in cancer patients. Current treatments do not satisfactorily control CABP and can elicit serious side effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via plasma membrane vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as Warburg effect, thus exacerbating the acidic microenvironment. Since acidosis is algogenic for primary afferent sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of these acid-sensing nociceptors are regulated may facilitate the development of novel therapeutic approaches for management of CABP. In this review, the contribution of the acidic extracellular microenvironment created by bone-colonized cancer cells and bone-resorbing osteoclasts to excitation and sensitization of sensory nerves innervating bone and elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic extracellular microenvironment will be described.

show abstract

“…To dissolve bone minerals, mature osteoclasts release protons (H þ ) and chloride ions (Cl À ) into the resorption lacunae via the plasma membrane (a3 isoform) vacuolar H þ -ATPase proton pump 36 and chloride ion-proton antiporter ClC-7, 37 acidifying the resorption lacunae to a pH of B4.5. 30,36,43 Concomitantly, the lysosomal cysteine peptidase cathepsin K 38 degrades bone matrix including type I collagen.…”

Section: Cancer-colonized Bonementioning

confidence: 99%

“…30 First, osteoclasts migrate and attach tightly to the bone surfaces via the a v b 3 integrin, thereby forming sealing zones, followed by plasma membrane ruffled border formation. To dissolve bone minerals, protons (H þ ) and chloride ions (Cl À ) are released via the plasma membrane (a3 isoform) vacuolar H þ -ATPase proton pump 36 and chloride ion-proton anti-porter ClC-7 37 clustered in the ruffled border into the resorption lacunae, respectively, acidifying the resorptive lacunae to a pH of B4.5.…”

Section: Proton Release By Osteoclasts In Cabpmentioning

confidence: 99%

Acidic microenvironment and bone pain in cancer-colonized bone

Yoneda¹,

Hiasa²,

Nagata³

et al. 2015

BoneKEy Reports

View full text Add to dashboard Cite

Solid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP.

show abstract

ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion

Cited by 9 publications

References 32 publications

Biotechnological approach for systemic delivery of membrane Receptor Activator of NF-κB Ligand (RANKL) active domain into the circulation

Biotechnological approach for systemic delivery of membrane Receptor Activator of NF-κB Ligand (RANKL) active domain into the circulation

Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain

Acidic microenvironment and bone pain in cancer-colonized bone

Contact Info

Product

Resources

About