Pathogenesis and treatment of multiple myeloma bone disease

Multiple myeloma (Plasma cell myeloma), a malignancy of the plasma cells, exhibits tumor expansion preferentially in the bone marrow and the development of bone-destructive lesions. Multiple myeloma is still an incurable disease with changes in the bone marrow microenvironment in favor of the survival and proliferation of multiple myeloma cells and bone destruction. In this review, we described the recent findings on the regulators involved in the development of myeloma bone diseases, and succinctly summarize currently available therapeutic options and the development of novel bone modifying agents for myeloma treatment

Myeloma–Bone Interaction : A Vicious Cycle via TAK1–PIM2 Signaling

Myeloma cells interact with their ambient cells in the bone, such as bone marrow stromal cells, osteoclasts, and osteocytes, resulting in enhancement of osteoclastogenesis and inhibition of osteoblastogenesis while enhancing their growth and drug resistance. The activation of the TAK1–PIM2 signaling axis appears to be vital for this mutual interaction, posing it as an important therapeutic target to suppress tumor expansion and ameliorate bone destruction in multiple myeloma.Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM

TACE カッセイ セイギョ ニヨル タンキュウ ブンカ ノ ケッテイ

Multiple myeloma (MM) almost exclusively expands in the bone marrow and generates devastating bone destruction. We recently reported that GM-CSF and IL-4, an inducer of dendritic cell (DC) differentiation, up-regulate TNFα converting enzyme (TACE) expression in monocytes to cleave their surface M-CSF receptor (M-CSFR), which drastically disrupts osteoclastogenesis. Because TACE activity is inhibited by TIMP3, we explored the expression of TIMP3 and its role in monocyte differentiation into osteoclasts and DCs in MM. Bone marrow stromal cells (BMSCs) secreted a large amount of TIMP3 protein whose production was further enhanced by IL-6 and TGFβ over-produced in MM bone lesions. BMSCs potently suppressed GM-CSF and IL-4-induced DC differentiation and resumed osteoclastogenesis from monocytes along with the suppression of surface M-CSFR and RANK shedding on monocytes. TIMP3 knockdown in BMSCs by TIMP3 siRNA enhanced M-CSFR shedding in monocytes in the presence of BMSCs and resumed GM-CSF and IL-4-mediated DC differentiation from monocytes, suggesting monocyte differentiation skewed by BMSC-derived TIMP3. These results suggest that TIMP3 over-produced in MM bone marrow microenvironment restores surface M-CSFR on monocytes to facilitate their downstream signaling, which causes extensive bone destruction and impaired DC differentiation in MM. TIMP3 may therefore become a novel target in the treatment of MM bone disease

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

Solid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse 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 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 the Warburg effect. Since acidosis is algogenic for 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 mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid-sensing nociceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers

埋伏下顎大臼歯の歯科用CB-CT画像の特徴と牽引可否との関連性

【目的】埋伏下顎大臼歯は，発生率は低いものの骨性癒着が認められた際は重大な不正咬合の原因となる．その治療予後の予測は未だ困難であり，重要な臨床課題の一つである．本研究では臨床的に牽引が不可能であった下顎大臼歯のエックス線画像を見直し，牽引可能であった例と比較することで，牽引の可否を鑑別するための特徴的な画像所見を検討した． 【方法】資料として徳島大学病院矯正歯科を受診した第三大臼歯を除く下顎大臼歯の埋伏を有する患者5 名の歯科用コーンビームCT （以下CB-CT） 画像とパノラマエックス線画像を用いた．Ducommun らの骨性癒着歯の評価項目である歯根膜腔消失・歯根吸収・組織置換に加え，置換性歯根吸収（歯根吸収により生じた歯根表面の凹凸部の骨硬化像），歯根彎曲の有無を評価した． 【結果】パノラマエックス線画像では5 例全てで歯根膜腔の消失を認めたが，歯根吸収や組織置換像は観察されなかった．一方，CB-CT 画像では牽引が不可能であった3 例全てで歯根膜腔の消失と置換性歯根吸収像を認めた．牽引が可能であった2 例でも歯根膜腔の消失がみられ，うち1 例では歯根吸収像も認めたがその近傍に骨硬化像はなかった． 【考察】Ducommun らの評価項目のみでは，牽引可能であった1 例が偽陽性となったが，置換性歯根吸収の評価項目への追加により偽陽性はなくなった．このことから置換性歯根吸収の評価が埋伏下顎大臼歯の牽引の可否の鑑別に極めて重要であると考えられた． 【結論】埋伏下顎大臼歯の診断において，CB-CT 画像での当該歯の周囲組織の詳細な観察により，牽引が可能であるかを非常に高い精度で診断できる可能性が示唆された

Orthodontic Approach to Hemifacial Microsomia

Aim and objective: To present a growing patient with unilateral mandibular hypoplasia and microtia involved in the first and second branchial arch syndrome (FSBAS) treated with functional appliance. Background: The FSBAS comprises several developmental facial hypoplasia in ear and maxillofacial bones, resulting in hemifacial microsomia. Treatment for hemifacial microsomia varies greatly depending on the grade of mandibular deformities. Functional appliance treatment during growth period is available for mild to moderate mandibular deformities. However, there are few reports of hemifacial microsomia treated with functional appliance. Case description: The patient, an 8-year-and-5-month-old girl, had a chief complaint of mandibular deviation. She had been diagnosed with the FSBAS at birth. Her facial profile was straight and panoramic radiograph indicated that the mandibular ramal height of the affected side was about 60.4% compared to the unaffected side. The occlusal cant was 6°, and the right maxilla and mandible showed severe growth deficiency. At the age of 10 years, functional appliance with expander was used; for 2 years 6 months, the maxillomandibular growth was controlled and from panoramic radiograph, the ramus height of the affected side was increased to 65.0% compared to the unaffected left mandibular ramus. At the age of 12 years and 8 months, multibracket treatment was initiated. After 32 months of active treatment, proper occlusion with functional Class I canine and molar relationships was obtained, although facial asymmetry associated with the difference of ramus heights still existed. The resulting occlusion was stable during 1.5-year retention period. Conclusion: Our results indicated the importance of orthopedic treatment during growth period in the patient with hemifacial macrosomia involving the FSBAS. Clinical significance: This report proposes an efficacy of conventional orthodontic treatment for growing patients with hemifacial macrosomia involved in the FSBAS

A treatment case of Sotos syndrome

Sotos syndrome is a genetic disorder characterized by overgrowth in childhood, specific facial manifestations, advanced bone age, and mental retardation. Although only one case report of Sotos syndrome treated with surgical orthodontics has thus far been published, there have also been a few detailed reports of long-term observation of Sotos syndrome through total orthodontic treatment. This article aimed to present the case of a growing patient with skeletal mandibular protrusion and unilateral posterior crossbite as present in Sotos syndrome treated with a non-surgical orthodontic technique. A 10-year-old boy was diagnosed with skeletal mandibular protrusion and posterior crossbite associated with Sotos syndrome. After maxillary lateral expansion, the skeletal Class III relationship with an anterior crossbite improved owing to mandibular clockwise rotation, while the facemask had a marginal effect. At the completion of growth at 16 years, he had a skeletal Class I relationship, and thus, conventional orthodontic treatment with preadjusted edgewise appliances was initiated. After 41 months of multibracket treatment, acceptable occlusion with a functional Class I relationship was obtained. At 12 months postretention, no or few changes in occlusion and facial features were observed. Our results demonstrate that considering the maxillofacial vertical growth during peripubertal period associated with Sotos syndrome, much attention should be paid to the early orthopedic treatment with the facemask and/or chin cap

LACTATE/MCT4/GPR81 AXIS IN BONE PAIN OF BREAST CANCER

Breast cancer (BC) bone metastasis causes bone pain (BP), which detrimentally damages the quality of life and outcome of patients with BC. However, the mechanism of BC‑BP is poorly understood, and effective treatments are limited. The present study demonstrated a novel mechanism of BC‑BP using a mouse model of bone pain, in which mouse (EO771) and human (MDA‑MB‑231) BC cells were injected in the bone marrow cavity of tibiae. Western blot analysis using sensory nerves, in vivo assessment of cancer pain and in vitro calcium flux analysis were performed. These mice developed progressive BC‑BP in tibiae in conjunction with an upregulation of phosphorylated pERK1/2 and cAMP‑response element‑binding protein (pCREB), which are molecular indicators of neuron excitation, in the dorsal root ganglia (DRG) of sensory nerves. Importantly, mice injected with BC cells, in which the expression of the lactic acid transporter monocarboxylate transporter 4 (MCT4) was silenced, exhibited decreased BC‑BP with downregulated expression of pERK1/2 and pCREB in the DRG and reduced circulating levels of lactate compared with mice injected with parental BC cells. Further, silencing of the cell‑surface orphan receptor for lactate, G protein‑coupled receptor 81 (GPR81), in the F11 sensory neuron cells decreased lactate‑promoted upregulation of pERK1/2 and Ca2+ influx, suggesting that the sensory neuro excitation was inhibited. These results suggested that lactate released from BC cells via MCT4 induced BC‑BP through the activation of GPR81 of sensory neurons. In conclusion, the activation of GPR81 of sensory neurons by lactate released via MCT4 from BC was demonstrated to contribute to the induction of BC‑BP, and disruption of the interactions among lactate, MCT4 and GPR81 may be a novel approach to control BC‑BP

Long-term Follow-up of Orthodontic Patient with Cervical Lymphangioma

Aim: To report a treatment case of mandibular deviation caused by congenital cervical lymphangioma with traditional orthodontic techniques, following-up by 10-year retention. Background: Lymphangiomas, developmental anomalies, can induce various disturbances of swallowing, mastication, speech, breathing, and skeletal deformities as well as psychological stress and anxiety for the patient and their family. Lymphangiomas are benign with virtually no possibility of turning into a malignant lesion, so clinical management aims to treat the patient functionally. Case description: A girl, aged 6 years and 4 months, complained about facial asymmetry and anterior crossbite caused by congenital cervical lymphangioma. Her facial profile was the straight type with an adequate lip position. Anterior and right-side posterior crossbites were observed. On the frontal cephalogram, the menton shifted 3.0 mm to the right. A functional appliance with an expander was placed to correct her dental midline deviation and posterior crossbite. After 2-year treatment, the anterior and right-side posterior crossbites were improved. Multibracket treatment began after the growth spurt. After 44-month active treatment, a functional occlusion, including a Class I molar relationship with a proper interincisal relationship, was achieved. A functional occlusion was maintained during a 10-year retention period, while a mandibular downward growth was observed through the retention period. Conclusion: Conventional orthodontic techniques enable functional and stable occlusion even in patients with mandibular deviation caused by congenital cervical lymphangioma, although only using early orthodontic management by itself may have some limitations. Clinical significance: The hybrid technique combining functional appliance and intermaxillary elastics proves to be an effective therapy for correcting occlusal cant and mandibular deviation caused by cervical lymphangioma