Johnston CC Jr, Lavy N, Lord T, Vellios F, Merritt AD, Deiss WP Jr (1968) Osteopetrosis. a clinical, genetic, metabolic, and morphologic study of the dominantly inherited, benign form. Medicine 47:149–167

Article  PubMed  Google Scholar 

Cleiren E, Bénichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, deVernejoul MC, Van Hul W (2001) Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 10(25):2861–2867

Article  CAS  PubMed  Google Scholar 

Waguespack SG, Koller DL, White KE, Fishburn T, Carn G, Buckwalter KA, Johnson M, Kocisko M, Evans WE, Foroud T, Econs MJ (2003) Chloride channel 7 (CICN7) gene mutations and autosomal dominant osteopetrosis, Type II. J Bone Miner Res 18(8):1513–1518

Article  CAS  PubMed  Google Scholar 

Waguespack SG, Hui SL, DiMeglio L, Econs MJ (2007) Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with chloride channel 7 (C1CN7) gene mutations. J Clin Endocrinol Metab 92(3):771–778

Article  CAS  PubMed  Google Scholar 

Weber DR, Econs MJ, Levine MA (2014) Osteopetrosis: pathogenesis, management and future directions for research. IBMS BoneKey 11:520

Article  Google Scholar 

Alam I, Gray AK, Chu K, Ichikawa S, Mohammad KS, Capannolo M, Capulli M, Maurizi A, Muraca M, Teti A, Econs MJ, Del Fattore A (2014) Generation of the first autosomal dominant osteopetrosis type II (ADO2) disease models. Bone 59:66–75

Article  CAS  PubMed  Google Scholar 

Chu K, Snyder R, Econs MJ (2006) Disease status in autosomal dominant osteopetrosis type 2 is determined by osteoclastic properties. J Bone Miner Res 21(7):1089–1097

Article  CAS  PubMed  Google Scholar 

Giembycz MA, Field SK (2010) Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther 4:147–58

CAS  PubMed  PubMed Central  Google Scholar 

Wedzicha JA, Calverley PM, Rabe KF (2016) Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis 11:81–90

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rahman N, Ramos-Espiritu L, Milner TA, Buck J, Levin LR (2016) Soluble adenylyl cyclase is essential for proper lysosomal acidification. J Gen Physiol 148(4):325–339

Article  CAS  PubMed  PubMed Central  Google Scholar 

Henriksen K, Sorensen MG, Nielsen RH, Gram J, Schaller S, Dziegiel MH, Everts V, Bollerslev J, Karsdal MA (2006) Degradation of the organic phase of bone by osteoclasts: a secondary role for lysosomal acidification. J Bone Miner Res 21(1):58–66

Article  CAS  PubMed  Google Scholar 

Park YG, Kim YH, Kang SK, Kim CH (2006) cAMP-PKA signaling pathway regulates bone resorption mediated by processing of cathepsin K in cultured mouse osteoclasts. Int Immunopharmacol 6(6):947–56

Article  CAS  PubMed  Google Scholar 

Mediero A, Perez-Aso M, Cronstein BN (2014) Activation of EPAC1/2 is essential for osteoclast formation by modulating NFκB nuclear translocation and actin cytoskeleton rearrangements. FASEB J 28(11):4901–13

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schulz P, Werner J, Stauber T, Henriksen K, Fendler K (2010) The G215R mutation in the Cl-/H+-antiporter ClC-7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect. PLoS ONE 5(9):e12585

Article  PubMed  PubMed Central  Google Scholar 

Weinert S, Jabs S, Hohensee S, Chan WL, Kornak U, Jentsch TJ (2014) Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions. EMBO Rep 15(7):784–791

Article  CAS  PubMed  PubMed Central  Google Scholar 

Henriksen K, Sørensen MG, Jensen VK, Dziegiel MH, Nosjean O, Karsdal MA (2008) Ion transporters involved in acidification of the resorption lacuna in osteoclasts. Calcif Tissue Int 83(3):230–242

Article  CAS  PubMed  Google Scholar 

Stauber T, Weinert S, Jentsch TJ (2012) Cell biology and physiology of CLC chloride channels and transporters. Compr Physiol 2(3):1701–1744

Article  PubMed  Google Scholar 

Hong JM, Gerard-O’Riley RL, Acton D, Alam I, Econs MJ, Bruzzaniti A. The PDE4 inhibitors Roflumilast and Rolipram rescue ADO2 osteoclast resorption dysfunction (Abstract accepted for publication in Journal of Bone and Mineral Research, supplement 38, 2023)

Hong JM, Rita L. Gerard-O’Riley RL, Acton D, Patel V, Lavu N, Alam I, Econs MJ and Angela Bruzzaniti A (2023) The PDE4 inhibitors Roflumilast and Rolipram Rescue ADO2 Osteoclast Resorption Dysfunction. Calcif Tissue Int (In Revision)

Dempster DW, Compston JE, Drezner MK et al (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res 28(1):2–17

Article  PubMed  Google Scholar 

Li H, Zuo J, Tang W (2018) Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol 9:1048

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kawamatawong T (2021) Phosphodiesterase-4 Inhibitors for Non-COPD Respiratory Diseases. Front Pharmacol 12:518345

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ifegwu OC, Awale G, Rajpura K, Lo KW, Laurencin CT (2017) Harnessing cAMP signaling in musculoskeletal regenerative engineering. Drug Discov Today 22(7):1027–1044

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hertz AL, Beavo JA (2011) Cyclic nucleotides and phosphodiesterases in monocytic differentiation. Handb Exp Pharmacol 204:365–390. https://doi.org/10.1007/978-3-642-17969-3_16

Article  CAS  Google Scholar 

Kalinkovich A, Livshits G (2021) Biased and allosteric modulation of bone cell-expressing G protein-coupled receptors as a novel approach to osteoporosistherapy. Pharmacol Res 171:105794

Article  CAS  PubMed  Google Scholar 

Chen T, Wang Y, Hao Z, Hu Y, Li J (2021) Parathyroid hormone and its related peptides in bone metabolism. Biochem Pharmacol 192:114669

Article  CAS  PubMed  Google Scholar 

Liu Q, Sun Y, Chen D, Chen K, Huang B, Chen Z (2021) Inhibitory effect of roflumilast on experimental periodontitis. J Periodontol. https://doi.org/10.1002/JPER.20-0858

Article  PubMed  PubMed Central  Google Scholar 

Koga Y, Tsurumaki H, Aoki-Saito H, Sato M, Yatomi M, Takehara K, Hisada T (2019) Roles of cyclic AMP response element binding activation in the ERK1/2 and p38 MAPK signaling pathway in central nervous system, cardiovascular system, osteoclast differentiation and mucin and cytokine production. Int J Mol Sci 20(6):1346

Article  CAS  PubMed  PubMed Central  Google Scholar 

Möllmann J, Kahles F, Lebherz C, Kappel B, Baeck C, Tacke F, Werner C, Federici M, Marx N, Lehrke M (2017) The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and leads to improved glucose metabolism. Diabetes Obes Metab 19(4):496–508

Article  PubMed  Google Scholar 

Cortijo J, Iranzo A, Milara X, Mata M, Cerdá-Nicolás M, Ruiz-Saurí A, Tenor H, Hatzelmann A, Morcillo EJ (2009) Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. Br J Pharmacol 156(3):534–44

Article  CAS  PubMed  PubMed Central  Google Scholar 

Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G (2005) Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 172(7):848–853

Article  PubMed  Google Scholar 

Bethke TD, Böhmer GM, Hermann R, Hauns B, Fux R, Mörike K, David M, Knoerzer D, Wurst W, Gleiter CH (2007) Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J Clin Pharmacol 47(1):26–36

Article  CAS  PubMed  Google Scholar 

Neville KA, Szefler SJ, Abdel-Rahman SM, Lahu G, Zech K, Herzog R, Bethke TD, Gleason MC, Kearns GL (2008) Single-dose pharmacokinetics of roflumilast in children and adolescents. J Clin Pharmacol 48(8):978–85

Article  CAS  PubMed  Google Scholar 

Moussa BA, El-Zaher AA, El-Ashrey MK, Fouad MA (2019) Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile. Drug Test Anal 11(6):886–897

Article  CAS  PubMed  Google Scholar 

Waki Y, Horita T, Miyamoto K, Ohya K, Kasugai S (1999) Effects of XT-44, a phosphodiesterase 4 inhibitor, in osteoblastgenesis and osteoclastgenesis in culture and its therapeutic effects in rat osteopenia models. Jpn J Pharmacol 79(4):477–83

Article  CAS  PubMed  Google Scholar 

Yao W, Tian XY, Chen J, Setterberg RB, Lundy MW, Chmielzwski P, Froman CA, Jee WS (2007) Rolipram, a phosphodiesterase 4 inhibitor, prevented cancellous and cortical bone loss by inhibiting endosteal bone resorption and maintaining the elevated periosteal bone formation in adult ovariectomized rats. J Musculoskelet Neuronal Interact 7(2):119–30

CAS  PubMed  Google Scholar 

Munisso MC, Kang JH, Tsurufuji M, Yamaoka T (2012) Cilomilast enhances osteoblast differentiation of mesenchymal stem cells and bone formation induced by bone morphogenetic protein 2. Biochimie 94(11):2360–5