title: Oral administration of soluble guanylate cyclase agonists to rats results in osteoclastic bone resorption and remodeling with new bone formation in the appendicular and axial skeleton.
abstract: Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration. Bone changes were mostly reversed following a 14-day recovery period, with complete reversal after 35 days. The mechanism responsible for the bone changes was investigated in the thyroparathyroidectomized rat model that creates a low state of bone modeling and remodeling due to deprivation of thyroid hormone, calcitonin (CT), and parathyroid hormone (PTH). The sGCa compounds tested increased both bone resorption and formation, thereby increasing bone remodeling independent of calciotropic hormones PTH and CT. Based on these studies, we conclude that the bone changes in rats were likely caused by increased sGC activity.
authors.affiliation: Pfizer, Worldwide Research & Development, Andover, Massachusetts, USA bruce.l.homer@pfizer.com.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Homer
authors.affiliation: Pfizer, Worldwide Research & Development, Andover, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morton
authors.affiliation: Pfizer, Worldwide Research & Development, Groton, Connecticut, USA.
authors.forename: Cedo M
authors.initials: CM
authors.lastname: Bagi
authors.affiliation: Pfizer, Worldwide Research & Development, Andover, Massachusetts, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Warneke
authors.affiliation: Pfizer, Worldwide Research & Development, Groton, Connecticut, USA.
authors.forename: Catharine J
authors.initials: CJ
authors.lastname: Andresen
authors.affiliation: Pfizer, Worldwide Research & Development, Andover, Massachusetts, USA.
authors.forename: Laurence O
authors.initials: LO
authors.lastname: Whiteley
authors.affiliation: Pfizer, Worldwide Research & Development, Andover, Massachusetts, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Morris
authors.affiliation: Pfizer, Worldwide Research & Development, Cambridge, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tones
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000139:chemically induced* / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D002116:Calcitonin / Q000172:deficiency; D002626:Chemistry, Pharmaceutical; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase; D010010:Osteoclasts / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000172:deficiency; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000071756:Soluble Guanylyl Cyclase; D013963:Thyroid Hormones / Q000172:deficiency
chemical_list: D010281:Parathyroid Hormone; D018160:Receptors, Cytoplasmic and Nuclear; D013963:Thyroid Hormones; D002116:Calcitonin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: bone; cGMP.; guanylate cyclase; osteoclasia; remodeling; skeleton