title: Inhibition of ectopic bone formation by a selective retinoic acid receptor alpha-agonist: a new therapy for heterotopic ossification?
abstract: Heterotopic ossification (HO) consists of formation of ectopic cartilage followed by endochondral bone and is triggered by major surgeries, large wounds, and other conditions. Current therapies, including low-dose irradiation, are not always effective and do not target the skeletogenic process directly. Because chondrogenesis requires a decrease of nuclear retinoic acid receptor alpha (RARalpha) action, we reasoned that pharmacologic activation of this receptor pathway should inhibit HO. Thus, we selected the synthetic retinoid NRX195183, a potent and highly selective RARalpha-agonist, and found that it did inhibit chondrogenesis in mouse limb micromass cultures. We established a mouse HO model consisting of subcutaneous implantation of Matrigel mixed with rhBMP-2. Control mice receiving daily oral doses of vehicle (peanut oil) or retinol (a natural nonactive retinoid precursor) developed large HO-like masses by days 9-12 that displayed abundant cartilage, endochondral bone, vessels, and marrow. In contrast, formation of HO-like masses was markedly reduced in companion mice receiving daily oral doses of alpha-agonist. These ectopic masses contained sharply reduced amounts of cartilage and bone, blood vessels, and TRAP-positive osteoclasts, and expressed markedly lower levels of master chondrogenic genes including Sox9, cartilage genes such as collagen XI and X, and osteogenic genes including Runx2. The data provide proof-of-principle evidence that a pharmacological strategy involving a selective RARalpha-agonist can indeed counteract an ectopic skeletal-formation process effectively and efficiently, and could thus represent a novel preventive treatment for HO.
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Kengo
authors.initials: K
authors.lastname: Shimono
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Morrison
authors.forename: Wei-en
authors.initials: WE
authors.lastname: Tung
authors.forename: Roshantha A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Julie A
authors.initials: JA
authors.lastname: Williams
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pacifici
mesh_terms: D000818:Animals; D020219:Chondrogenesis / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D009999:Ossification, Heterotopic / Q000188:drug therapy* / Q000517:prevention & control; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D020011:Protective Agents / Q000008:administration & dosage*; D018168:Receptors, Retinoic Acid / Q000008:administration & dosage* / Q000819:agonists*; D000072482:Retinoic Acid Receptor alpha; D016896:Treatment Outcome
chemical_list: D020011:Protective Agents; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha