title: Molecular mechanisms underlying skeletal growth arrest by cutaneous scarring.
abstract: In pediatric surgeries, cutaneous scarring is frequently accompanied by an arrest in skeletal growth. The molecular mechanisms responsible for this effect are not understood. Here, we investigated the relationship between scar contracture and osteogenesis. An excisional cutaneous wound was made on the tail of neonatal mice. Finite element (FE) modeling of the wound site was used to predict the distribution and magnitude of contractile forces within soft and hard tissues. Morphogenesis of the bony vertebrae was monitored by micro-CT analyses, and vertebral growth plates were interrogated throughout the healing period using assays for cell proliferation, death, differentiation, as well as matrix deposition and remodeling. Wound contracture was grossly evident on post-injury day 7 and accompanying it was a significant shortening in the tail. FE modeling indicated high compressive strains localized to the dorsal portions of the vertebral growth plates and intervertebral disks. These predicted strain distributions corresponded to sites of increased cell death, a cessation in cell proliferation, and a loss in mineralization within the growth plates and IVD. Although cutaneous contracture resolved and skeletal growth rates returned to normal, vertebrae under the cutaneous wound remained significantly shorter than controls. Thus, localized contractile forces generated by scarring led to spatial alterations in cell proliferation, death, and differentiation that inhibited bone growth in a location-dependent manner. Resolution of cutaneous scarring was not accompanied by compensatory bone growth, which left the bony elements permanently truncated. Therefore, targeting early scar reduction is critical to preserving pediatric bone growth after surgery.
authors.affiliation: Department of Oral and Maxillofacial Surgery, West China Stomatology Hospital, Chengdu 610041, China; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford CA 94035, USA.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford CA 94035, USA; College of Medicine, University of Arizona, Tucson, AZ 85719, USA.
authors.forename: Chelsey A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford CA 94035, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Smith
authors.affiliation: Department of Oral and Maxillofacial Surgery, West China Stomatology Hospital, Chengdu 610041, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shi
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford CA 94035, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Brunski
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford CA 94035, USA. Electronic address: jhelms@stanford.edu.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Helms
mesh_terms: D000293:Adolescent; D000818:Animals; D000831:Animals, Newborn; D001696:Biomechanical Phenomena; D001846:Bone Development; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology; D002921:Cicatrix / Q000473:pathology*; D020342:Finite Element Analysis; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008954:Models, Biological; D010012:Osteogenesis; D012867:Skin / Q000473:pathology*; D013314:Stress, Mechanical; D014945:Wound Healing
keywords: Contracture; Finite element model; Growth inhibition; Osteogenesis; Scarring