title: Genetic variation in the patterns of skeletal progenitor cell differentiation and progression during endochondral bone formation affects the rate of fracture healing.
abstract: These studies examined how genetic differences that regulate architectural and bone material properties would be expressed during fracture healing and determine whether any of these features would affect rates of healing as defined by regain of strength. Controlled fractures were generated in three inbred strains of mice: A/J, C57Bl/6J (B6), and C3H/HeJ (C3H). Both the A/J and B6 strains showed faster healing than the C3H strain based on regains in strength and stiffness. Strain-specific architectural features such as moment of inertia, cross-sectional area, and cortical thickness were all recapitulated during the development of the callus tissues. None of these traits were directly relatable to rates of fracture healing. However, rates of healing were related to variations in the temporal patterns of chondrogenic and osteogenic lineage development. The B6 strain expressed the highest percentage of cartilage gene products and had the longest period of chondrocyte maturation and hypertrophy. The slowest healing strain (C3H) had the shortest period of chondrogenic development and earliest initiation of osteogenic development. Although the A/J strain showed an almost identical pattern of chondrogenic development as the C3H strain, A/J initiated osteogenic development several days later than C3H during fracture healing. Long bone growth plates at 28 days after birth showed similar strain-specific variation in cartilage tissue development as seen in fracture healing. Thus, the B6 strain had the largest growth plate heights, cell numbers per column, and the largest cell size, whereas the C3H columns were the shortest, had the smallest number of cells per column, and showed the smallest cell sizes. These results show that (1) different strains of mice express variations of skeletal stem cell lineage differentiation and (2) that these variations affect the rate of fracture healing.
authors.affiliation: Department of Orthopaedics, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Jepsen
authors.forename: Christopher
authors.initials: C
authors.lastname: Price
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Silkman
authors.forename: Fred H
authors.initials: FH
authors.lastname: Nicholls
authors.forename: Phillip
authors.initials: P
authors.lastname: Nasser
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Nicole
authors.initials: N
authors.lastname: Hadi
authors.forename: Michael
authors.initials: M
authors.lastname: Alapatt
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Stapleton
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kakar
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Einhorn
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001846:Bone Development / Q000235:genetics*; D002356:Cartilage / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D020219:Chondrogenesis; D024121:Collagen Type X / Q000378:metabolism; D005264:Femoral Fractures / Q000473:pathology*; D005269:Femur / Q000473:pathology*; D017102:Fracture Healing / Q000235:genetics*; D020869:Gene Expression Profiling; D014644:Genetic Variation; D006132:Growth Plate / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020127:Recovery of Function; D013234:Stem Cells / Q000166:cytology*
chemical_list: D024121:Collagen Type X