title: Mechanical stimulation alters tissue differentiation and molecular expression during bone healing.
abstract: Further understanding of how mechanical cues modulate skeletal tissue differentiation can identify potential means of enhancing repair following injury or disease. Prior studies examined the effects of mechanical loading on osteogenesis, chondrogenesis, and fibrogenesis in an effort to enhance bony union. However, exploring how mechanical stimuli can divert the bone healing process towards formation of other mesenchymal tissues, as an endpoint, may elucidate new avenues for repair and regeneration of tissues such as cartilage and fibrous tissue. This study investigated the use of mechanical stimulation to promote cartilage rather than bone formation within an osteotomy. Our overall goal was to define skeletal tissue distribution and molecular expression patterns induced by the stimulation. Retired breeder Sprague-Dawley rats (n = 85) underwent production of a mid-diaphyseal, transverse femoral osteotomy followed by external fixation. Beginning on postoperative day 10 and continuing for 1, 2, or 4 weeks, a cyclic bending motion (+35 degrees/-25 degrees at 1 Hz) was applied in the sagittal plane for 15 min/day for 5 consecutive days/week. Control animals experienced continuous rigid fixation. Histological and molecular analyses indicated that stimulation substantially altered normal bone healing. Stimulated specimens exhibited an increase in cartilage volume over time, while control specimens demonstrated bony bridging. Stimulation induced upregulation of cartilage-related genes (COL2A1 and COL10A1) and downregulation of bone morphogenetic proteins (BMPs) -4, -6 and -7. However, BMP-3 was upregulated with stimulation. These findings illustrate that mechanical cues can selectively modulate osteogenesis and chondrogenesis in vivo, and suggest a potential basis for treatment regimens for injured or diseased cartilaginous tissues.
authors.affiliation: Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Kristy T Salisbury
authors.initials: KT
authors.lastname: Palomares
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Gleason
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Mason
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Cullinane
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Einhorn
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
authors.forename: Elise F
authors.initials: EF
authors.lastname: Morgan
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D020219:Chondrogenesis / Q000502:physiology*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D017102:Fracture Healing / Q000502:physiology*; D008297:Male; D010012:Osteogenesis / Q000502:physiology*; D010027:Osteotomy; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D016474:Weight-Bearing / Q000502:physiology*
chemical_list: C525811:Bmp4 protein, rat; C525818:Bmp6 protein, rat; C525821:Bmp7 protein, rat; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; C511513:COL2A1 protein, rat; D024043:Collagen Type II; D024121:Collagen Type X; D012333:RNA, Messenger