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 ¼ 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 (þ358/À258 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. ß

Numerical modeling of cell differentiation and proliferation in force-induced substrates via encapsulated magnetic nanoparticles

“…Consequently, besides other cell reactions [38,39,41], cells may respond to changes in their mechanical environment, such as changes in matrix rigidity, by undergoing differentiation and/or proliferation [13,43]. For instance, experiments have demonstrated that for soft matrices that resembling brain tissue (0.1-1 kPa) SCs differentiate to neurogenic cells, for intermediate matrices that mimicking cartilage tissue (20-25 kPa) they differentiate into chondrogenic cells, and comparatively hard matrices that mimic the tissue of collagenous bone (30-45 kPa) they differentiate into osteogenic cells [13,26,40,55]. Although MSCs have demonstrated quicker differentiation and an increase in the proliferation rate when cultured on osteogenic substrates [40,42], mechanical forces induced into their micro-environment can actively accelerate these processes [34,35].…”

Temporal Variation in Fixation Stiffness Affects Healing by Differential Cartilage Formation in a Rat Osteotomy Model

“…The recent development of well-controlled external fixation systems for the rat allows exploration of how mechanical stimulation in terms of the IFM can temporally influence the healing process [7,24,29,30,32,37].…”

Role of Bone Morphogenetic Proteins and Their Antagonists during Fracture Healing

“…BMP-3 is the most abundant BMP in demineralized bone, accounting for approximately 65% of the total 17) . It is a negative regulator of bone density 18) .Several lines of evidence suggest that BMP-3 activates signaling through an activin pathway, leading to antagonism of BMP-2, 4 induced osteogenesis.…”