TY - JOUR
T1 - Cellular and molecular factors in flexor tendon repair and adhesions
T2 - A histological and gene expression analysis
AU - Juneja, Subhash C.
AU - Schwarz, Edward M.
AU - O'Keefe, Regis J.
AU - Awad, Hani A.
N1 - Funding Information:
The study was supported by Grants R01AR056696 and P30AR061307 from NIAMS/NIH.
PY - 2013
Y1 - 2013
N2 - Flexor tendon healing is mediated by cell proliferation, migration, and extracellular matrix synthesis that contribute to the formation of scar tissue and adhesion. The biological mechanisms of flexor tendon adhesion formation have been linked to transforming growth factor β (TGF-β). To elucidate the cellular and molecular events in this pathology, we implanted live flexor digitorum longus grafts from the reporter mouse Rosa26LacZ/+ in wild-type recipients, and used histological β-galactosidase (β-gal) staining to evaluate the intrinsic versus extrinsic cellular origins of scar, and reverse transcription-polymerase chain reaction to measure gene expression of TGF-β and its receptors, extracellular matrix proteins, and matrix metalloproteinases (MMPs) and their regulators. Over the course of healing, graft cellularity and β-gal activity progressively increased, and β-gal-positive cells migrated out of the Rosa26LacZ/+ graft. In addition, there was an evidence of influx of host cells (β-gal-negative) into the gliding space and the graft, suggesting that both graft and host cells contribute to adhesions. Interestingly, we observed a biphasic pattern in which Tgfb1 expression was the highest in the early phases of healing and gradually decreased thereafter, whereas Tgfb3 increased and remained upregulated later. The expression of TGF-β receptors was also upregulated throughout the healing phases. In addition, type III collagen and fibronectin were upregulated during the proliferative phase of healing, confirming that murine flexor tendon heals by scar tissue. Furthermore, gene expression of MMPs showed a differential pattern in which inflammatory MMPs were the highest early and matrix MMPs increased over time. These findings offer important insights into the complex cellular and molecular factors during flexor tendon healing.
AB - Flexor tendon healing is mediated by cell proliferation, migration, and extracellular matrix synthesis that contribute to the formation of scar tissue and adhesion. The biological mechanisms of flexor tendon adhesion formation have been linked to transforming growth factor β (TGF-β). To elucidate the cellular and molecular events in this pathology, we implanted live flexor digitorum longus grafts from the reporter mouse Rosa26LacZ/+ in wild-type recipients, and used histological β-galactosidase (β-gal) staining to evaluate the intrinsic versus extrinsic cellular origins of scar, and reverse transcription-polymerase chain reaction to measure gene expression of TGF-β and its receptors, extracellular matrix proteins, and matrix metalloproteinases (MMPs) and their regulators. Over the course of healing, graft cellularity and β-gal activity progressively increased, and β-gal-positive cells migrated out of the Rosa26LacZ/+ graft. In addition, there was an evidence of influx of host cells (β-gal-negative) into the gliding space and the graft, suggesting that both graft and host cells contribute to adhesions. Interestingly, we observed a biphasic pattern in which Tgfb1 expression was the highest in the early phases of healing and gradually decreased thereafter, whereas Tgfb3 increased and remained upregulated later. The expression of TGF-β receptors was also upregulated throughout the healing phases. In addition, type III collagen and fibronectin were upregulated during the proliferative phase of healing, confirming that murine flexor tendon heals by scar tissue. Furthermore, gene expression of MMPs showed a differential pattern in which inflammatory MMPs were the highest early and matrix MMPs increased over time. These findings offer important insights into the complex cellular and molecular factors during flexor tendon healing.
KW - Adhesions
KW - Allograft
KW - Autograft
KW - Extracellular matrix
KW - Flexor tendon
KW - Matrix metalloproteinase
KW - Tendoplasty
KW - Tenocytes
KW - Transforming growth factor
UR - http://www.scopus.com/inward/record.url?scp=84877288223&partnerID=8YFLogxK
U2 - 10.3109/03008207.2013.787418
DO - 10.3109/03008207.2013.787418
M3 - Article
C2 - 23586515
AN - SCOPUS:84877288223
SN - 0300-8207
VL - 54
SP - 218
EP - 226
JO - Connective Tissue Research
JF - Connective Tissue Research
IS - 3
ER -