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Low-Intensity Pulsed Ultrasound-Promoted Bone Healing Is Not Entirely Cyclooxgenase 2 Dependent

Institute of Physical Education, Health, and Leisure Studies (T.-H.H.) and Department of Physiology (H.-I.C.), National Cheng Kung University, Tainan, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan (C.-H.T.); Department of Pharmacology, National Taiwan University, Taipei, Taiwan (W.-M.F.); and Department of Orthopedics, National Taiwan University Hospital, Taipei, Taiwan (R.-S.Y).

Address correspondence to Rong-Sen Yang, MD, PhD, Department of Orthopedics, National Taiwan University Hospital, 7 Chung-Shan South Rd, Taipei 100, Taiwan. E-mail: rsyang{at}ntuh.gov.tw

Objective. The purpose of this study was to investigate whether low-intensity pulsed ultrasound (LIPUS) promotes bone healing through the cyclooxgenase 2 (COX-2) pathway. Methods. Each male Sprague Dawley rat (n = 48 total) in the study underwent bilateral drilled hole injury in the proximal tibiae. Then the animals were randomly assigned to 2 groups: a COX-2 inhibitor (COX-2in) group, treated with the selective COX-2 inhibitor rofecoxib (3 mg/kg/d), and a control (CON) group, treated with distilled water. Low-intensity pulsed ultrasound was applied to the injured site of a single limb of each rat for 20 min/d at a consistent intensity (30 mW/cm²) and frequency (1.5 MHz). Subsets of animals from both groups were killed after 3, 7, or 14 days of single-limb LIPUS treatment. Tissue sections were subjected to alcian blue staining, and the healing status was quantified according to a scoring system. Results. After 3 and 7 days, the CON group’s LIPUS-treated limbs had significantly higher healing scores than its nontreated limbs and the COX-2in group’s LIPUS-treated limbs (P < .05). Interestingly, after the 14-day treatment, the COX-2in group’s LIPUS-treated limbs had significantly higher healing scores than its nontreated limbs (P < .05) but showed no difference when compared with the CON group. Conclusions. Low-intensity pulsed ultrasound did show accelerative efficacy on bone healing. Selective inhibition of COX-2 could delay but not entirely block the benefits of LIPUS on bone healing. Low-intensity ultrasound treatment could promote bone healing through other, non–COX-2-dependent, pathways.

Key Words: bone injury • cyclooxygenase 2 • drilled hole • low-intensity pulsed ultrasound • rofecoxib

Abbreviations: CON, control • COX-2, cyclooxygenase 2 • COX-2in, COX-2 inhibitor • LIPUS, low-intensity pulsed ultrasound • PGE₂, prostaglandin E₂