Soft tissue injury in the limbs increased regional bone turnover

•Soft tissue injury by femoral cutaneous incision induced expression of osteoblast and osteoclast differentiation regulators in femoral bone.•Bisphosphonate significantly improved the increased pain-like behaviors resulting from cutaneous incision in a soft tissue injury model mouse.•Bisphosphonate significantly improved the increases in osteoblast and osteoclast differentiation regulator expression in femoral bone.•Pathophysiological changes in soft tissue resulting from cutaneous incisions could be related to the induction of regional bone turnover. Pathological conditions after skeletal tissue injury such as trauma and surgical intervention are often accompanied with regional osteoporotic changes, which are recognized to be mainly caused by limb immobility after injury. However, the mechanisms for the progression of regional osteoporotic changes related to the injury remains unknown. Previous studies reported that the pathophysiological conditions related to tissue injury include the acidic micro-environment formation and increased ATP levels. In addition, we previously demonstrated that those changes in the micro-environment induced a high bone turnover state through the activation of TRPV1, ASICs and P2X expressed in bone cells. We, therefore, hypothesized that tissue injury could enhance a high bone turnover state due to those pathophysiological changes in soft tissue in the injured limb. The aim of this study was to examine whether soft tissue injury associated with cutaneous incisions in a limb affects regional bone turnover. Eight-week-old male C57BL/6 J mice underwent soft tissue injury associated with cutaneous incisions in the right femoral skin. During the 14 days after the incision, changes in the expression of osteoblast and osteoclast differentiation regulators and ATP were evaluated in comparison with those in uninjured mice. The pain-like behaviors and the expression of those differentiation regulators with and without treatment with bisphosphonate and Cox2 inhibitor were assessed in the injured limb. Consistent with the wound healing process, the expression levels of Osterix, osteocalcin and RANKL in the femur of the incised limb were significantly increased up to 7 days, and then decreased to the same level as those in the control limbs by 14 days after the incisions. The levels of TRAP 5b and ATP were initially significantly increased, and then decreased to the same level as before injury by day 14. Bisphosphonate significantly improve