Inhibin A enhances bone formation during distraction osteogenesis

Abstract

Given the aging population and the increased incidence of fracture in the elderly population, the need exists for agents that can enhance bone healing, particularly in situations of delayed fracture healing and/or non-union. Our previous studies demonstrated that over-expression of the gonadal peptide, human Inhibin A (hInhA), in transgenic mice enhances bone formation and strength via increased osteoblast activity. We tested the hypothesis that hInhA can also exert anabolic effects in a murine model of distraction osteogenesis (DO), using both transgenic hInhA overexpression and administration of normal physiological levels of hInhA in adult male Swiss-Webster mice. Tibial osteotomies and external ring fixation were performed, followed by a 3 day latency period, 14 day distraction, and sacrifice on day 18. Supraphysiological levels of hInhA in transgenic mice, but not normal physiological levels of hInhA, significantly increased endosteal bone formation and mineralized bone area in the distraction gap, as determined by radiographic and µCT analysis. Significantly, increased PCNA and osteocalcin expression in the primary matrix front suggested that hInhA increased osteoblast proliferation. This mechanism is consistent with the effects of other agents and pathologies that modulate bone formation during DO, and demonstrates the potential of hInhA to enhance bone repair and regeneration.

Cisplatin inhibits bone healing during distraction osteogenesis

“…The distracted tibia including the entire distraction gap was scanned in cross section with an isotropic voxel size of 12 μm at 55 kV, 114 μA, and 1000 projections per rotation with threshold and noise filter the same as that used for the trabecular analysis of intact mouse bones (sigma 0.8, support 1, threshold 245). The DO gaps and new bone formation were analyzed as we have described 25 .…”

“…Five to seven micron longitudinal sections were cut on a microtome (Leitz 1512, Wetzlar, Germany) for hematoxylin and eosin staining (H&E). Sections were selected to represent a central or near central gap location as we have described 14, 22, 25 . To be included in both radiographic and histologic analyses the DO samples had to 1) be well aligned, 2) have no broken pin sites, 3) have few bone chips within the DO gap, 4) have an intact ankle, and 5) have had no significant weight loss or health problems during the distraction period as we have described previously 14, 22, 25 .…”

Distraction Osteogenesis and Its Challenges in Bone Regeneration

“…These include alpha-tocopherol (Kurklu et al, 2011); Adiponectin ; Inhibin A (Perrien et al, 2011); Nerve growth factor via a hydrogel (Cao et al, 2011); Thrombin peptide 508 (Cakarer et al, 2010); Bone marrow progenitor cell mobilizing agent (Davidson et al, 2011); Calcium sulphate injection (Song et al, 2004); Osteoblast-like cells (Shao et al, 2007); Stromal cell derived factor-1 (Fujio et al, 2011); NEL-like molecule-1 (Xue et al, 2011).…”

BMP-4 increasesactivin Agene expression during osteogenic differentiation of mouse embryonic stem cells

“…Inhibins and activins are known as gonadal hormones that regulate functions of the reproductive system (Ciarmela et al, 2011;Florio et al, 2011;Reis et al, 2012;Rocha et al, 2011;Tsigkou et al, 2008). In addition, activin A promotes osteoblast recruitment and osteoclast differentiation, while its antagonist, inhibin A, may have anabolic or catabolic effects on bone cells depending on whether the stimulus is continuous or intermittent (Gaddy-Kurten et al, 2002;Nicks et al, 2010;Perrien et al, 2012). During menopause transition, while estradiol levels are still normal, the decreased gonadal inhibin release favors activin and BMP tone in osteoblasts and osteoclasts, with a consequent increase in bone turnover (Nicks et al, 2010;Perrien et al, 2012).…”