Abstract
Backgroundp21(WAF1/CIP1/SDI1), a cyclin dependent kinase inhibitor has been shown to influence cell proliferation, differentiation and apoptosis; but more recently, p21 has been implicated in tissue repair. Studies on p21(−/−) knockout mice have demonstrated results that vary from complete regeneration and healing of tissue to attenuated healing. There have however been no studies that have evaluated the role of p21 inhibition in bone healing and remodeling.MethodsThe current study employs a burr-hole fracture model to investigate bone regeneration subsequent to an injury in a p21−/− mouse model. p21−/− and C57BL/6 mice were subjected to a burr-hole fracture on their proximal tibia, and their bony parameters were measured over 4 weeks via in vivo μCT scanning.Resultsp21−/− mice present with enhanced healing from week 1 through week 4. Differences in bone formation and resorption potential between the two mouse models are assessed via quantitative and functional assays. While the μCT analysis indicates that p21−/− mice have enhanced bone healing capabilities, it appears that the differences observed may not be due to the function of osteoblasts or osteoclasts. Furthermore, no differences were observed in the differentiation of progenitor cells (mesenchymal or monocytic) into osteoblasts or osteoclasts respectively.ConclusionsTherefore, it remains unknown how p21 is regulating enhanced fracture repair and further studies are required to determine which cell type(s) are responsible for this regenerative phenotype.
Highlights
The natural remodeling process of the bone is effective in maintaining tissue homeostasis, a diversity of medical conditions exist that adversely affect the mechanical and biological integrity of the tissue such as physical injuries to the bone, osteoporosis, cancer and inflammatory bone disease [1]
The Chinzei et al study established that p21 inhibition did not have an effect on endochondral ossification, Scheijen et al, demonstrated that overexpression of E2F1 delayed endochondral bone formation owing to altered chondrocyte maturation [14]
By week 1, trabecular bone had filled the burr-hole in both groups of mice (Fig. 1 arrows), and by week 4 after injury, the bone in both groups (p21−/− and C57BL/6) demonstrated morphology similar to bone prior to injury (Fig. 1) and a clear injury site was not observable
Summary
The natural remodeling process of the bone is effective in maintaining tissue homeostasis, a diversity of medical conditions exist that adversely affect the mechanical and biological integrity of the tissue such as physical injuries to the bone, osteoporosis, cancer and inflammatory bone disease [1]. While several studies assessed p21 inhibition in adult mouse tissue, Chinzei et al evaluated the role of p21 in embryonic endochondral ossification in vivo, and found that p21 deficiency appears not to influence ossification with other signaling pathways likely compensating [11]. When E2F1 was inhibited in a Rb-deficient embryo, bone defects caused by Rb deficiency was reversed, demonstrating a role of E2F1 in osteoblast differentiation [15]. These results, taken together suggest that the p21-E2F1 signaling pathway may play a role in bone development and/or repair after injury, to date no study has examined if p21 KO mice demonstrate enhanced fracture repair
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