Dose-Dependent Effects of a Novel Selective EP4 Prostaglandin Receptor Agonist on Treatment of Critical Size Femoral Bone Defects in a Rat Model

Abstract

Difficulties in treating pseudarthrosis and critical bone defects are still evident in physicians’ clinical routines. Bone morphogenetic protein 2 (BMP-2) has shown promising osteoinductive results but also considerable side effects, not unexpected given that it is a morphogen. Thus, the bone regenerative potential of the novel selective, non-morphogenic EP4 prostaglandin receptor agonist KMN-159 was investigated in this study. Therefore, mineralized collagen type-1 matrices were loaded with different amounts of BMP-2 or KMN-159 and implanted into a 5 mm critical-sized femoral defect in rats. After 12 weeks of observation, micro-computed tomography scans were performed to analyze the newly formed bone volume (BV) and bone mineral density (BMD). Histological analysis was performed to evaluate the degree of defect healing and the number of vessels, osteoclasts, and osteoblasts. Data were evaluated using Kruskal-Wallis followed by Dunn’s post hoc test. As expected, animals treated with BMP-2, the positive control for this model, showed a high amount of newly formed BV as well as bone healing. For KMN-159, a dose-dependent effect on bone regeneration could be observed up to a dose optimum, demonstrating that this non-morphogenic mechanism of action can stimulate bone formation in this model system.

Friend or foe? Inflammation and the foreign body response to orthopedic biomaterials

“…In contrast the local release of a selective EP4-prostaglandin receptor agonist from a mineralized collagen scaffold can increase bone formation. 146 Hayashi et al demonstrated that titanium-coated rough-surfaced implants had an increased implant fixation strength, if osteoporotic animals were treated with a selective EP4-prostaglandin receptor agonist. 147 Bone Morphogenetic Protein 2 is a clinically approved growth factor for facilitating bone regeneration.…”

“…Nonsteroidal anti‐inflammatory drugs and corticosteroid reduce the inflammatory reaction and subsequent bone formation. In contrast the local release of a selective EP4‐prostaglandin receptor agonist from a mineralized collagen scaffold can increase bone formation 146 . Hayashi et al demonstrated that titanium‐coated rough‐surfaced implants had an increased implant fixation strength, if osteoporotic animals were treated with a selective EP4‐prostaglandin receptor agonist 147 …”

Cause and chondroprotective effects of prostaglandin E2 secretion during mesenchymal stromal cell chondrogenesis

“…Beyond that, PGE2 has been functionally implicated in endochondral development by in vitro studies with the murine pro-chondrogenic cell line ATDC5 and rat periosteum cultures, in which COX-2 inhibition was reported to reduce Col10a1 and Alpl gene expression [20], while in turn PGE2 stimulated Col10a1 expression [21]. Moreover, an impaired endochondral bone formation and fracture healing was apparent in COX-2 loss-of-function models in mice, rats, and rabbits that could be rescued by PGE2 or an EP4 agonist [22][23][24][25][26][27]. While altogether, this may indicate a prohypertrophic activity of PGE2, a large body of opposing studies reported that PGE2 or EP4 activation decreased Col10a1 and Alpl expression, ALP activity, and mineralization in chick or murine limb bud mesenchymal cells and growth plate chondrocytes [28][29][30][31][32], attributing an antihypertrophic activity to PGE2.…”