McDonald, Michelle, Mikulec, Kathy, Peacock, Lauren, Morse, Alyson, Baldock, Paul Andrew, Kostenuik, Paul and Little, David G (2013) Osteoclasts are redundant during MMP-driven endochondral fracture repair. McDonald MM, Morse A, Mikulec K, Peacock L, Baldock P, Kostenuik PJ, Little DG. Osteoclasts are redundant during MMP driven endochondral fracture repair, but essential to hard callus remodelling. J Bone Miner Res. 2013 Jul;28(7):1550-60.

Abstract

As new insights into the complexities of endochondral fracture repair emerge, the role of osteoclast activity remains ambiguous. With numerous anti-resorptive agents available to treat bone disease, understanding their impact on bone repair is vital. Further, in light of recent work suggesting osteoclast activity is redundant during early endochondral fracture union, we hypothesize a pivotal role of MMP secreting cells in driving this process. We examined a number of anti-resorptive treatments to either block osteoclast activity, including the potent bisphosphonates zoledronic acid (ZA) and clodronate (CLOD), which work via differing mechanisms, or antagonize osteoclastogenesis with recombinant OPG (HuOPG-Fc), comparing these directly to an inhibitor of matrix metalloproteinase (MMP) activity (MMI270). Endochondral ossification to union occurred normally in all anti-resorptive groups. In contrast, MMP inhibition greatly impaired endochondral union, significantly delaying cartilage callus removal. MMP inhibition also produced smaller, denser hard calluses. Hard callus remodeling was, as expected, delayed with ZA, CLOD and OPG treatment at 4 and 6 weeks, resulting in larger more mineralized calluses at 6 weeks. As a result of reduced hard callus turnover, bone formation was reduced with anti-resorptive agents at these time points. These results confirm that osteoclast activity is redundant to the achievement of endochondral fracture union. Alternatively, MMP secretion by invading cells is obligatory to endochondral union. This study provides new insight into cellular contributions to bone repair and may abate concerns regarding anti-resorptive therapies impeding fracture union.

Item Type:	Article
Keywords:	Osteoclast, Fracture Repair, Matrix Metalloproteinase’s, Endochondral Ossification, Remodeling
Date Deposited:	02 May 2016 23:45
Last Modified:	02 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/8468