UCLA

The jaw and long bone (LB) are part of bones that make up the skeleton. Although the jaw is, to some extent, analogous to long bone and other bones of the body, they have a distinct developmental origin and mode of ossification. Systemic diseases affect the jaw differently compared to other bones, and the existence of jaw-specific bone pathologies suggests that it employs a different bone homeostatic mechanism. Marrow cells are the functioning orchestrators that maintain the balance between bone formation and bone resorption. The apparent distinction of mandible (MB) and its specific diseases justify that the understanding of MB cell functions and differentiation cannot be concluded from studies of other bone sites. Thus our overall objective is to study MB vs. LB marrow cell characteristics and functions. We, first, established a protocol for rat MB marrow cell isolation, including bone marrow stromal cells (BMSCs) and osteoclast (OC) precursors. Characterization of BMSCs uncovered an enhanced ability of the MB vs. LB BMSCs to induce bone formation both in vitro and in vivo. Taking molecular differences into consideration, we assessed the potential clinical relevance of the MB vs. LB BMSC bone regeneration potential in the critical-sized intramembranous calvarial and endochondral femoral defects. MB BMSCs could regenerate both types of bone and produced better quality bone in intramembranous bone defects. Next, differences in osteoclastogenesis were investigated. Our data demonstrate that although the MB marrow contains an increased number of OC precursors, under parathyroid hormone and 1,25 dihydroxyvitaminD3 stimulation, the LB marrow has a higher osteoclastogenic potential. This appears to be, at least in part, due to the higher RANKL stimulation and OPG inhibition of LB vs. MB BMSCs by these hormones. The differences in the MB vs. LB at the cellular level elucidate the existence of jaw specific diseases, particularly bisphosphonate-related osteonecrosis of the jaw (BRONJ). The jaw intrinsically has reduced osteoclast formation ability and cannot counteract the inhibitory effect of bisphosphonates to reestablish the normal bone resorption process. The increased sensitivity in nature of the jaw to antiresorptive treatments could explain, at least in part, the pathophysiology of BRONJ and its exclusive clinical manifestations in the jaw bone.