Osteonecrosis of the jaw (ONJ) is a well-recognized complication of antiresorptive medications, such as bisphosphonates (BPs). Although ONJ is most common after tooth extractions in patients receiving high dose BPs, many patients do not experience oral trauma. Animal models utilizing tooth extractions and high BP doses recapitulate several clinical, radiographic and histologic findings of ONJ. We and others have reported on rat models of ONJ utilizing experimental dental disease in the absence of tooth extraction. These models emphasize the importance of dental infection/inflammation for ONJ development. Here, we extend our original report in the rat, and present a mouse model of ONJ in the presence of dental disease. Mice were injected with high dose zoledronic acid and pulpal exposure of mandibular molars was performed to induce periapical disease. After 8 weeks, quantitative and qualitative radiographic and histologic analyses of mouse mandibles were executed. Periapical lesions were larger in vehicle- vs. BP treated mice. Importantly, radiographic features resembling clinical ONJ, including thickening of the lamina dura, periosteal bone deposition and increased trabecular density, were seen in the drilled site of BP treated animals. Histologically, osteonecrosis, periosteal thickening, periosteal bone apposition, epithelial migration and bone exposure were present in the BP treated animals in the presence of periapical disease. No difference in TRAP+ cell numbers was observed, but round, detached, and removed from the bone surface cells were present in BP animals. Although 88% of the BP animals showed areas of osteonecrosis in the dental disease site, only 33% developed bone exposure, suggesting that osteonecrosis precedes bone exposure. Our data further emphasize the importance of dental disease in ONJ development, provide qualitative and quantitative measures of ONJ, and present a novel mouse ONJ model in the absence of tooth extraction that should be useful in further exploring ONJ pathophysiological mechanisms.

Although fundamentally similar to other bones, the jaws demonstrate discrete responses to developmental, mechanical, and homeostatic regulatory signals. Here, we hypothesized that rat mandible vs. long-bone marrow-derived cells possess different osteogenic potential. We established a protocol for rat mandible and long-bone marrow stromal cell (BMSC) isolation and culture. Mandible BMSC cultures formed more colonies, suggesting an increased CFU-F population. Both mandible and long-bone BMSCs differentiated into osteoblasts. However, mandible BMSCs demonstrated augmented alkaline phosphatase activity, mineralization, and osteoblast gene expression. Importantly, upon implantation into nude mice, mandible BMSCs formed 70% larger bone nodules containing three-fold more mineralized bone compared with long-bone BMSCs. Analysis of these data demonstrates an increased osteogenic potential and augmented capacity of mandible BMSCs to induce bone formation in vitro and in vivo. Our findings support differences in the mechanisms underlying mandible homeostasis and the pathophysiology of diseases unique to the jaws.

Background Mandible (MB) and maxilla possess unique metabolic and functional properties and demonstrate discrete responses to homeostatic, mechanical, hormonal and developmental stimuli. Osteogenic potential of bone marrow stromal cells (BMSCs) differs between MB versus long bones (LB). Furthermore, MB versus LB derived osteoclasts (OCs) have disparate functional properties. Here, we explored the osteoclastogenic potential of rat MB versus LB marrow in vitro and in vivo under basal and stimulated conditions. Methods Bone marrow from rat MB and LB was cultured in osteoblastic or osteoclastic differentiation media. Tartrate resistant acid phosphatase (TRAP) staining, resorption pit assays, and real-time PCR were performed. Additionally, osmotic mini-pumps were implanted in animals, mandibles and tibiae were isolated and multinucleated cells (MNCs) were measured. Results MB versus LB marrow cultures differentiated with RANKL and M-CSF produced more TRAP+ multinucleated cells (MNCs) and greater resorptive area. To explore MB versus LB BMSC supported osteoclastogenesis, confluent BMSCs were cultured with parathyroid hormone (PTH), 1α,25-dihydroxyvitaminD3 (1,25D3), or PTH+1,25D3. 1,25D3 or PTH+1,25D3 treated LB BMSCs expressed significantly higher RANKL and lower OPG mRNA and increased RANKL:OPG ratio. When whole marrow was cultured with PTH+1,25D3, more TRAP+ MNCs were seen in LB versus MB cultures. Ultimately, rats were infused with PTH+1,25D3 and MB versus tibia MNCs were measured. Hormonal stimulation increased osteoclastogenesis in both MB and tibia. However, higher TRAP+ MNC numbers were observed in tibia versus MB under basal and hormonal stimulation. Conclusions Collectively, our data illustrate differences both on osteoclastogenic potential and OC numbers of MB versus LB marrow.

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