BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described.

Opioids are potent analgesic agents, frequently being used to manage severe pain associated with musculoskeletal (MSK) trauma. The adverse effects of systemic opioids, such as respiratory depression, development of dependency and tolerance have impeded clinical opioid utility. To overcome these limitations, we have developed N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive polymeric prodrugs (ProGel-HMP) of hydromorphone (HMP) as a novel peripherally restricted analgesic agent for local management of MSK pain. In the present study, ProGel-HMP formulations were synthesized and characterized for their physicochemical properties. The localized retention and tissue biodistribution were assessed using near-infrared (NIR) optical imaging in a mouse model of closed femoral fracture. Analgesic efficacy was evaluated through static weight-bearing (incapacitance test) and dynamic gait analysis (CatWalk XT) over three weeks post-ProGel-HMP administration. Potential systemic analgesia was assessed via tail-flick latency. The risk of respiratory depression was evaluated using whole-body plethysmography in rats. Quantitative micro-computed tomography (micro-CT) was performed at 6 weeks post-ProGel-HMP treatment to screen for any potential impacts on the fracture healing process. NIR optical imaging confirmed that local intra-callus injection of ProGel-HMP resulted in its sustained retention at the fracture site for at least 14 days. A single local administration of ProGel-HMP provided sustained pain relief, maintaining balanced static weight distribution and improved dynamic gait parameters for up to 21 days post-fracture, whereas dose-equivalent free HMP lost efficacy within 2 days. Tail-flick testing demonstrated substantially reduced systemic antinociceptive activity following ProGel-HMP administration compared with dose-equivalent free HMP. Whole body plethysmography revealed no significant impairment in respiratory rate, tidal volume, or minute ventilation. Quantitative micro-CT analysis verified that ProGel-HMP treatment did not compromise the fracture healing process, with similar callus morphology, bone mineral density, and microstructural parameters when compared to controls. In conclusion, intra-callus administration of thermoresponsive ProGel-HMP provides potent and sustained local analgesia in a closed femoral fracture mouse model. These findings support ProGel-HMP’s potential as a promising peripherally restricted analgesia for pain management in orthopaedic trauma.