Elucidating the Molecular Signatures Associated with Elevated Bone Formation Rate

Osteoporosis is a disease of decreased bone density that occurs when bone resorption exceeds bone formation, thereby placing individuals at greater risk of fracture and disability. We previously reported that deletion of the Bmpr2 gene in embryonic skeletal progenitor cells causes substantially elevated bone density in young adulthood and reduced age-related decline in bone density, likely due to elevated bone formation rate. Thus, these mice may serve as a novel model in which to explore the mechanisms regulating bone formation in the aging skeleton. Here, we performed transcriptome profiling and identified a concise gene signature associated with elevated bone formation rate in Bmpr2 mutant mice, with 120 transcripts up-regulated and 131 transcripts down-regulated. Candidate-driven qRT-PCR provided secondary confirmation of this dataset. Notably, only 8 of these differentially-expressed transcripts have been previously implicated in bone physiology (Pak4, Rpl38, B2m, Fgf1, Nmu, Phospho1, Smpd3 and Inbe), thus representing potentially novel regulators of osteoblast function in the aging skeleton. Additionally, we sought to examine the cell communication events that are associated with elevated bone formation rate. Using protein samples from control and mutant mice, we took advantage of recent advancements in high-throughput phospho-profiling antibody arrays, which allow simultaneous detection of \u3e1,300 targets using very small quantities of protein. These results indicate that the phosphorylation status of at least 86 signaling effectors is differentially regulated in Bmpr2 mutant mice as compared to control littermates, including numerous proteins known to regulate osteoblast differentiation and/or activity. Collectively, our work highlights novel factors associated with elevated bone formation rate and may identify new opportunities for treating low bone density in humans

Bringing Attention to Lesser-known Bone Remodeling Pathways

Osteoporosis, a disease of low bone mass, places individuals at enhanced risk for fracture, disability, and death. In the USA, hospitalizations for osteoporotic fractures exceed those for heart attack, stroke, and breast cancer and, by 2025, the number of fractures due to osteoporosis is expected to rise to nearly three million in the USA alone. Pharmacological treatments for osteoporosis are aimed at stabilizing or increasing bone mass. However, there are significant drawbacks to current pharmacological options, particularly for long-term management of this chronic condition. Moreover, the drug development pipeline is relatively bereft of new strategies. Consequently, there is an urgent and unmet need for developing new strategies and targets for treating osteoporosis. Casual observation led us to hypothesize that much of the bone remodeling research literature focused on relatively few molecular pathways. This led us to perform bibliometric analyses to determine the relative popularity of bone remodeling pathways in publications and US National Institutes of Health funding of the last 10 years. In this review article, we discuss these findings and highlight several less-examined signaling pathways that may hold promise for future therapies

Bringing Attention to Lesser-known Bone Remodeling Pathways

Osteoporosis, a disease of low bone mass, places individuals at enhanced risk for fracture, disability, and death. In the USA, hospitalizations for osteoporotic fractures exceed those for heart attack, stroke, and breast cancer and, by 2025, the number of fractures due to osteoporosis is expected to rise to nearly three million in the USA alone. Pharmacological treatments for osteoporosis are aimed at stabilizing or increasing bone mass. However, there are significant drawbacks to current pharmacological options, particularly for long-term management of this chronic condition. Moreover, the drug development pipeline is relatively bereft of new strategies. Consequently, there is an urgent and unmet need for developing new strategies and targets for treating osteoporosis. Casual observation led us to hypothesize that much of the bone remodeling research literature focused on relatively few molecular pathways. This led us to perform bibliometric analyses to determine the relative popularity of bone remodeling pathways in publications and US National Institutes of Health funding of the last 10 years. In this review article, we discuss these findings and highlight several less-examined signaling pathways that may hold promise for future therapies