TLE4 Is a Critical Mediator of Osteoblast and Runx2-Dependent Bone Development

Healthy bone homeostasis hinges upon a delicate balance and regulation of multiple processes that contribute to bone development and metabolism. While examining hematopoietic regulation by Tle4, we have uncovered a previously unappreciated role of Tle4 on bone calcification using a novel Tle4 null mouse model. Given the significance of osteoblasts in both hematopoiesis and bone development, this study investigated how loss of Tle4 affects osteoblast function. We used dynamic bone formation parameters and microCT to characterize the adverse effects of Tle4 loss on bone development. We further demonstrated loss of Tle4 impacts expression of several key osteoblastogenic genes, including Runx2, Oc, and Ap, pointing toward a potential novel mechanism for Tle4-dependent regulation of mammalian bone development in collaboration with the RUNX family members.

Evidence Supporting the Regulatory Relationships through a Paracrine Pathway between the Sternum and Pectoral Muscles in Ducks

Muscles and bones are anatomically closely linked, and they can conduct communication by mechanical and chemical signals. However, the specific regulatory mechanism between the pectoral muscle and sternum in birds was largely unknown. The present study explored the potential relationship between them in ducks. The result of the sections showed that more nuclei in proliferate states were observed in the pectoral muscle fibers attached to the calcified sternum, than those attached to the un-calcified sternum. The RNA-seq identified 328 differentially expressed genes (DEGs) in the sternum between the calcified and un-calcified groups. Gene ontology (GO) showed that the DEGs were mainly enriched in pathways associated with calcification. In addition, DEGs in the muscles between the calcified and un-calcified sternum groups were mainly annotated to signal transduction receptor pathways. The expression patterns of genes encoding for secreted proteins, in bone (CXCL12, BMP7 and CTSK) and muscle (LGI1), were clustered with muscle development (MB) and bone calcification (KCNA1, OSTN, COL9A3, and DCN) related genes, respectively, indicating the regulatory relationships through a paracrine pathway existing between the sternum and pectoral muscles in ducks. Together, we demonstrated that the pectoral muscle development was affected by the sternal ossification states in ducks. The VEGFA, CXCL12, SPP1, NOG, and BMP7 were possibly the key genes to participate in the ossification of the duck sternum. We firstly listed evidence supporting the regulatory relationships through a paracrine pathway between the sternum and pectoral muscles in ducks, which provided scientific data for the study of the synergistic development of bone and skeletal muscle.

The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

Human patients carrying PAPP‐A2 inactivating mutations have low bone mineral density. The underlying mechanisms for this reduced calcification are poorly understood. Using a zebrafish model, we report that Papp-aa regulates bone calcification by promoting Ca2+-transporting epithelial cell (ionocyte) quiescence-proliferation transition. Ionocytes, which are normally quiescent, re-enter the cell cycle under low [Ca2+] stress. Genetic deletion of Papp-aa, but not the closely related Papp-ab, abolished ionocyte proliferation and reduced calcified bone mass. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-Akt-Tor signaling in ionocytes. Under low Ca2+ stress, Papp-aa cleaved Igfbp5a. Under normal conditions, however, Papp-aa proteinase activity was suppressed and IGFs were sequestered in the IGF/Igfbp complex. Pharmacological disruption of the IGF/Igfbp complex or adding free IGF1 activated IGF signaling and promoted ionocyte proliferation. These findings suggest that Papp-aa-mediated local Igfbp5a cleavage functions as a [Ca2+]-regulated molecular switch linking IGF signaling to bone calcification by stimulating epithelial cell quiescence-proliferation transition under low Ca2+ stress.

The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

Human patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca2+]-dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca2+]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.

A Brief Review about the Role of Nanomaterials, Mineral-Organic Nanoparticles, and Extra-Bone Calcification in Promoting Carcinogenesis and Tumor Progression

People come in contact with a huge number of nanoparticles (NPs) throughout their lives, which can be of both natural and anthropogenic origin and are capable of entering the body through swallowing, skin penetration, or inhalation. In connection with the expanding use of nanomaterials in various industrial processes, the question of whether there is a need to study the potentially adverse effects of NPs on human health becomes increasingly important. Despite the fact that the nature and the extent of damage caused depends on the chemical and the physical characteristics of individual NPs, there are also general mechanisms related to their toxicity. These mechanisms include the ability of NPs to translocate to various organs through endocytosis, as well as their ability to stimulate the production of reactive oxygen species (ROS), leading to oxidative stress, inflammation, genotoxicity, metabolic changes, and potentially carcinogenesis. In this review, we discuss the main characteristics of NPs and the effects they cause at both cellular and tissue levels. We also focus on possible mechanisms that underlie the relationship of NPs with carcinogenesis. We briefly summarize the main concepts related to the role of endogenous mineral organic NPs in the development of various human diseases and their participation in extra-bone calcification. Considering data from both our studies and those published in scientific literature, we propose the revision of some ideas concerning extra-bone calcification, since it may be one of the factors associated with the initiation of the mechanisms of immunological tolerance.

Bioactive peptide isolated from casein phosphopeptides promotes calcium uptake in vitro and in vivo

A monomeric peptide isolated from casein phosphopeptides promoted calcium uptake in cells via the transcellular pathway and was beneficial for bone calcification in rats.