Counter-regulatory Phosphatases Tnap And Npp1 Temporally Regulate Tooth Root Cementogenesis

Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate (P-i) to mineral inhibitor pyrophosphate (PPi), where local P-i and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected.712741Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH

Inflammatory bone loss associated with MFG‐E8 deficiency is rescued by teriparatide

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154457/1/fsb2fj201701238r-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154457/2/fsb2fj201701238r.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154457/3/fsb2fj201701238r-sup-0001.pd

Anabolic actions of PTH in murine models: two decades of insights

Parathyroid hormone (PTH) is produced by the parathyroid glands in response to low serum calcium concentrations where it targets bones, kidneys, and indirectly, intestines. The N- terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild- type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12- weeks of age, a treatment duration lasting 5- 6- weeks, and a PTH dose of 30- 60- μg/kg/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1- α- hydroxylase (Pth;1α(OH)ase, 62- fold), amphiregulin (Areg, 15.8- fold), and PTH related protein (Pthrp, 10.2- fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, - 9.7- fold), low- density lipoprotein receptor- related protein 6 (Lrp6, 1.3- fold), and low- density lipoprotein receptor- related protein 5 (Lrp5, - 1.0- fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170862/1/jbmr4389.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170862/2/jbmr4389_am.pd

Anabolic actions of PTH

Parathyroid hormone (PTH) is produced by the parathyroid glands in response to low serum calcium concentrations where it targets bones, kidneys, and indirectly, intestines. The N‐terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild‐type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12 weeks of age, a treatment duration lasting 5–6 weeks, and a PTH dose of 30–60 μg/kg/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1‐α‐hydroxylase (Pth;1α(OH)ase, 62‐fold), amphiregulin (Areg, 15.8‐fold), and PTH related protein (Pthrp, 10.2‐fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, −9.7‐fold), low‐density lipoprotein receptor‐related protein 6 (Lrp6, 1.3‐fold), and low‐density lipoprotein receptor‐related protein 5 (Lrp5, −1.0‐fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)