Stimulation of bone formation in cortical bone of the mice treated with a novel bone anabolic peptide with osteoclastogenesis inhibitory activity

AbstractParathyroid hormone (PTH) is a key regulator of bone turnover. Depending on the duration of action, the hormone causes catabolic and anabolic effects by binding with specific receptors (PTHR1) in the bone. Various cells expressing PTHR1 on their surface are involved in the process – osteoblasts, osteocytes, bone marrow stromal cells, T-lymphocytes and macrophages. In physiological conditions PTH balances the bone metabolism. Intermittent pharmacological doses of PTH lead to the prevalence of bone formation and are used in the treatment of osteoporosis. Persistently elevated levels of PTH stimulate bone resorption by impacting mainly the cortical bone. New imaging and analysis techniques show that high PTH levels can also have an adverse effect on trabecular microarchitecture. Primary hyperparathyroidism (PHPT) is a disease characterized by increased bone metabolism, decreased bone mineral density (BMD), inadequate osteoid mineralization and an increased risk of fractures. Prolonged overproduction of PTH leads to stimulation of bone resorption and defects in bone formation, mainly causing loss of cortical bone mass, while in the trabecular bone predominate demineralization processes. One explanation of these findings is the enhanced stimulation of RANKL expression by osteoblasts with decreased OPG expression and bone formation at the same time.

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Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2016.02.021 ◽

2016 ◽

Vol 26 (6) ◽

pp. 1525-1528 ◽

Cited By ~ 14

Author(s):

James E. Tarver ◽

Praveen K. Pabba ◽

Joseph Barbosa ◽

Qiang Han ◽

Michael W. Gardyan ◽

...

Keyword(s):

Bone Formation ◽

Cortical Bone ◽

Stimulation Of

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Review for "Mechanically driven counter‐regulation of cortical bone formation in response to sclerostin‐neutralizing antibodies"

10.1002/jbmr.4193/v1/review2 ◽

2020 ◽

Keyword(s):

Bone Formation ◽

Cortical Bone ◽

Neutralizing Antibodies

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Limitations to anabolic stimulation of bone formation

Bone Abstracts ◽

10.1530/boneabs.3.s5.1 ◽

2014 ◽

Author(s):

Roland Baron

Keyword(s):

Bone Formation ◽

Stimulation Of

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The Role of BMP Signaling in Osteoclast Regulation

Journal of Developmental Biology ◽

10.3390/jdb9030024 ◽

2021 ◽

Vol 9 (3) ◽

pp. 24

Author(s):

Brian Heubel ◽

Anja Nohe

Keyword(s):

Bone Formation ◽

Bone Morphogenetic Proteins ◽

Bone Diseases ◽

Bmp Signaling ◽

Bone Homeostasis ◽

Direct Stimulation ◽

Federal Drug Administration ◽

Bmp Pathway ◽

Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

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Osteopontin Deficiency Induces Parathyroid Hormone Enhancement of Cortical Bone Formation

Endocrinology ◽

10.1210/en.2002-220996 ◽

2003 ◽

Vol 144 (5) ◽

pp. 2132-2140 ◽

Cited By ~ 36

Author(s):

Keiichiro Kitahara ◽

Muneaki Ishijima ◽

Susan R. Rittling ◽

Kunikazu Tsuji ◽

Hisashi Kurosawa ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Cancellous Bone ◽

Wild Type ◽

Mineral Density ◽

Cortical Bone Mass ◽

Intermittent Pth

Intermittent PTH treatment increases cancellous bone mass in osteoporosis patients; however, it reveals diverse effects on cortical bone mass. Underlying molecular mechanisms for anabolic PTH actions are largely unknown. Because PTH regulates expression of osteopontin (OPN) in osteoblasts, OPN could be one of the targets of PTH in bone. Therefore, we examined the role of OPN in the PTH actions in bone. Intermittent PTH treatment neither altered whole long-bone bone mineral density nor changed cortical bone mass in wild-type 129 mice, although it enhanced cancellous bone volume as reported previously. In contrast, OPN deficiency induced PTH enhancement of whole-bone bone mineral density as well as cortical bone mass. Strikingly, although PTH suppressed periosteal bone formation rate (BFR) and mineral apposition rate (MAR) in cortical bone in wild type, OPN deficiency induced PTH activation of periosteal BFR and MAR. In cancellous bone, OPN deficiency further enhanced PTH increase in BFR and MAR. Analysis on the cellular bases for these phenomena indicated that OPN deficiency augmented PTH enhancement in the increase in mineralized nodule formation in vitro. OPN deficiency did not alter the levels of PTH enhancement of the excretion of deoxypyridinoline in urine, the osteoclast number in vivo, and tartrate-resistant acid phosphatase-positive cell development in vitro. These observations indicated that OPN deficiency specifically induces PTH activation of periosteal bone formation in the cortical bone envelope.

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