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Osteoporosis is a systemic bone disease characterized by low bone density, poor bone microstructure, increased bone fragility, and susceptibility to fracture. Current drugs for the treatment of osteoporosis mostly use bone mineralization promoters such as calcium and vitamin D and bone resorption inhibitors such as bisphosphonates and estrogen. The above-mentioned drugs can significantly improve bone density and reduce the risk of fractures, but they cannot reconstruct damaged bones, and the use of anti-bone resorptive drugs may cause adverse reactions. In recent years, some scholars have subcutaneously injected synthetic human parathyroid hormone-related protein (PTHRP) into menopausal women and found that the indicators reflecting bone formation, osteocalcin and alkaline phosphatase, increased in the subjects, but the indicators reflecting bone resorption did significantly decreased, this characteristic is better than the currently clinically used bone formation accelerators. This article reviews the mechanism of PTHRP in regulating bone synthesis and catabolism.
PTHRP is a secreted peptide found in humoral hypercalcemia. It is named because its N-terminus is similar to parathyroid hormone. The 5' end of the human PTHRP gene contains three different transcription promoters, and the 3' flanking region has alternative splicing, encoding three different PTHRP proteins. PTHRP can activate PTH1R (PTH1R is the receptor that recognizes N-terminal PTHRP) to function.
Figure 1. The cells that make up bone mainly include osteocytes, osteoblasts, osteoclasts, and chondrocytes in bone tissue, as well as bone marrow mesenchymal cells and bone marrow adipocytes in the bone marrow cavity.(Source: Zhou R, et al. 2021)
PTHRP widely exists in human tissues and is expressed in skin, bones, heart, smooth muscle, teeth, growth plate chondrocytes, kidneys, neurons and glial tissues, and mainly regulates cell proliferation in an autocrine or paracrine manner and differentiation. PTHRP participates in the regulation of normal human breast, tooth and cardiovascular development, and is secreted in many tumor tissues such as squamous cell carcinoma, breast cancer, kidney cancer, prostate cancer, colon cancer and oral cancer. However, its role in tumor development and development is still unclear. The physiological role of PTHRP in bone tissue has been confirmed. Studies have found that PTHRP-deficient mice die immediately after birth and exhibit head cartilage and costal cartilage dysplasia and tooth eruption disorders, indicating that PTHRP plays an important role in bone development, osteogenesis, and breakdown. Plays an important role in bone processes.
The important physiological functions of PTHRP in bone were confirmed using embryonic and postnatal transgenic mice. Mice homozygous for PTHRP gene knockout have abnormal endochondral bone formation at birth, leading to thoracic disorders and eventually death from respiratory failure. Mice with a haploinsufficient dose of PTHRP were phenotypically normal at birth, but showed decreased bone mass 3 months after birth, a significant decrease in trabecular thickness and connectivity, and an abnormal increase in the number of adipocytes in the bone marrow. Transgenic mice that knock out PTHRP in osteoblasts also have the same phenotype. At the same time, the number of osteoclast formation is also reduced, which may be because knocking out PTHRP hinders the role of osteoblasts in promoting osteoclastogenesis. Recent studies have shown that mice lacking the entire middle region and C-terminus of the PTHRP gene suffer premature death, low bone mass, reduced osteoblast proliferation and differentiation, and increased apoptosis, which further illustrates the importance of these regions of PTHRP in bone development.
In the growth plate, PTHRP produced by the distal perichondrium interacts with PPR expressed in the proliferative layer and prehypertrophic layer of the growth plate, forming a negative feedback loop with the Indianhedgehog (Ihh) signal, inhibiting the premature differentiation of chondrocytes into prehypertrophic chondrocytes. thereby regulating the development process of the growth plate. During the cartilage-osteogenesis process, differentiated chondrocytes secrete Ihh, which induces chondrocyte hypertrophy, while immature chondrocytes around the joint secrete PTHRP. PTHRP acts on proliferation and prehypertrophic chondrocytes, slowing down their differentiation process. In addition, the fibrous layer of the periosteum also expresses PTHRP, which regulates the remodeling of cortical bone at the metaphyseal-diaphyseal junction in long bones during linear growth.
Bone metabolism is a dynamic balance process in which old bone tissue is absorbed and new bone is formed. It is the key to maintaining normal bone mass. Bone metabolism includes bone formation and bone resorption, that is, two processes: osteogenesis and osteoclasts. During the osteoclast process, lining cells retract, osteoclast precursor cells accumulate and then form mature osteoclasts that burrow into the bone surface. In terms of osteogenesis, osteoblast cells gather around new bone matrix to form bone through cell-to-cell interactions.
Transient PTH and PTHRP N-terminal peptide stimulation can promote the proliferation of osteoblasts in a low-density state, but inhibit the proliferation of osteoblasts in a high-density state. This dual effect is related to cyclin D1 Related to cell cycle inhibitory factors such as p27. PTHRP can reduce the expression of cyclin D1, induce G1 phase cell cycle arrest, and regulate the survival of osteoblasts. In vitro and in vivo experiments show that short-term administration of PTHRP can increase the expression of RUNX2 gene and protein levels in osteoblasts. The stability and expression of RUNX2 are affected by cyclin D1 and cell cycle inhibitory factors. It is an important early transcription factor for the differentiation of mesenchymal cells into osteoblasts. Intermittent PTH/PTHRP promotes the expression of osteocalcin, a late factor in osteoblast differentiation and a marker of bone formation. In addition, the expression of PTHRP in undifferentiated or incompletely differentiated osteoblasts is higher than its expression in mature osteoblasts, which also proves the role of PTHRP in promoting bone differentiation.
A large number of studies have proven that PTHRP stimulates the synthesis of IGF-1 and promotes osteoblast anabolism by interacting with PTH1R. The study also found that cAMP-dependent signaling cascades and extracellular signal-regulated kinases (ERKs) mediate this process. However, some studies have confirmed that PTHRP can affect bone cell metabolism through a mechanism independent of PTH1R. PTHRP is internalized into the nucleus or nucleolus of osteoblasts and chondrocytes through nuclear localization signals, thereby regulating cell activity and function. Some scholars have transfected MC3T3-E1 osteoblasts with different configurations of PTHRP and confirmed that the nuclear internalization of the PTHRP/PTH1R complex can induce some osteogenic effects such as anti-apoptosis, and found that its carboxyl terminus may produce Significant osteogenesis was achieved. Studies have found that the PTHRP carboxyl-terminal fragment consisting of gene sequences 107 to 139 can not only promote the activity and proliferation of osteoblasts but also promote the maturation of osteoblasts. Recently, it was reported that the carboxyl-terminal 107-111 region of PTHRP (osteostatin) can enhance the pro-angiogenic and osteogenic effects of FGF-2 on osteoblasts. Initially, this PTHRP fragment was considered to be a powerful bone resorption inhibitor that directly interacts with osteoclasts, exerting most of the effects of PTHRP (107-139) in various types of bone cells. This polypeptide can interact with atypical receptors in osteoblasts, activate intracellular protein kinase C (PKC), Src kinase, transactivate and induce vascular endothelial growth factor (VEGF) receptor 2, etc. In addition, the first amino acid of human, mouse and rat osteostatin - threonine - plays a crucial role in the biological activity of osteoblasts and osteoclasts. Recent studies have shown that threonine may be involved shuttling of PTHRP from the cytoplasm to the nucleus.
The development of the crown part of the teeth of the PTHRP gene knockout mice is basically normal, but the alveolar bone covering the tooth surface in the tooth eruption tract is blocked, so that the erupting teeth cannot break through the alveolar bone, and the tooth roots are underdeveloped, eventually leading to abnormal tooth eruption, becoming impacted teeth, which is related to osteosclerosis and is a manifestation of impaired osteoclast function. In mice with the PTHRP gene knocked out, osteoclast formation and differentiation are almost normal, but there are functional defects, indicating that PTHRP plays an important role in the osteoclast activation process. It has been confirmed that there are PTH/PTHRP receptors on osteoclasts, and it was found that the expression of PTH1R is weak under normal physiological conditions and enhanced under pathological conditions. On the one hand, PTHRP directly acts on osteoclasts to promote osteolysis by binding to the osteoclast surface receptor PTH1R. On the other hand, it is believed that PTHRP indirectly induces the regulatory function of osteoclasts by stimulating the paracrine action of osteoblasts. After osteoblasts are stimulated by PTHRP, they secrete osteolytic cytokines such as IL-6 and IL-11 to activate osteoclasts. In addition, recent studies have shown that PTHRP is involved in regulating the classic Wnt/β-catenin signaling pathway, thereby stimulating the synthesis of IL-6 and NF-κB receptor activator ligand (RANKL), inhibiting the expression of osteoprotegerin (OPG), and thereby promoting osteoclastosis Cell formation and activity. However, it has also been reported that PTHRP can regulate the overexpression of RANKL by affecting the ephrinB2/EphB4 signaling pathway of osteoblasts and osteoclasts, thereby limiting osteoclastogenesis.
References
| Target | Cat. No. | Product Name | Expression System | Tag/Conjugate | Application | |
| PTH | DAG-WT1941 | Recombinant Human PTH Protein [GST] | GST | WB, ELISA | Inquiry | |
| DAG-WT1942 | Recombinant Human PTH Protein [hFc] | hFc | WB, ELISA | Inquiry | ||
| DAG-IV03 | Recombinant Human PTH Protein | N/A | Inquiry | |||
| PTH1R | DAG-WT1693 | Recombinant Human PTH1R VLP | N/A | N/A | Inquiry | |
| PTH2R | DAG-WT1694 | Recombinant Human PTH2R VLP | N/A | N/A | Inquiry |
| Target | Cat. No. | Product Name | Size | Species Reactivity | Application | Detection Sample | |
| PTH | ABPR-0738 | Human PTH ELISA Matched Antibody Pair | ELISA | Inquiry | |||
| DEIA1826B | Bovine Intact Parathormone ELISA Kit | 96T | Quantitative | serum, plasma, tissue homogenates and other biological fluids. | Inquiry | ||
| DEIA1836 | Human Intact-PTH ELISA Kit | 96T | Quantitative | Human Serum | Inquiry | ||
| DEIA-BJ659 | Mouse I-PTH(intact PaRathormone) ELISA Kit | 96T | Quantitative | Serum, plasma, tissue homogenates, other biological fluids | Inquiry | ||
| ABPR-ZB224 | Human Parathyroid Hormone/PTH Antibody Pair Set | 5 Plates, 15 Plates | sELISA | Inquiry | |||
| DEIABL239D | PTH (1-84) Depletion Kit | 10 x 96 tests | Qualitative | Serum; Plasma. | Inquiry | ||
| DEIABL239 | PTH (1-34)-Teriparatide ELISA Kit | 96T | Quantitative | serum | Inquiry | ||
| PTHLH | DEIA-BJ695 | Human Parathormone 1-34 ELISA Kit | 96T | Quantitative | serum, plasma | Inquiry | |
| DEIA-BJ2246 | Rat Parathyroid Hormone Related Protein ELISA Kit | 96T | Quantitative | Serum, plasma, cell culture supernatants, body fluid and tissue homogenate | Inquiry | ||
| DEIA-BJ2556 | Mouse Parathyroid Hormone Related Protein ELISA Kit | 96T | Quantitative | Serum, plasma, cell culture supernatants, body fluid and tissue homogenate | Inquiry | ||
| DEIA2034 | PTH-RP ( 1-34 ) ( human, rat, mouse ) ELISA Kit | 96T | Quantitative | plasma | Inquiry |
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