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The bone formation promoter recombinant human parathyroid hormone 1-34 [PTH (1-34)] has a short half-life and low bioavailability. In this study, we prepared a biodegradable and temperature-sensitive hyaluronic acid-poly-N-isopropyl acrylamide (AHA-g-PNIPAAm), and further investigated its effects of PTH (1-34) release and cell behavior as drug carrier. The structure of AHA-g-PNIPAAM was confirmed by hydrogen nuclear magnetic resonance spectroscopy and infrared spectroscopy. Next, PTH (1-34) loaded thermo-sensitive hydrogels were prepared by physical swelling method and their stability was investigated. The morphology of hydrogel was observed by scanning electron microscope. The minimum critical transition temperature and drug release behavior of hydrogels were investigated by ultraviolet spectrophotometry. The tetrazolium-based colorimetric assay (MTT assay) was used to investigate the toxicity and proliferation effects of PTH (1-34)-loaded thermo-sensitive hydrogel on mouse mononuclear macrophage RAW264.7 and mouse precranial osteoblasts MC3T3-E1. The effect of PTH (1-34)-loaded thermo-sensitive hydrogel on the differentiation of RAW264.7 was investigated by the tartrate-resistant acid phosphatase assay. The results showed that the PTH (1-34)-loaded thermo-sensitive hydrogel prepared in this study displayed regular three-dimensional honeycomb structure, and had good stability, thermo-sensitivity and sustained and controlled release properties, which could promote the proliferation of MC3T3-E1 cells more effectively and inhibit the differentiation of RAW264.7 into osteoclasts.
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BACKGROUND: Recombinant human parathyroid hormone 1-34 (rhPTH 1-34), also known as teriparatide, is the amino terminal fragment of parathyroid hormone. Teriparatide, as a bone anabolic drug, has become a research hotspot because it can directly stimulate new bone formation and increase bone mass. It also attracts attention and application in the oral field due to its strong osteogenesis effect. OBJECTIVE: To review the osteogenic mechanisms, efficacy and safety of teriparatide and its research progress in the oral field. METHODS: The first author searched the PubMed and WanFang databases for relevant literature published over the past two decades. The keywords were “rhPTH(1-34); teriparatide; osteoporosis; stomatology; Jaw; implant-osseointegration; periodontal” in English and Chinese, respectively. Fifty-six eligible articles were finally reviewed. RESULTS AND CONCLUSION: Teriparatide can directly stimulate the formation of osteoblasts in new bone and achieve effective anabolic metabolism. Studies of teriparatide in the oral field have shown good results in promoting implant-osseointegration, periodontal regeneration, bone defect healing and the stability of orthodontics, but increasing high-quality animal experiments and clinical studies are still needed. Future use of parathyroid hormone drugs and their analogues can be combined with bone tissue engineering technology to provide favorable effects in bone repair as well as in oral and maxillofacial repair.
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Abstract The aim of this study was to evaluate the effect of a lower dose of parathyroid hormone- PTH (1-34) on osteogenic potential of bone healing around titanium implants inserted into the tibia of rats. A blind parallel study was conducted in 45 adult male Wistar rats. Each rat received one titanium implant (4.5 x 2.2 mm) and was randomly assigned to receive subcutaneous injections, three times/week for 30 days, of the following treatments: group 1 - 40 µg/kg of PTH (1-34) (n=15); group 2 - 2 µg/kg of PTH (1-34) (n=15) and; group 3 - only the vehicle required for hormone dissolution (n=15). Thirty days after surgery, the animals were sacrificed and specimens containing the implant and the surrounding bone were removed and processed for non-decalcified sections. The sections were evaluated according to the following histometric parameters: proportion of mineralized tissue (PMT) adjacent to the implant threads (500 µm band); bone filling within the limits of the threads (BF) and; bone-to-implant contact (BIC). For the cortical region, both hormone dosages (groups 1 and 2) promoted better results, for all parameters, when compared to control group (p<0.05). Similar results were observed for the BF parameter in the cancellous region (p=0.0394). Therefore, systemic administration of PTH (1-34) stimulates bone formation around titanium implants, even at low doses.
Resumo O objetivo deste estudo foi avaliar o efeito de uma menor dose de PTH (1-34) sobre o potencial osteogênico da cicatrização óssea ao redor de implantes de titânio inseridos na tíbia de ratos. Um estudo paralelo cego foi conduzido em 45 ratos Wistar machos adultos. Cada rato recebeu um implante de titânio (4,5 x 2,2 mm) e foi aleatoriamente designado para receber injeções subcutâneas, três vezes / semana por 30 dias, dos seguintes tratamentos: grupo 1 - 40 µg/kg de PTH (1-34) (n = 15); grupo 2 - 2 µg/kg de PTH (1-34) (n = 15) e; grupo 3 - apenas o veículo necessário para a dissolução do hormônio (n = 15). Trinta dias após a cirurgia, os animais foram sacrificados e os espécimes contendo o implante e o osso ao redor foram removidos e processados para cortes não descalcificados. As seções foram avaliadas de acordo com os seguintes parâmetros histométricos: proporção de tecido mineralizado (PTM) adjacente aos fios do implante (banda de 500 µm); preenchimento ósseo dentro dos limites dos fios (PO) e; contato osso-implante (COI). Para a região cortical, ambas as dosagens hormonais (grupos 1 e 2) promoveram melhores resultados, para todos os parâmetros, quando comparados ao grupo controle (p<0,05). Resultados semelhantes foram observados para o parâmetro PO na região esponjosa (p = 0,0394). Portanto, a administração sistêmica de PTH (1-34) estimula a formação óssea ao redor de implantes de titânio, mesmo em doses baixas.
Subject(s)
Animals , Male , Rats , Parathyroid Hormone/administration & dosage , Bone and Bones/drug effects , Dental Implants , Osseointegration , Rats, Wistar , Models, Animal , Dose-Response Relationship, DrugABSTRACT
Objective To evaluate the effects of the human recombinant parathyroid hormone [rhPTH (1 -34)] on the initial adhesion of MC3T3-E1 osteoblasts cultured on titanium surfaces of sand-blasted large grift acid-etched (SLA). Methods The optimal concentration of the rhPTH(1-34) action was determined by the CCK8 method. Then the MC3T3-E1 cells were divided into experimental groups treated with the optimal concentration of the rhPTH(1-34) medium and control groups treated with blank medium, and inoculated on SLA-treated titanium plates. DAPI immunocytochemistxy, scanning electron microscopy, and RT-PCR were used to count the cell adhesion of MC3T3-E1 cells on the surface of titanium plates. Morphological changes were observed and the expression of the integrin α1, α5, β1 mRNA in MC3T3-E1 cells was determined. Results Compared with the control group, the adherence of osteoblasts was more than that of the control group. The remodeling of actin filaments, the change of cell morphology, and the speed of adhesion and extension on the titanium plate were faster than that of the control group. The expression of the osteoblast integrin subunit α1, α5 and (31 was higher than that of the control group. Conclusion rhPTH (1-34) can promote the adhesion of MC3T3-E1 cells on pure titanium surface.
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Objective To investigate changes in serum sclerostin (SO) in postmenopausal women before and after treatment with recombinant human parathyroid hormone (1-34) [rhPTH (1-34)],and to explore the relationship of serum SO with estradiol (E2),and bone mineral density (BMD).Methods Ninety-five postmenopausal women were divided into normal BMD group (n =41) and osteoporosis group (n =54).Body mass index,alkaline phosphatase (ALP),serum E2,calcium,phosphate,and SO were determined in both groups.The patients in osteoporosis group were treated with rhPTH (1-34) 20 μg/d by subcutaneous injection and oral calcium 500 mg/d for 12 months.Serum calcium,serum phosphate,BMD,serum ALP,serum E2,and sclerostin were determined in osteoporosis group by 6 months and 12 months of treatment.Results (1) Serum level of SO in osteoporosis group was raised significantly as compared with normal BMD group (P ＜ 0.05) ; E2 and BMD were negatively correlated with SO; age and postmenopausal years were positively correlated with SO (P ＜ 0.05).(2) Serum SO was reduced gradually with treatment of rhPTH (1-34) by 6 months and 12 months (P ＜ 0.05).Conclusions Serum SO was increased in postmenopausal women,which was related to E2 and BMD,and was reduced gradually with treatment of rhPTH (1-34).SO may participate in the development of postmenopausal osteoporosis.
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ObjectiveTo investigate the effect of rhPTH (1-34) and elcatonin on bone metabolism and serum secreted protein acidic and rich in cysteine ( SPARC ) in postmenopausal women with osteoporosis.Methods One hundred and twenty-four postmenopausal women with osteoporosis were randomly divided into 2 groups:One group was treated with recombinant human parathyroid hormone ( 1-34 ) [ rhPTH ( 1-34 ) ] 200 U/d by subcutaneous injection (PTH group,n =89 )and another group was treated with elcatonin 20 U/week by intramuscular injection (CT group,n =35 ) for 12 months.All patients received a basic therapy with oral calcium ( Ca 600 mg+ Vit D3125 U,q..d.).The bone mineral density ( BMD ) of lumbar spine( L2-4 ),the left femoral neck,greater trochanter,and Ward's triangle,serum calcium and phosphate were measured by baseline,6 months' and 12 months.Levels of serum bone-specific alkaline phosphatase( BSAP),serum secreted protein acidic and rich in cysteine (SPARC)were determined by an ELISA assay.ResultsBy 12 months,rhPTH ( 1-34 ) treatment significantly increased the lumbar spine L2-4 BMD 7.9％ (P＜0.05),serum calcium 8.3 ％ ( P＜ 0.05 ),serum BSAP 93.4％ ( P＜ 0.05 ),serum SPARC by 12.6％[ ( 195.68±59.57 vs 173.81 ±81.33 ) pμg/L,P＜0.05 ].Elcatonin therapy increased the lumbar spine L2-4 BMD by 3.2％ (P＜0.05) at the end of 12 months,but elcatonin did not influence serum calcium,BSAP and SPARC.The rhPTH( 1-34 ) increased lumbar spine L2-4 BMD more than elcatonin did at 12 months( P＜0.05 ).ConclusionrhPTH (1-34) could promote the bone anabolism more effectively than elcatonin did.Serum SPARC may play an important role in promoting osteogenesis by rhPTH.
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Objective:To study the effects of parathyroid hormone(PTH) upon dentinogenesis by investigating the effects of hPTH1-34 on the development and calcification of parathyroidectomy rats' dentin. Methods: hPTH1-34 were injected into SD rats at different dosages after parathyroidectomy. Six weeks later lower incisors were dissected and prepared for light microscopy and image analysis. Results:The concentration of serum calcium decreased after parathyroidectomy, while increased after being injected hPTH1-34. The results of light microscopy and image analysis revealed the enlargement of the predentinal tubules and the presence of mineralization defects in the PTX group(P
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A RIA method for determining human plasma parathyroid hormone (hPTH1-34) was established. This was possible mainly by the production of an antiserum of high liter raised in rabbit against hPTH1-34. The methodological investigation data were listed below: the affinity constant, Ka= 1,95?1010 mol/L; the cross reactivity with each of the three analogous peptides, i.e., hACTH1-34, hCT and hPTH44_68, being all less than 0.005%; the intra- and inter-batch coefficients of variation being 6.0% and 13.0% respectively; the recoveries for different levels of hPTH1_34 being ranged within 83.1 - 102.6%; and the sensitivity being 1.1 pmol/L. The reference value obtained by testing 50 male and 50 female normal adults was 11.7 ?4.4 pmol/L. It has been applied clinically for patients with various endocrine diseases including hyper- and hypoparathyroidisms and metabolic bone diseases especially in the aged population and the results fitted well with clinical diagnosis.