Recently fluid flow has been shown to be a potent physical stimulus in the regulation of bone cell metabolism. However, most investigators have applied steady or pulsing flow profiles rather than oscillatory fluid flow, which occurs in vivo because of mechanical loading. Here oscillatory fluid flow was demonstrated to be a potentially important physical signal for loading-induced changes in bone cell metabolism. We selected three well known biological response variables including intracellular calcium (Ca

Previously a distinct D 1 -like dopamine receptor (DAR) that selectively couples to phospholipase C/phosphatidylinositol (PLC/PI) was proposed. However, lack of a selective agonist has limited efforts aimed at characterizing this receptor. We characterized the in vitro and in vivo effects of SKF83959 in regulating PI metabolism. SKF83959 stimulates (EC 50

The tetrahydroprotoberberines (THPBs) are compounds isolated from Chinese herbs that possess a unique pharmacological profile as D2 dopamine receptor antagonists and D1 receptor agonists. l-Tetrahydropalmatine (l-THP) and l-stepholidine (SPD), members of the THPB family, were shown to have potential clinical use in the treatment of pain. However, their mechanism of action is not clear. In the past decades, Chinese scientists have made a great deal of effort to explore the mechanisms by which the THPBs and its analogues elicit antinociception and their potential utility in treating drug abuse. It is now clear that the antinociception produced by l-THP is related to inhibition of D(2) dopamine receptors. The present review focuses on the recent progress made in understanding the mechanisms of l-THP- and l-SPD-mediated antinociception and the sequel of drug addiction.

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Parathyroid hormone (PTH) and its related peptide regulate endochondral ossification by inhibiting chondrocyte differentiation toward hypertrophy. However, the intracellular pathway for transducing PTH/PTH-related peptide signals in chondrocytes remains unclear. Here, we show that this pathway is mediated by mitogen-activated protein kinase (MAPK) p38. Incubation of hypertrophic chondrocytes with PTH (1-34) induces an inhibition of p38 kinase activity in a time-and dose-dependent manner. Inhibition of protein kinase C prevents PTH-induced p38 MAPK inhibition, whereas inhibition of protein kinase A has no effect. Thus, protein kinase C, but not protein kinase A, is required for the inhibition of p38 MAPK by PTH. Treatment of hypertrophic chondrocytes by PTH or by p38 MAPK inhibitor SB203580 up-regulates Bcl-2, suggesting that Bcl-2 lies downstream of p38 MAPK in the PTH signaling pathway. Inhibition of p38 MAPK in hypertrophic chondrocytes by either PTH, SB303580, or both together leads to a decrease of hypertrophic marker type X collagen mRNA and an increase of the expression of prehypertrophic marker cartilage matrix protein. Therefore, inhibition of p38 converts a hypertrophic cell phenotype to a prehypertrophic one, thereby preventing precocious chondrocyte hypertrophy. Taken together, these data suggest a major role for p38 MAPK in transmitting PTH signals to regulate chondrocyte differentiation.During endochondral ossification, chondrocytes undergo a differentiation process including proliferation, maturation, hypertrophy, and apoptosis (1). Cells from these different stages of differentiation synthesize specific molecules, for example, type X collagen is synthesized specifically by hypertrophic chondrocytes (2, 3), whereas cartilage matrix protein (CMP) 1 / matrilin-1, is a marker of prehypertrophic chondrocytes (1). Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) are major regulators of the chondrocyte differentiation process. PTH and PTHrP both bind to PTH receptors, which belong to G protein-coupled receptors (4). In a growth plate, PTH receptors are expressed at specific stages during chondrocyte differentiation, with the highest level at the prehypertrophic to hypertrophic transition (5). This suggests that PTH receptors may be important for the regulation of chondrocyte differentiation from the prehypertrophic state to the hypertrophic state. Indeed, overexpression of PTHrP or its constitutively active receptor in growth plates of transgenic mice delays endochondral bone formation (6), whereas mice with ablation of the PTH/PTHrP receptor gene develop skeletal dysplasia because of accelerated chondrocyte hypertrophy (7-9). Thus, the PTH/PTHrP receptor plays a fundamental role in the control of endochondral bone formation by transducing signals inhibiting chondrocyte hypertrophy. However, the intracellular signaling mechanism for PTH/PTHrP to regulate chondrocyte differentiation remains unknown.The PTH/PTHrP receptor may exert its biological action via at least two signaling p...

Adenomyosis is a tough disease to manage nonsurgically. Levo-tetrahydropalmatine (l-THP), a known analgesic, and andrographolide, a nuclear factor kappa B (NF-κB) inhibitor, are both active ingredients extracted from Chinese medicinal herbs. We sought to determine whether treatment of l-THP, andrographolide, and valproic acid (VPA) would suppress the myometrial infiltration, improve pain behavior, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 55 female ICR mice neonatally dosed with tamoxifen, while another 8 (group C) were dosed with solvent only. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 6 groups, each receiving different treatment for 3 weeks: low- or high-dose l-THP, andrographolide, low-dose l-THP and andrographolide jointly, VPA, and untreated. Group C received no treatment. After treatment, the hotplate test was administered and all mice were killed. The depth of myometrial infiltration of ectopic endometrium and uterine contractility were measured and compared across groups. We found that induction of adenomyosis resulted in progressive generalized hyperalgesia, along with elevated amplitude and irregularity of uterine contractions. Treatment with either l-THP, andrographolide, VPA, or l-THP and andrographolide jointly suppressed myometrial infiltration, improved generalized hyperalgesia, and reduced the amplitude and irregularity of uterine contractions. These results suggest that increased uterine contractility, in the form of increased contractile amplitude and irregularity, may contribute to dysmenorrhea in women with adenomyosis. More importantly, l-THP, andrographolide, and VPA all seem to be promising compounds for treating adenomyosis.

The dopamine (DA) D(1) receptor is the most highly expressed DA receptor subtype among the DA receptor family. Although the first DA D(1) receptor selective ligand SCH-23390 (1) was introduced more than two decades ago, clinically useful D(1) receptor selective ligands are rare. A renewed interest was ignited in the early 1990s by Nichols and Mailman who developed dihydrexidine (27a), the first high affinity full efficacy agonist for the D(1) receptor. Since then, a number of D(1) receptor agonists with full intrinsic activity, including A-86929 (31a), dinapsoline (32a), dinoxyline (34a), and doxanthrine (35a) were identified. These compounds all contain a conformationally rigid structure. However, the fate of such ligands for clinical use as treatments of Parkinson's disease and other related CNS disorders is not optimistic since the clinical trial with dihydrexidine (27a) was not successful. Further investigations on other compounds which are currently in the discovery stage will be crucial for determining the future of the D(1) receptor agonists.

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