Bone multicellular units (BMUs) maintain the viability of the skeletal tissue by coordinating locally the sequence of bone resorption and bone formation performed by cells of the osteoclastic and osteoblastic lineage. Understanding the emergence and the net bone balance of such structured microsystems out of the complex network of biochemical interactions between bone cells is fundamental for many bone-related diseases and the evaluation of fracture risk. Based on current experimental knowledge, we propose a spatio-temporal continuum model describing the interactions of osteoblastic and osteoclastic cells. We show that this model admits travelling-wave-like solutions with well-confined cell profiles upon specifying external conditions mimicking the environment encountered in cortical bone remodelling. The shapes of the various cell concentration profiles within this travelling structure are intrinsically linked to the parameters of the model such as differentiation, proliferation, and apoptosis rates of bone cells. The internal structure of BMUs is reproduced, allowing for experimental calibration. The spatial distribution of the key regulatory factors can also be exhibited, which in diseased states could give hints as to the biochemical agent most accountable for the disorder.

The aim of this study was to examine the vasodilatory effects of parathyroid hormone-related protein (PTHrP) (1–34) and parathyroid hormone (PTH) (1–34) on the human fetal-placental circulation utilising an in vitro placental perfusion model. In all experiments, the vasculature of an isolated human placental cotyledon was pre-constricted with the throm☐ane A2 mimetic U46619. A single dose of PTHrP (1–34) or PTH (1–34) (1.7–300 n m) was then infused into the fetal-placental circulation of the cotyledon. In other experiments, cotyledons were repeatedly infused with PTHrP (1–34) or PTH (1–34) (51.3 n m). Vasodilatory responses were significantly reduced in response to repeated exposure to PTHrP (1–34) and PTH (1–34) (P<0.001), indicating that this peptide desensitizes the fetal-placental vasculature. PTHrP (1–34) and PTH (1–34) equipotently stimulated a significant vasodilatation of the fetal-placental circulation (P<0.0001). The PTHrP receptor antagonist [Asn10, Leu11]PTHrP (7–34) (102 nM) was infused in U46619-constricted placentae in the presence and absence of PTHrP (1–34) (10.2 nM). The PTHrP antagonist alone had no significant effect in the fetal-placental circulation. The antagonist significantly attenuated the response to PTHrP (1–34) (P<0.015). Based on the data obtained in this study it is suggested that locally produced PTHrP (1–34) may be involved in the regulation of normal human fetal-placental vascular tone in an autocrine and/or paracrine fashion.

Basic fibroblast growth factor (bFGF), a potent mitogen, has been found to restore trabecular bone mass and connectivity in osteopenic rats. The purpose of this study was to determine how sequential treatment of ovariectomized (OVXed) mice with bFGF followed by risedronate would restore trabecular microarchitecture and improve bone strength through alterations in bone mineralization. Six-month old female Swiss–Webster mice were OVXed or sham-operated and left untreated for 4 weeks to develop osteopenia. At week 5, a group of Sham and OVXed mice were treated with vehicle, and 3 other groups of OVXed mice were treated with bFGF (1 mg/kg daily, s.c., 5×/week) for 3 weeks. At week 8, one group of bFGF-treated mice was sacrificed and the other two bFGF-treated groups were treated with vehicle or risedronate (Ris, 5 μg/kg, s.c., 3×/week) for an additional 6 weeks. Study endpoints included trabecular microarchitecture by microCT, histomorphometry, bone turnover, degree of bone mineralization (DBM), and whole bone strength for the lumbar vertebral body. Compared to sham-operated animals, OVXed mice had significant reductions in trabecular bone volume, connectivity density, DBM, and bone biomechanical properties (P < 0.05). Treatment with bFGF resulted in higher trabecular bone structure and bone strength compared to pre-treatment sham control (P < 0.05). Treatment of OVXed mice with bFGF for 3 weeks followed by 6 weeks Ris maintained the trabecular microarchitecture gained by bFGF treatment, and DBM and bone strength were restored to baseline control levels. Also compared to Sham-operated animals, serum TGF-β1 was transiently increased after OVX, increased an additional 100% after bFGF withdrawal, and decreased by 30% with risedronate. In addition, DBM was the strongest predictor for bone biomechanical properties (R2 > 0.7, P < 0.001). Serum TGF-β1 correlated with bone turnover (DPD/Cr, osteocalcin) and was negatively correlated to DBM. Thus, in osteopenic mice, sequential treatment with bFGF followed by risedronate increased trabecular bone microarchitecture, DBM, and bone strength. In addition, suppression of the serum TGF-β1 with risedronate was associated with increased DBM. Therefore, sequential treatment with bFGF and Ris restores trabecular architecture and allows mineralization of bone to increase, which appears to be beneficial to bone strength.

Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. A custom-built DNA single nucleotide polymorphism (SNP) chip containing 3404 SNPs was used to test genomic DNA from myeloma patients classified by the extent of bone disease. Correlations identified with a Total Therapy 2 (TT2) (Arkansas) data set were validated with Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) data sets. Univariate correlates with bone disease included: EPHX1, IGF1R, IL-4 and Gsk3β . SNP signatures were linked to the number of bone lesions, log 2 DKK-1 myeloma cell expression levels and patient survival. Using stepwise multivariate regression analysis, the following SNPs: EPHX1 ( P =0.0026); log 2 DKK-1 expression ( P =0.0046); serum lactic dehydrogenase (LDH) ( P =0.0074); Gsk3β ( P =0.02) and TNFSF8 ( P =0.04) were linked to bone disease. This assessment of genetic polymorphisms identifies SNPs with both potential biological relevance and utility in prognostic models of myeloma bone disease.