The Cell Origin and Role of Osteoclastogenesis and Osteoblastogenesis in Vascular Calcification

Arterial calcification refers to the abnormal deposition of calcium salts in the arterial wall, which results in vessel lumen stenosis and vascular remodeling. Studies increasingly show that arterial calcification is a cell mediated, reversible and active regulated process similar to physiological bone mineralization. The osteoblasts and chondrocytes-like cells are present in large numbers in the calcified lesions, and express osteogenic transcription factor and bone matrix proteins that are known to initiate and promote arterial calcification. In addition, osteoclast-like cells have also been detected in calcified arterial walls wherein they possibly inhibit vascular calcification, similar to the catabolic process of bone mineral resorption. Therefore, tilting the balance between osteoblast-like and osteoclast-like cells to the latter maybe a promising therapeutic strategy against vascular calcification. In this review, we have summarized the current findings on the origin and functions of osteoblast-like and osteoclast-like cells in the development and progression of vascular progression, and explored novel therapeutic possibilities.

Myelofibrosis osteoclasts are clonal and functionally impaired

Bone marrow (BM) sclerosis is commonly found in patients with late-stage myelofibrosis (MF). Because osteoclasts (OCs) and osteoblasts play a key role in bone remodeling, and MF monocytes, the OC precursors, are derived from the neoplastic clone, we wondered whether decreased OC numbers or impairment in their osteolytic function affects the development of osteosclerosis. Analysis of BM biopsies from 50 MF patients showed increased numbers of multinucleated tartrate-resistant acid phosphatase (TRAP)/cathepsin K+ OCs expressing phosphorylated Janus kinase 2 (JAK2). Randomly microdissected TRAP+ OCs from 16 MF patients harbored JAK2 or calreticulin (CALR) mutations, confirming MF OCs are clonal. To study OC function, CD14+ monocytes from MF patients and healthy individuals were cultured and differentiated into OCs. Unlike normal OCs, MF OCs appeared small and round, with few protrusions, and carried the mutations and chromosomal abnormalities of neoplastic clones. In addition, MF OCs lacked F-actin–rich ring-like structures and had fewer nuclei and reduced colocalization signals, compatible with decreased fusion events, and their mineral resorption capacity was significantly reduced, indicating impaired osteolytic function. Taken together, our data suggest that, although the numbers of MF OCs are increased, their impaired osteolytic activity distorts bone remodeling and contributes to the induction of osteosclerosis.

Microscopy of crustacean cuticle: formation of a flexible extracellular matrix in moulting sea slaters Ligia pallasii

Structural and functional properties of exoskeleton in moulting sea slaters Ligia pallasii from the Eastern Pacific coast were investigated with CT scanning and electron microscopy. Ultrastructure of preecdysial and postecdysial cuticular layers was described in premoult, intramoult and postmoult animals. Cuticle is a flexible extracellular matrix connected to the epidermal cells through pore channels. During premoult epicuticle and exocuticle are formed and during intramoult and postmoult endocuticular lamellae are deposited and the cuticle is progressively constructed by thickening and mineralization. Cuticle permeability, flexibility and waterproofing capacity change accordingly. Elaboration of epicuticular scales connected to an extensive network of nanotubules, establish its anti-adhesive and hydrophobic properties. Labelling with gold conjugated WGA lectins on Tokuyashu thawed cryosections exposes differences in chitin content between exocuticle and endocuticle. Histochemical staining of cuticle shows presence of acidic carbohydrates/glycoconjugates and lipoproteins in epicuticular layer. Chitin microfibrils are formed at the microvillar border of epidermal cells with abundant Golgi apparatus and secretory vesicles. Numerous spherules associated with nanotubules were observed in the ecdysial space in intramoult animals. The mineral component of the cuticle as visualized with CT scanning indicates progressive mineral resorption from the posterior to the anterior half of the body in premoult animals, its translocation from the anterior to posterior part during intramoult and its progressive deposition in the posterior and anterior exoskeleton during postmoult. Cuticle of sea slaters is a unique biocomposite and biodynamic material constantly reconstructed during frequent moults, and adapted to specific physical and biotic conditions of the high intertidal rocky zone.

Abstract 422: Relationship Between N-Telopeptide-Mediated Bone Mineral Resorption and Peripheral Arterial Disease

Background: Patients with peripheral arterial disease (PAD) have a higher incidence of hip bone loss and non-spinal fractures independent of their cardiovascular risk or degree of claudication. The mechanisms explaining this excess risk of osteoporosis are poorly understood. N-telopeptide (NTX) is an amino-terminal cross-linked type I collagen peptide that is released during fibrillogenesis, reflecting both the derivative products of bone collagen and bone resorption. When elevated, it serves as an early marker for osteoporosis and predictor of therapeutic response. We hypothesized that patients with PAD have reduced bone mineral content and that PAD is associated with biomarkers of accelerated bone mineral resorption. Methods: We analyzed data from 4354 participants ages 40 years or older with measured ankle-brachial indexes (ABI) from the National Health and Nutrition Examination Survey from 1999 to 2002, defining PAD as an ABI < 0.9 in either leg. N-telopeptides were measured in the urine. Total bone mineral content and bone mineral density were measured using dual energy X-ray absorptiometry. Results: The overall prevalence of PAD was 4.4 % (S.E, 0.3). The geometric mean of NTX was 248.3 nmol (S.E, 7.0). NTX decreased with age. Women, non-Hispanic blacks and obese individuals had significantly higher NTX levels, whereas diabetics had reduced NTX levels. Current smokers, chronic kidney disease and PAD patients tended to have higher levels as well. In an age, gender, and race adjusted multivariate analysis, one standard deviation increase in NTX level was associated with a three-fold increase in the odds of having reduced total bone mineral density (OR 3.22, p <0.0001). Additionally, patients with PAD had significantly increased odds of having NTX levels in the higher tertile (O.R 1.57, p=0.035). This association persisted even after further adjustment for obesity, smoking, and C-reactive protein. Conclusion: Peripheral arterial disease is associated with reduced levels of bone mineral content and density. PAD is independently associated with N-telopeptides, suggesting abnormal type I collagen metabolism abnormalities. Further prospective studies will determine the role of NTX as a marker of osteoporosis found in PAD and their relationship with walking activity.