scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis

2018 ◽  
Vol 178 (2) ◽  
pp. R33-R44 ◽  
Author(s):  
Ernesto Canalis
Keyword(s):  
Growth Factor ◽  
Bone Formation ◽  
Vertebral Fractures ◽  
Mineral Density ◽  
Anabolic Agents ◽  
Amino Terminal ◽  
Terminal Fragment ◽  
Igf I ◽  
And Function ◽  
Amino Terminal Fragment

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors. Sclerostin is a Wnt antagonist that binds to Wnt co-receptors and prevents Wnt signal activation. Teriparatide, a 1–34 amino terminal fragment of parathyroid hormone (PTH), and abaloparatide, a modified 1–34 amino terminal fragment of PTH-related peptide (PTHrp), induce IGF-I, increase bone mineral density (BMD), reduce the incidence of vertebral and non-vertebral fractures and are approved for the treatment of postmenopausal osteoporosis. Romosozumab, a humanized anti-sclerostin antibody, increases bone formation, decreases bone resorption, increases BMD and reduces the incidence of vertebral fractures. An increased incidence of cardiovascular events has been associated with romosozumab, which is yet to be approved for the treatment of osteoporosis. In conclusion, cell and molecular studies have formed the foundation for the development of new anabolic therapies for osteoporosis with proven efficacy on the incidence of new fractures.

scholarly journals Skeletal Overexpression of Connective Tissue Growth Factor Impairs Bone Formation and Causes Osteopenia

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4374-4381 ◽  
Author(s):  
Anna Smerdel-Ramoya ◽  
Stefano Zanotti ◽  
Lisa Stadmeyer ◽  
Deena Durant ◽  
Ernesto Canalis
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Bone Formation ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Bmp Signaling ◽  
Mrna Levels ◽  
Mineral Density ◽  
Ccn Family ◽  
Igf I

Connective tissue growth factor (CTGF), a member of the CCN family of proteins, is expressed in skeletal cells, and the ctgf null mutation leads to neonatal lethality due to defects in skeletal development. To define the function of CTGF in the postnatal skeleton, we created transgenic mice overexpressing CTGF under the control of the human osteocalcin promoter. CTGF transgenic female and male mice exhibited a significant decrease in bone mineral density, compared with wild-type littermate controls. Bone histomorphometry revealed that CTGF overexpression caused decreased trabecular bone volume due to impaired osteoblastic activity because mineral apposition and bone formation rates were decreased. Osteoblast and osteoclast number and bone resorption were not altered. Calvarial osteoblasts and stromal cells from CTGF transgenics displayed decreased alkaline phosphatase and osteocalcin mRNA levels and reduced bone morphogenetic protein (BMP) signaling mothers against decapentaplegic, Wnt/β-catenin, and IGF-I/Akt signaling. In conclusion, CTGF overexpression in vivo causes osteopenia, secondary to decreased bone formation, possibly by antagonizing BMP, Wnt, and IGF-I signaling and activity.

scholarly journals Inhibition of Cell Migration and Angiogenesis by the Amino-terminal Fragment of 24kD Basic Fibroblast Growth Factor

2002 ◽  
Vol 277 (34) ◽  
pp. 31056-31061 ◽  
Author(s):  
Lan Ding ◽  
Fernando Doñate ◽  
Graham C. N. Parry ◽  
Xiaojun Guan ◽  
Pamela Maher ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Fibroblast Growth ◽  
Amino Terminal ◽  
Terminal Fragment ◽  
Amino Terminal Fragment

scholarly journals Intact IGF-Binding Protein-4 and -5 and Their Respective Fragments Isolated from Chronic Renal Failure Serum Differentially Modulate IGF-I Actions in Cultured Growth Plate Chondrocytes

2001 ◽  
Vol 12 (11) ◽  
pp. 2400-2410
Author(s):  
DANIELA KIEPE ◽  
DENNIS L. ANDRESS ◽  
SUBBURAMAN MOHAN ◽  
LUDGER STÄNDKER ◽  
TIM ULINSKI ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Amino Terminal ◽  
Growth Cartilage ◽  
Terminal Fragment ◽  
Igf I ◽  
Igf Binding ◽  
Amino Terminal Fragment

Abstract. Impairment of longitudinal growth among children with chronic renal failure (CRF) may be partly attributable to the inhibition of insulin-like growth factor (IGF) activity by an excess amount of high-affinity IGF-binding proteins (IGFBP). Elevated levels of immunoreactive IGFBP-4 in CRF serum are inversely correlated with the standardized heights of these children, whereas levels of IGFBP-5, which circulates mainly as proteolyzed fragments, are positively correlated with growth parameters. To delineate the respective effects of these IGFBP on growth cartilage, the biologic effects of intact and fragmented forms of IGFBP-4 and IGFBP-5 on rat growth plate chondrocytes in primary cultures were characterized. Intact IGFBP-4 and IGFBP-5 and the amino-terminal fragment IGFBP-51-169 were recombinant proteins; the carboxy-terminal fragments IGFBP-5144-252 and IGFBP-4136-237 and the amino-terminal fragment IGFBP-41-122 were purified to homogeneity from CRF hemofiltrates. Intact IGFBP-4 and, to a lesser extent, IGFBP-41-122 inhibited IGF-I-induced cell proliferation. In contrast, intact IGFBP-5 was stimulatory in the absence or presence of exogenous IGF-I, whereas the amino-terminal fragment IGFBP-51-169 was inhibitory. Studies on the mechanism by which IGFBP-4 and IGFBP-5 exert opposite effects on chondrocyte proliferation demonstrated that intact IGFBP-4 prevented the binding of 125I-IGF-I to chondrocytes, whereas intact IGFBP-5 enhanced ligand binding and was able to bind specifically to the cell membrane. These data suggest that intact IGFBP-4 and, to a lesser extent, IGFBP-41-122 act exclusively as growth-inhibitory binding proteins in the growth cartilage. IGFBP-5, however, can either stimulate (if it remains intact) or inhibit (if amino-terminal forms predominate) IGF-I-stimulated chondrocyte proliferation.

scholarly journals Evolution of the hedgehog Gene Family

Genetics ◽  
1996 ◽  
Vol 142 (3) ◽  
pp. 965-972 ◽  
Author(s):  
Sudhir Kumar ◽  
Kristi A Balczarek ◽  
Zhi-Chun Lai
Keyword(s):  
Intercellular Communication ◽  
Short Range ◽  
Gene Duplications ◽  
Future Directions ◽  
Amino Terminal ◽  
Terminal Fragment ◽  
Carboxyl Terminal ◽  
Multicellular Organisms ◽  
Amino Terminal Fragment

Abstract Effective intercellular communication is an important feature in the development of multicellular organisms. Secreted hedgehog (hh) protein is essential for both long- and short-range cellular signaling required for body pattern formation in animals. In a molecular evolutionary study, we find that the vertebrate homologs of the Drosophila hh gene arose by two gene duplications: the first gave rise to Desert hh, whereas the second produced the Indian and Sonic hh genes. Both duplications occurred before the emergence of vertebrates and probably before the evolution of chordates. The amino-terminal fragment of the hh precursor, crucial in long- and short-range intercellular communication, evolves two to four times slower than the carboxyl-terminal fragment in both Drosophila hh and its vertebrate homologues, suggesting conservation of mechanism of hh action in animals. A majority of amino acid substitutions in the amino- and carboxyl-terminal fragments are conservative, but the carboxyl-terminal domain has undergone extensive insertion-deletion events while maintaining its autocleavage protease activity. Our results point to similarity of evolutionary constraints among sites of Drosophila and vertebrate hh homologs and suggest some future directions for understanding the role of hh genes in the evolution of developmental complexity in animals.

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