Siglec-15-targeting therapy increases bone mass in rats without impairing skeletal growth.
Bone
; 116: 172-180, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-30076992
ABSTRACT
The treatment of juvenile osteoporosis has not been established due to a lack of data regarding the efficacy and adverse effects of therapeutic agents. The possible adverse effects of the long-term use of antiresorptive therapies on skeletal growth in children is of particular concern. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption, and its deficiency suppresses bone remodeling in the secondary spongiosa, but not in the primary spongiosa, due to a compensatory mechanism of osteoclastogenesis. This prompted us to develop an anti-Siglec-15 therapy for juvenile osteoporosis because most anti-resorptive drugs have potential adverse effects on skeletal growth. Using growing rats, we investigated the effects of an anti-Siglec-15 neutralizing antibody (Ab) on systemic bone metabolism and skeletal growth, comparing this drug to bisphosphonate, a first-line treatment for osteoporosis. Male 6-week-old F344/Jcl rats were randomized into six groups control (PBS twice per week), anti-Siglec-15 Ab (0.25, 1, or 4â¯mg/kg every 3â¯weeks), and alendronate (ALN) (0.028 or 0.14â¯mg/kg twice per week). Treatment commenced at 6â¯weeks of age and continued for the next 6â¯weeks. Changes in bone mass, bone metabolism, bone strength, and skeletal growth during treatment were analyzed. Both anti-Siglec-15 therapy and ALN increased bone mass and the mechanical strength of both the femora and lumbar spines in a dose-dependent manner. Anti-Siglec-15 therapy did not have a significant effect on skeletal growth as evidenced by micro-CT-based measurements of femoral length and histology, whereas high-dose ALN resulted in growth retardation with histological abnormalities in the growth plates of femurs. This unique property of the anti-Siglec-15 Ab can probably be attributed to compensatory signaling for Siglec-15 inhibition in the primary spongiosa, but not in the secondary spongiosa. Thus, anti-Siglec-15 therapy could be a safe and effective for juvenile osteoporosis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osso e Ossos
/
Desenvolvimento Ósseo
/
Terapia de Alvo Molecular
/
Proteínas de Membrana
Limite:
Animals
Idioma:
En
Revista:
Bone
Assunto da revista:
METABOLISMO
/
ORTOPEDIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Japão