Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans
Mathieu Ferron1, Maya Boudiffa, Michel Arsenault
1Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
Abstract:
Osteoporosis is a multifactorial genetic disease characterized by reduction of bone mass due to dysregulation of osteoclast differentiation or maturation. Herein, we identified a regulator of osteoclastogenesis, the murine homolog of inositol polyphosphate 4-phosphatase type IIα (Inpp4bα). Expression of Inpp4bα is detected from early osteoclast differentiation to activation stage. Targeted expression of native Inpp4bα ex vivo repressed whereas phosphatase-inactive Inpp4bα stimulated osteoclast differentiation. Inpp4bα acts on intracellular calcium level that modulates NFATc1 nuclear translocation and activation. In vivo mice deficient in Inpp4b displayed increased osteoclast differentiation rate and potential resulting in decreased bone mass and osteoporosis. Importantly, INPP4B in human was identified as a susceptibility locus for osteoporosis. This study defined Inpp4b as a major modulator of the osteoclast differentiation and as a gene linked to variability of bone mineral density in mice and humans.
Insights
Inositol polyphosphate 4-phosphatase type IIα (Inpp4bα) regulates osteoclast differentiation, a key process in osteoporosis. This gene influences bone mineral density in both mice and humans.
Area of Science:
- Molecular Biology
- Genetics
- Bone Biology
Background:
- Osteoporosis is a complex genetic disorder causing reduced bone mass.
- Dysregulation of osteoclast differentiation or maturation is a primary cause of osteoporosis.
Purpose of the Study:
- To identify and characterize novel regulators of osteoclastogenesis.
- To investigate the role of Inpp4bα in bone metabolism and its link to osteoporosis.
Main Methods:
- Investigated the expression of Inpp4bα during osteoclast differentiation.
- Utilized ex vivo and in vivo models with targeted Inpp4bα expression.
- Analyzed intracellular calcium levels and NFATc1 activation.
- Examined bone mineral density in Inpp4b-deficient mice.
Main Results:
- Inpp4bα expression is present throughout osteoclast differentiation.
- Native Inpp4bα repressed, while inactive Inpp4bα stimulated, osteoclast differentiation.
- Inpp4bα modulates intracellular calcium, affecting NFATc1 activation.
- Inpp4b deficiency led to increased osteoclastogenesis, reduced bone mass, and osteoporosis in mice.
- Human INPP4B was identified as a susceptibility locus for osteoporosis.
Conclusions:
- Inpp4b is a significant regulator of osteoclast differentiation.
- Inpp4b influences bone mineral density variability in both mice and humans.
- Inpp4b represents a potential therapeutic target for osteoporosis.
More Related Videos
09:22Absolute Quantitation of Inositol Pyrophosphates by Capillary Electrophoresis Electrospray Ionization Mass Spectrometry
Published on: August 13, 2021
09:01Extraction and Quantification of Soluble, Radiolabeled Inositol Polyphosphates from Different Plant Species using SAX-HPLC
Published on: June 26, 2020
Related Concept Videos
Phosphoinositides and PIPs
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Hormones and Bone Tissue
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...
Skeleton and Calcium Homeostasis
Roles of Electrolytes: Calcium and Phosphate
The calcium concentration in blood plasma is primarily regulated...
IP3/DAG Signaling Pathway
The JAK-STAT Signaling Pathway
