Extracellular NAD+ metabolism modulates osteoclastogenesis.

Area of Science:

• Biochemistry
• Bone Biology
• Metabolism

Background:

• Nicotinamide adenine dinucleotide (NAD+) and its metabolites are crucial for cellular processes, influencing longevity and age-related diseases.
• The specific role of NAD+ metabolism in bone diseases, particularly osteoporosis, remains largely unexplored.
• Osteoporosis is a significant cause of morbidity and mortality in aging populations.

Purpose of the Study:

• To investigate the role of NAD+ metabolites in osteoclast formation and bone metabolism.
• To determine the specific enzymatic activities of CD38 involved in regulating osteoclastogenesis.

Main Methods:

• Assessment of tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation in vitro using C57 Bl/6J mouse bone marrow.
• Addition of varying concentrations of NAD+ metabolites (cyclic ADPribose, ADPribose) and enzymes (ADPribosyl cyclase, NADase).
• Utilized the specific antagonist 8-Br-cADPr to block cyclic ADPribose activity.

Main Results:

• The NAD+ metabolite cyclic ADPribose (cADPr) and exogenous ADPribosyl cyclase stimulated osteoclast formation.
• Blocking cADPr with 8-Br-cADPr significantly inhibited osteoclast formation.
• Conversely, ADPribose (ADPr) and exogenous NADase inhibited osteoclastogenesis.
• CD38, the primary NAD+-degrading enzyme in bone marrow, was implicated.

Conclusions:

• CD38-mediated regulation of osteoclastogenesis is linked to its NADase activity, not its ADPribosyl cyclase activity.
• These findings suggest a novel mechanism involving NAD+ metabolism in the pathogenesis of bone diseases like osteoporosis.
• Targeting CD38's NADase activity could represent a therapeutic strategy for osteoporosis.