What are the common early signs and symptoms of juvenile Paget disease (JPD) that might indicate a problem with bone remodeling?

Early signs of juvenile Paget disease often include bone pain, particularly in the long bones of the arms and legs, and sometimes in the skull.

TNFRSF11B Gene

The TNFRSF11B gene provides instructions for making a protein critical to bone remodeling, and variants in this gene are responsible for causing juvenile Paget disease.

Normal Function

The TNFRSF11B gene provides instructions for making a protein that plays an important role in bone remodeling, a normal process in which old bone is broken down and replaced by new bone. The TNFRSF11B protein is involved in the regulation of specialized cells called osteoclasts, which break down bone tissue during this process.

Receptor Mechanism

The TNFRSF11B protein belongs to a larger family of receptor proteins. Other proteins, called ligands, can fit into specific sites on receptor proteins like a key into a lock. Together, ligands and their receptors trigger signaling pathways that affect cell development and function. The TNFRSF11B protein works outside of the cell membrane.

The TNFRSF11B protein and a receptor protein called RANK can each attach to a ligand called RANKL. Because RANKL can only bind to one of these proteins at a time, the TNFRSF11B protein and RANK compete with one another:

When RANKL is bound to RANK: A series of chemical signals cause osteoclasts to mature and turn on, leading to the breakdown of bone.
When RANKL is bound to the TNFRSF11B protein: These chemical signals are blocked.

The TNFRSF11B protein is called a "decoy" receptor protein because no chemical signals are transmitted when RANKL is attached to this protein. By influencing the amount of RANKL that is available to bind to RANK and activate osteoclasts, the TNFRSF11B protein plays a critical role in regulating the process of bone remodeling.

Health Conditions Related to Genetic Changes

Juvenile Paget Disease

Variants (also called mutations) in the TNFRSF11B gene cause juvenile Paget disease. This disorder appears in infancy or childhood and causes bones throughout the body to be abnormally large, misshapen, and easily broken (fractured).

The TNFRSF11B gene variants that cause juvenile Paget disease reduce the amount of functional TNFRSF11B protein. When functional TNFRSF11B proteins are not available, more RANKL binds to RANK. The resulting increase in chemical signaling causes osteoclasts to be overactive. As a result, bone is broken down and then replaced much faster than usual, and the new bone tissue is less organized and weaker than normal bone. These problems with bone remodeling cause bones throughout the skeleton to become unusually large, misshapen, and prone to fracture.

Other Names for This Gene

OCIF
OPG
osteoclastogenesis inhibitory factor
TR1
tumor necrosis factor receptor superfamily, member 11b

Genomic Location

The TNFRSF11B gene is found on chromosome 8.