Multicentric osteolysis, nodulosis, and arthropathy (MONA) describes a rare inherited disease characterized by a loss of bone tissue (osteolysis), particularly in the hands and feet. MONA includes a condition formerly called nodulosis-arthropathy-osteolysis (NAO) syndrome. It may also include a similar disorder called Torg syndrome, although it is unknown whether Torg syndrome is actually part of MONA or a separate disorder caused by a mutation in a different gene.

In most cases of MONA, bone loss begins in the hands and feet, causing pain and limiting movement. Bone abnormalities can later spread to other areas of the body, with joint problems (arthropathy) occurring in the elbows, shoulders, knees, hips, and spine. Most people with MONA develop low bone mineral density (osteopenia) and thinning of the bones (osteoporosis) throughout the skeleton. These abnormalities make bones brittle and more prone to fracture. The bone abnormalities also lead to short stature.

Many affected individuals develop subcutaneous nodules, which are firm lumps of noncancerous tissue underneath the skin, especially on the soles of the feet. Some affected individuals also have skin abnormalities including patches of dark, thick, and leathery skin. Other features of MONA can include clouding of the clear front covering of the eye (corneal opacity), excess hair growth (hypertrichosis), overgrowth of the gums, heart abnormalities, and distinctive facial features that are described as "coarse."

MONA results from mutations in the MMP2 gene. This gene provides instructions for making an enzyme called matrix metallopeptidase 2, whose primary function is to cut (cleave) a protein called type IV collagen. Type IV collagen is a major structural component of basement membranes, which are thin, sheet-like structures that separate and support cells in many tissues. The activity of matrix metallopeptidase 2 appears to be important for a variety of body functions, including bone remodeling, which is a normal process in which old bone is broken down and new bone is created to replace it.

The MMP2 gene mutations that cause MONA completely eliminate the activity of the matrix metallopeptidase 2 enzyme, preventing the normal cleavage of type IV collagen. It is unclear how a loss of enzyme activity leads to the specific features of MONA. Researchers suspect that it somehow disrupts the balance of new bone creation and the breakdown of existing bone during bone remodeling, resulting in a progressive loss of bone tissue. How a shortage of matrix metallopeptidase 2 leads to the other features of MONA, such as subcutaneous nodules and skin abnormalities, is unknown.

Normal Function

The MMP2 gene provides instructions for making an enzyme called matrix metallopeptidase 2. This enzyme is produced in cells throughout the body and becomes part of the extracellular matrix, which is an intricate lattice of proteins and other molecules that forms in the spaces between cells. One of the major known functions of matrix metallopeptidase 2 is to cut (cleave) a protein called type IV collagen. Type IV collagen is a major structural component of basement membranes, which are thin, sheet-like structures that separate and support cells as part of the extracellular matrix.

The activity of matrix metallopeptidase 2 appears to be important for a variety of body functions. These include the breakdown of the uterine lining (endometrium) during menstruation, formation and growth of new blood vessels, repair of damaged tissues, and inflammation. Matrix metallopeptidase 2 also plays a role in bone remodeling, which is a normal process in which old bone is broken down and new bone is created to replace it.

Health Conditions Related to Genetic Changes

Multicentric osteolysis, nodulosis, and arthropathy

At least eight mutations in the MMP2 gene have been found to cause multicentric osteolysis, nodulosis, and arthropathy (MONA), a rare inherited bone disease that is characterized by the loss of bone tissue (osteolysis), particularly in the hands and feet, and related joint problems described as arthropathy. Each of the known MMP2 gene mutations eliminates the function of the matrix metallopeptidase 2 enzyme, preventing the normal cleavage of type IV collagen. It is unclear how a loss of enzyme activity leads to the specific features of MONA. Researchers suspect that it somehow disrupts the balance of new bone creation and the breakdown of existing bone during bone remodeling, resulting in a progressive loss of bone tissue. How a shortage of matrix metallopeptidase 2 leads to other features of MONA, such as firm lumps under the skin (subcutaneous nodules) and skin abnormalities, is unknown.

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Other Names for This Gene

• 72 kDa gelatinase
• 72 kDa type IV collagenase
• CLG4
• CLG4A
• collagenase type IV-A
• gelatinase A
• matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)
• matrix metalloproteinase-2
• matrix metalloproteinase-II
• MMP-2
• MMP-II
• MMP2_HUMAN
• neutrophil gelatinase
• TBE-1

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

MONA is rare; its prevalence is unknown. This condition has been reported in multiple populations worldwide.