What Are the Causes of Chondrocalcinosis?

Chondrocalcinosis is a disease characterized by the accumulation of calcium phosphate crystals (Pyrophosphate) in the joints. It is mainly due to magnesium deficiency; however, it can also be related to other diseases and metabolic disorders.

I. How is Pyrophosphate Produced in the joints?

Chondrocytes are specialized cells that control the synthesis of cartilage, from collagen and proteoglycan, and its degradation by enzymes such as collagenase, cathepsins, and proteinases. They also produce inorganic pyrophosphate (PPi) that is used for the formation of calcium pyrophosphate crystals [1].

II. Causes of Chondrocalcinosis

1- Magnesium Deficiency

When there is an excess of calcium pyrophosphate production by the chondrocytes, enzymes including alkaline phosphatase (ALP) and inorganic pyrophosphatases, transform calcium pyrophosphate back into inorganic pyrophosphate.

However, the enzymatic activity of alkaline phosphatase (ALP) requires the presence of magnesium (Mg). Therefore, deficiency in Mg supply results in excessive production and accumulation of calcium pyrophosphate crystals that cannot be transformed into inorganic pyrophosphate (PPi) by alkaline phosphatase (ALP).

2- Post-Injury Arthritis

Although the mechanism is not known, a study that included 3350 arthroscopy samples found an association between chondrocalcinosis and post-traumatic degenerative changes in the meniscus of the knee [2].

3- Hypercalcemia

Hypercalcemia is the presence of calcium at a high level in the blood. It is mainly caused by alterations of the parathyroid function, cancer, vitamin D disorders, and high bone turnover (bone resorption and replacement).

Crystals that are generated in the joint during chondrocalcinosis are made from calcium and inorganic pyrophosphate (PPi) through a process known as nucleation. During hyperglycemia, there is an excess of calcium that increases the formation of calcium pyrophosphate.

4- Acromegaly

Acromegaly is a disorder that is associated with an increased release of growth hormone (GH) by the pituitary gland due to the presence of a tumor.  

Growth hormone (GH) is known to stimulate the activity of the insulin growth factor -1 (IGF-1) that limits the capacity of chondrocytes to produce inorganic pyrophosphate necessary for the formation of calcium pyrophosphate crystals.

Therefore, the increase of growth hormone (GH) by the pituitary gland tumor also increases the stimulation of IGF-1, and thus, should limit the activity of chondrocytes. However, due to the overstimulation of IGF-1, chondrocytes become insensitive and develop resistance to its inhibiting activity leading to excessive production of inorganic pyrophosphate (PPi) and calcium pyrophosphate crystals that accumulate in the joints.

Hypothyroidism

Hypothyroidism is a disorder characterized by a reduced production of the thyroid hormones thyroxine (T4), and triiodothyronine (T3), by the thyroid which is mainly due to iodine deficiency. Iodine is an essential component in the synthesis of T3 and T4. The most common disease associated with hypothyroidism is simple goiter.

Thyroid hormones are known to inhibit the proliferation of mature chondrocytes into hypertrophic chondrocytes that produce mineralized cartilage; however, during hypothyroidism, this inhibition is lifted as these hormones are not sufficiently produced resulting in excessive production of calcium pyrophosphate crystals in the joints.

Gitelman Syndrome

Gitelman Syndrome is a genetic disorder of the kidney characterized by low blood levels of magnesium, potassium, and chloride. The low availability of magnesium (Mg) results in magnesium deficiency leading to excessive production and accumulation of calcium pyrophosphate crystals that cannot be transformed into inorganic pyrophosphate (PPi) by alkaline phosphatase (ALP).

Wilson Disease

Gitelman Syndrome is a genetic disorder characterized by excessive accumulation of copper in the body resulting in neurological and liver anomalies.

Although the mechanism by which copper increases the production of calcium pyrophosphate crystals by chondrocytes is not well known, it was proposed that copper increases the expression of a growth factor known as transforming growth factor-beta 1 (TGFb1) that is involved in stimulating the production of inorganic pyrophosphate (PPi) by chondrocytes.

Another potential mechanism is the association between copper accumulation that excessively stimulates the expression of insulin growth factor -1 (IGF-1) leading to chondrocytes insensitivity to the inhibiting effect of insulin growth factor -1 (IGF-1).

Hemochromatosis

Hemochromatosis is a genetic disorder characterized by excessive intestinal absorption of iron and its accumulation in tissues and organs of the body.

Although the mechanism by which hemochromatosis promotes chondrocalcinosis is not known, it is possible that the accumulation of iron in the joints may promote the function of chondrocytes in producing calcium pyrophosphate crystals through anomalies in iron homeostasis [3].

Pseudogout

Pseudogout or calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is characterized by the deposition of calcium pyrophosphate crystals in the joints.

Although the cause is unknown, it is suggested that the cause may be related to the excessive breakdown of ATP (Adenosine triphosphate) into pyrophosphate which is secreted by the cells of the joints.

How is Chondrocalcinosis Diagnosed?

Chondrocalcinosis manifests with stiffness and inflammation of the joints. It is diagnosed through needle collection of synovial liquid to look for the presence of calcium pyrophosphate crystals. Imaging techniques include X-rays, CT (computerized tomography) scan, MRI (Magnetic resonance imaging), and ultrasound.

The diagnosis is also based on the coexistence of stiffness and inflammation of the joints together with diseases and metabolic disorders such as magnesium deficiency, hypothyroidism, acromegaly, Gitelman Syndrome, Wilson disease, and hypercalcemia.

How is Chondrocalcinosis Treated?

The treatment of chronic chondrocalcinosis appears to be irreversible due to the degeneration of the cartilage tissue. However, the treatment of temporary chondrocalcinosis requires treatment of its related causes. Symptoms such as pain and inflammation are treated using nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids.

Conclusion

Chondrocalcinosis appears to affect mainly and equally women and men over the age of 50; however, it can also affect individuals at a younger age, if associated with post-traumatic injury. Magnesium deficiency appears to be the main cause, and therefore, diet supplementation should help from chondrocalcinosis if there is no degeneration of the joint cartilage.

Although the cellular mechanisms of chondrocalcinosis are not well known, they appear to be associated with alterations in the function of chondrocytes and enzymes that ensure the homeostasis between inorganic pyrophosphate (PPi) production and calcium pyrophosphate crystals generation.

Finally, the stiffness and inflammation associated with chondrocalcinosis can be significantly debilitating for the affected individuals resulting in poor quality of life, and therefore, its early detection can considerably reduce its progression to irreversible degeneration of the cartilage.