Osteoimmunology - An Overview

Introduction

Osteoimmunology was termed several years ago to describe the link between bone cells and the immune system. The main function of bone is locomotion, regulation of phosphate and calcium homeostasis, and protection of vital organs. Bones also play an essential role in glucose metabolism regulation, male fertility, energy expenditure, and cognitive functions by secreting osteocalcin through osteoblast. In addition, this research has shown the part of bone in the immune system. Osteoimmunology is an interdisciplinary field that studies the interactions between bone cells and the immune system. This field also shows the link of bone cells to autoimmune diseases such as osteoporosis, rheumatoid arthritis, and the destruction of bone. Thus, it shows that bone cells influence immune cells.

What Is Osteoimmunology?

The term osteoimmunology was developed to describe the function of T-cell-mediated regulation of osteoclast cells. As the immune cells and osteoclast arise from hematopoietic cells of the bone marrow, osteoimmunology mainly focuses on these two terms. Osteoclast precursors can also be detected in the blood as circulating cells, and there will be an increase in the number of cells in the inflammatory conditions, which are characterized by high levels of Tumor Necrosis Factor (TNF).

What Is the Biology of Bone?

Studies have shown that bone continues undergoing modeling and remodeling during the growth and adulthood phases with proper mechanical properties and shape. Bone modeling and remodeling take place by three types of cells, namely:

• Osteoclast - Cells that resorb bone.

• Osteoblast - Cells that depose bone.

• Osteocytes - Cells that are buried in a bone matrix that resorb and depose bone.

Bone remodeling happens in four phases, which include:

1. Latent Phase - In this phase, a stimulus is formed to activate the osteocytes by bone lining cells to start the differentiation of the osteoclast and expose the bone surface.

2. Activation Phase - In this phase, the osteoclast cells resorb the part of the bone that is left exposed by the bone lining cells. When the resorption is done, they get separated from the bone and undergo apoptosis.

3. Reverse Phase - Some reverse cells, like macrophages, move to the lacuna of the resorbed cells and clean the debris left by the osteoclast cells. These reverse cells also secrete some factors that attract the osteoblast in the resorption lacuna.

4. Formation Phase - This is the longest phase of bone remodeling and may last up to six months. In this phase, the osteoblast occupies the resorption lacunae and fills the overall space with an osteoid matrix, and then they get mineralized to form new bone.

What Is the Link Between Bone Cells and the Immune System?

Many studies have shown that bone cells influence immune cells and regulate immunity. Some of the descriptions may include:

Osteoblasts

• Some researchers have studied by using mice that the parathyroid hormones and parathyroid receptors in osteoblastic cells have more hematopoietic stem cells. This may be due to an increase in the osteoblastic jagged1 and activation of Notch1.

• Another study has shown that there is a direct correlation between spindle-shaped N-cadherin+CD45- osteoblast and hematopoietic stem cells. Thus, in turn, it shows osteoblast plays a vital role in the regulation of hematopoietic stem cells, thus showing the new term in the bone marrow called endosteal niche.

• Further, it has been studied that osteoblast cells contribute to the differentiation and commitment in the B-lymphocytes from the HSCs (Hematopoietic stem cells).

Osteocytes

• Osteocytes are the main cells that are responsible for producing activators and receptors of nuclear factor Kappa B ligand (RANKL) in the bone. This type of cytokines plays a crucial role in osteoclasts and the development of lymphocytes. Thus, it can be said that this type of cell influences the immune system.

• It is studied that in some persons with estrogen-deficient conditions, the RANKL that arises from the osteoclast results in increased osteoclast genesis and bone loss.

• Some of the studies showed that ablation of osteocytes causes lymphopenia.

Osteoclasts

• Osteoclasts are responsible for regulating the hematopoietic stem cell niche through osteoblast. Firstly, osteoclast cells are capable of increasing the mobilization of hematopoietic stem cells by secreting the crucial protein that functions the osteoclast called cathepsin K, which tears the OsteoPontiN (OPN), stem cell factor (SCF), and SDF1 that in turn deprive the bone niche of hematopoietic stem cell binding sites.

• Some studies with mice with improper lymphopoiesis blocked at the pro B stage lead to the formation of lesser B-cells. Due to this, T-cell activation is also affected, causing B-T-cell immunodeficiency.

What Is the Role of Osteoimmunology in Bone and Immune Diseases?

Many diseases of bone have an immunologic origin. However, some immunological diseases like acute myeloid leukemia may originate from bone-derived signals.

• Rheumatoid Arthritis

It is a T-helper type 1 degenerative disease. It is characterized by persistent inflammation, synovitis, and generation of antibodies against rheumatoid factor. Studies have shown that there is a close correlation between rheumatoid arthritis and osteoclast deregulation. In this condition, the T cell activation results in increased osteoclast activation due to IFN-gamma, which is known to inhibit osteoclast genesis. In addition, in the synovium in rheumatoid arthritis patients, interleukin-17 induces the production of interleukin-32 that stimulates the interleukin-17 expression, which in turn creates the feed-forward loop. Thus, this type of cytokine not only plays a crucial role in the onset of rheumatoid arthritis, but it also plays a role in bone destruction in the condition.

• Osteoporosis

The deficiency of estrogen hormone is the major cause of osteoporosis in postmenopausal women.

Studies show that osteoporosis results in increased production of inflammatory cytokines. Early studies show that estrogen increases apoptosis and decreases RANKL-dependent osteoclast formation. Furthermore, studies have shown that estrogen reduces RANKL production not only in osteoblasts but also in B and T cells.

• Periodontal Diseases

Periodontal diseases are another pathological phenomenon in which immune cell deregulation causes bone loss. This may be due to the stimulation of osteoclast resorption by RANKL production through activated B and T cells.

Conclusion

It has been almost 20 years since the term osteoimmunology was coined. Although many studies and research have answered various questions about osteoimmunology, it needs further work and study to overcome all the questions related to the interactions between bone and the immune system. Thus, studies have strongly described the link between bone cells and the immune system as the bone cells influence immune function. Inversely, the immune cells also influence the bone cells.