April 1, 2021

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This article was originally published as a chapter in the book “Design and Catastrophe: 51 Scientists Explore Evidence in Nature"

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Our bones are not just rigid structures made up of collagen and minerals but are living and dynamic organs that grow, change shape, and regenerate themselves throughout our lives through a process called “bone remodeling.” This process involves development, maintenance, repair, and growth and depends on the complex and tightly controlled activity of two major cells—osteoblasts (OB), which make new bone, and osteoclasts (OC), which resorb or break down bone. Both cell types work with opposing functions, with timely precision, and in perfect balance. Their activity is controlled by cartilage-making cells; by osteocytes, which are cells embedded in the bone mineralized matrix; and by an extensive regulatory network of genes and signaling pathways.

These complex multistep pathways are driven by a vast array of active proteins, each of which is explicitly coded by DNA for a specific purpose. Each step in a signaling pathway involves several of these proteins working in a synchronized and hierarchical manner. The entire process of bone remodeling is tightly regulated at the level of DNA through a variety of chemical changes in the DNA molecule.[1] In turn, DNA is tightly regulated by numerous short non-coding RNA molecules called microRNA.

OC and OB derive from different types of stem cells and follow two independent, multistep processes of development before reaching maturity and full activity. Both processes need to coexist and function simultaneously in a coupled manner to keep a balance between bone formation and resorption. If one exceeds the other, formation and maintenance of a healthy and well-functioning skeleton does not occur.

Multitasking Bone Cells

OB originate primarily from a subset of mesenchymal stem cells (MSC) which, depending on signaling, can also develop into cartilage, muscle, or fat cells. Once OB reach maturity, they secrete new bone. In addition, a fraction of mature OB become embedded in the bone matrix as osteocytes, which release proteins that are critical for the regulation of bone remodeling.[2]

OC are giant cells containing not just one, but multiple nuclei. Unlike OB, they originate from hematopoietic stem cells (HSC).[3] Depending on signaling, HSC can develop into at least 12 different types of white blood cells. One of these, the monocyte, can remain a monocyte or develop into either of two immune cells—dendritic cells or macrophages. Macrophages can either remain as they are or develop into OC through the combined action of several proteins in a multistep process facilitated by OB and osteocytes.[4] Therefore, preexisting functional OB and osteocytes are required for the development of fully functional OC.

Once mature, OC create a “bone resorption pit” through a complex process in which the cell secretes hydrogen ions that break down bone matrix minerals and enzymes that break down collagen and generate reactive oxygen species. As the bone matrix is broken down, it releases several proteins. These, together with OC, help to recruit immature OB to the “construction site” and also push their development into mature cells that secrete new bone to fill the resorption pit.[5] Therefore, preexisting functional OC are required for the development and full functionality of OB.

Interestingly, the stem cells (MSC and HSC) that give rise to OB and OC, both reside in the bone marrow that fills the cavity inside bones. In addition, the OC plays a major role in the establishment and maintenance of the HSC niche from which it itself derives.[6] In other words, preexisting, fully functional bone is required for the development of fully functional bone. Bone cells also play multifunctional regulatory roles outside the skeleton.[7] For example, OB influence the function of blood vessels and cells of the central nervous system, gut, muscle, fat, and testis, while OC have effects on the hematopoietic (blood cells) and immune systems.[8]

Imbalance and Catastrophe

The balance between bone formation and resorption is achieved through multiple mechanisms that involve bone cells, immune cells, and numerous functional proteins, all of which can respond quickly to varying stimuli. The astounding complexity of these mechanisms indicates that for bone development and remodeling to occur successfully, all independent processes and cells must codevelop and coexist to synchronize and synergize in a balanced and coupled manner.

The entire process is so tightly regulated that any disruption results in an imbalance between bone formation and resorption, leading to catastrophic events that cause disease and mortality. The most common of these is osteoporosis, where bone resorption exceeds formation, leading to decreased bone density and fractures.[9] Uncontrolled OC activation contributes to inflammatory arthritis and to painful bone-resorbing tumors that spread to the skeleton from common cancers such as breast, prostate, or melanoma. Our own research[10] has shown that OC play a major role in osteosarcoma, an aggressive juvenile bone cancer. A recent finding shows that alterations in bone cells can lead to the development of leukemia stem cells. On the other hand, genetic mutations that inhibit OC formation or function lead to the accumulation of dense but brittle bone in rare disorders such as osteopetrosis.[11]

Design or Evolution?

This brief synopsis of a mechanism that is exceedingly much more intricate argues in favor of the simultaneous existence of numerous established and interdependent regulatory proteins and pathways, working with synergistic precision to facilitate the formation and maintenance of a functioning organ. Such observed complexity and codependence challenge an evolutionary model of stepwise and slow bone development over millions of years. Instead, the evidence highlights the need for a rapid, responsive, highly complex, tightly regulated, and coupled design with high plasticity, which is sensitive to the slightest imbalance and which not only influences its immediate environment, but coregulates the entire organism. We are only scratching the surface of this multifaceted process, and I look forward to spending eternity with the Designer to learn the rest of the story.

NOTES

[1] A Husain, MA Jeffries. Epigenetics and bone remodeling. Current Osteoporosis Reports 2017; 15:450–458.

[2] PJ Marie, M Cohen-Solal. The expanding life and functions of osteogenic cells: from simple bone making cells to multifunctional cells and beyond. Journal of Bone and Mineral Research 2018; 33:199–210.

[3] T Ono, T Nakashima. Recent advances in osteoclast biology. Histochemistry and Cell Biology 2018; 149:325–341.

[4] Ibid.

[5] Ibid.

[6] Marie and Cohen-Solal, op. cit.

[7] Ibid.

[8] K Okamoto, H Takayanagi. Osteoimmunology. Cold Spring Harbor Perspectives in Medicine 2019; 9(1):a031245.

[9] Ono and Nakashima, op. cit.

[10] L Endo-Munoz, A Cumming, D Rickwood, D Wilson, C Cueva, C Ng, G Strutton, AI Cassady, A Evdokiou, S Sommerville, et al. Loss of osteoclasts contributes to development of osteosarcoma pulmonary metastases. Cancer Research 2010; 70(18):7063–7072.

[11] Ono and Nakashima, op. cit.

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Liliana Endo-Munoz works in the pharmaceutical and healthcare industry, managing the medical affairs, clinical trial, and healthcare/scientific writing portfolios, and is an Honorary Fellow at the University of Queensland, from which she holds a PhD in Medicine. She has published widely in her research fields of virology and oncology in major scientific journals including Cancer Research, BBA Reviews on Cancer, British Journal of Cancer, Oncotarget, and Virology Journal.