Bone Formation, Growth, and Repair

This special issue of Hormone and Metabolic Research focuses on the topics of bone formation, growth, and repair [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]. This is a timely collection of articles, as our understanding of these topics has advanced significantly in the last decade. Historically, bone has been a “hard” tissue to study. This pun underlies the simple fact that bone has been, and remains, a difficult tissue to study. The cells are entombed in layer upon layer of calcified extracellular matrix and many of the techniques required to access the cells and macromolecules they express destroy the very objects of investigation. It is owing to this simple fact that progress in the area of bone research has to some extent lagged behind that of their related soft tissues. This collection of articles provides an up-to-date understanding of the recent progress made in this field.

The skeletal stem cell (SSC), which gives rise to the cells that make up the postnatal bone organ, is a mesodermally-derived cell that resides in the bone marrow, and ultimately gives rise to the cells involved in bone formation, growth, and repair (see figure on the cover). While the definition and locus of postnatal skeletal stem cells is not yet perfectly defined, its earliest origins have been traced to blood vessel-associated, pericyte-like, CD146-positive cells that reside in the marrow space [11]. Bone marrow stromal cells (BMSCs) are the morphologically fibroblast-like cells in the bone marrow, a subset of which probably retain stem cell potential, derivatives of SSCs. They give rise to the cells capable of differentiating down the pathways that give rise to the various cell types involved in bone formation, growth, and repair, specifically the osteoblast, chondrocyte, and bone lining cell, respectively [12]. Different, step-wise, tightly-regulated programs, some better defined than others, give rise to each of the cell types. Advances in the identification and understanding of the various programs that give rise to mesenchymal components of bone (osteoblasts, osteocytes, chondrocytes, adipocytes, and hematopoietic supportive stroma, reviewed in [13]), have not only advanced our understanding of the bone organ, but allowed for the creation of complex animal models with phenotypes confined to the various lines of bone cell differentiation. This, combined with advances in imaging techniques, including back-scatter microscopy, and micro computed tomography (CT), have given insight into the mineralized tissue that makes up bone (reviewed in [14]). The articles included in this special supplement advance, and help to organize our understanding of the biology of these processes.

In this issue, Hsiao et al. [1] and Liu et al. [3] provide a better understanding of the great strides made in this area by examining the critical role of the G-protein/protein kinase A (PKA)/cAMP signaling pathway in the normal differentiation of SSCs to bone-forming mesenchyme [1] [3]. Given the organ- and tissue-forming potential of SSCs/BMSCs it is clear that understanding and harnessing the tissue regenerating capacity of these cells will be important in the near future. Polymeri et al. [2] and Shapiro et al. [4] provide excellent perspectives on this important topic. Moving on to the BMSC-derived chondrocyte, Nilsson et al. [5] review the literature and report on a fascinating case of accelerated skeletal maturation that sheds light on the critical role of retinoic acid signaling in the regulation of the growth plate chondrocyte and linear growth.

Often overlooked in recent years is the importance of the extracellular matrix in bone biology. After all, many of the key roles of the skeleton, support, movement, and protection, are to a large extent made possible by the massive mineralized extracellular matrix that is bone. Taylan et al. provide insight on this important feature of bone in their report on the important role of proteoglycans in bone health disease [6].

Well known to all, yet still not well-defined, are the multifactorial processes glucocorticoids play in bone formation, growth, and repair – some advantageous (glucocorticoids are essential for BMSC differentiation in vitro), but often deleterious (glucocorticoid-induced osteoporosis). In this issue, Komori [7] lays the groundwork for understanding the complex roles of glucocorticoids in bone by detailing the signaling pathways involved in glucocorticoid action. Tack et al. [8] take an interesting approach to shed light on our understanding of the deleterious effects of glucocorticoid excess on bone through the window of the fascinating experiment in nature of Cushing syndrome. On the other end of pediatric bone is the ageing skeleton. By examining the entwined effects of diabetes and ageing on the skeleton Dhaliwal et al. [9] give context to not only our understanding of normal skeletal aging, but of the effects on bone of one of the most common endocrine disorders, diabetes. Bone repair, both microscopic and macroscopic, is one of the most important aspects of bone biology. Using the extremely informative model of non-union fractures, Jha et al. [10] explain fracture repair in the context of its similarities to bone formation and growth, and as such provide an extremely informative avenue by which to enhance our understanding of not only bone repair, but growth and development as well.

Our journal has repeatedly covered hormonal effects on bone density and structure, from thyroid hormone, testosterone, and estrogen to obesity and related disorders [15] [16] [17] [18] [19] [20]. But this is the first time that we present a collection of articles dedicated directly to bone growth, formation, structure and repair. We hope that this collection of articles will be useful to our audience, as it provides an excellent primer for endocrine clinicians and scientists alike to understand all aspects of bone biology, from cradle to grave.

• References

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• 2 Polymeri A, Giannobile WV, Kaigler D. Bone marrow stromal stem cells in tissue engineering and regenerative medicine. Horm Metab Res 2016; 48: 700-713
• 3 Liu S, Shapiro JM, Saloustros E, Stratakis CA. Bone abnormalities in mice with protein kinase A (PKA) defects reveal a role of cyclic AMP signaling in bone stromal cell-dependent tumor development. Horm Metab Res 2016; 48: 714-725
• 4 Shapiro JM, Oyen ML. Engineering approaches for understanding osteogenesis: hydrogels as synthetic bone microenvironments. Horm Metab Res 2016; 48: 726-736
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