Osteoporosis

CaMKK2 Signaling in Metabolism and Skeletal Disease: a New Axis with Therapeutic Potential Abstract Purpose of Review Age and metabolic disorders result in the accumulation of advanced glycation endproducts (AGEs), oxidative stress, and inflammation, which cumulatively cause a decline in skeletal health. Bone becomes increasingly vulnerable to fractures and its regenerative capacity diminishes under such conditions. With a rapidly aging population in the USA and the global increase in diabetes, efficacious, multi-dimensional therapies that can treat or prevent skeletal diseases associated with metabolic dysfunction and inflammatory disorders are acutely needed. Recent Findings Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of nutrient intake, glucose metabolism, insulin production, and adipogenesis. Recent studies suggest a pivotal role for CaMKK2 in bone metabolism, fracture healing, and inflammation. Summary Aside from rekindling previous concepts of CaMKK2 as a potent regulator of whole-body energy homeostasis, this review emphasizes CaMKK2 as a potential therapeutic target to treat skeletal diseases that underlie metabolic conditions and inflammation.

Integrins in Osteocyte Biology and Mechanotransduction Abstract Purpose of Review Osteocytes are the main mechanosensitive cells in bone. Integrin-based adhesions have been shown to facilitate mechanotransduction, and therefore play an important role in load-induced bone formation. This review outlines the role of integrins in osteocyte function (cell adhesion, signalling, and mechanotransduction) and possible role in disease. Recent Findings Both β1 and β3 integrins subunits have been shown to be required for osteocyte mechanotransduction. Antagonism of these integrin subunits in osteocytes resulted in impaired responses to fluid shear stress. Various disease states (osteoporosis, osteoarthritis, bone metastases) have been shown to result in altered integrin expression and function. Summary Osteocyte integrins are required for normal cell function, with dysregulation of integrins seen in disease. Understanding the mechanism of faulty integrins in disease may aid in the creation of novel therapeutic approaches.

Contextual Regulation of Skeletal Physiology by Notch Signaling Abstract Purpose of Review This article reviews the past 2 years of research on Notch signaling as it relates to bone physiology, with the goal of reconciling seemingly discrepant findings and identifying fruitful areas of potential future research. Recent Findings Conditional animal models and high-throughput omics have contributed to a greater understanding of the context-dependent role of Notch signaling in bone. However, significant gaps remain in our understanding of how spatiotemporal context and epigenetic state dictate downstream Notch phenotypes. Summary Biphasic activation of Notch signaling orchestrates progression of mesenchymal progenitor cells through the osteoblast lineage, but there is a limited understanding of ligand- and receptor-specific functions. Paracrine Notch signaling through non-osteoblastic cell types contributes additional layers of complexity, and we anticipate impactful future work related to the integration of these cell types and signaling mechanisms.

Investigating Osteocytic Perilacunar/Canalicular Remodeling Abstract Purpose of Review In perilacunar/canalicular remodeling (PLR), osteocytes dynamically resorb, and then replace, the organic and mineral components of the pericellular extracellular matrix. Given the enormous surface area of the osteocyte lacuna-canalicular network (LCN), PLR is important for maintaining homeostasis of the skeleton. The goal of this review is to examine the motivations and critical considerations for the analysis of PLR, in both in vitro and in vivo systems. Recent Findings Morphological approaches alone are insufficient to elucidate the complex mechanisms regulating PLR in the healthy skeleton and in disease. Understanding the role and regulation of PLR will require the incorporation of standardized PLR outcomes as a routine part of skeletal phenotyping, as well as the development of improved molecular and cellular outcomes. Current PLR outcomes assess PLR enzyme expression, the LCN, and bone matrix composition and organization, among others. Summary Here, we discuss current PLR outcomes and how they have been applied to study PLR induction and suppression in vitro and in vivo. Given the role of PLR in skeletal health and disease, integrated analysis of PLR has potential to elucidate new mechanisms by which osteocytes participate in skeletal health and disease.

Studies on Osteocytes in Their 3D Native Matrix Versus 2D In Vitro Models Abstract Purpose of Review Osteocytes are responsible for mechanosensing and mechanotransduction in bone and play a crucial role in bone homeostasis. They are embedded in a calcified collagenous matrix and connected with each other through the lacuno-canalicular network. Due to this specific native environment, it is a challenge to isolate primary osteocytes without losing their specific characteristics in vitro. This review summarizes the commonly used and recently established models to study the function of osteocytes in vitro. Recent Findings Osteocytes are mostly studied in monolayer culture, but recently, 3D models of osteocyte-like cells and primary osteocytes in vitro have been established as well. These models mimic the native environment of osteocytes and show superior osteocyte morphology and behavior, enabling the development of human disease models. Summary Osteocyte-like cell lines as well as primary osteocytes isolated from bone are widely used to study the role of osteocytes in bone homeostasis. Both cells lines and primary cells are cultured in 2D-monolayer and 3D-models. The use of these models and their advantages and shortcomings are discussed in this review.

Impact of Induced Pluripotent Stem Cells in Bone Repair and Regeneration Abstract Purpose of Review The main objective of this article is to investigate the current trends in the use of induced pluripotent stem cells (iPSCs) for bone tissue repair and regeneration. Recent Findings Pluripotent stem cell–based tissue engineering has extended innovative therapeutic approaches for regenerative medicine. iPSCs have shown osteogenic differentiation capabilities and would be an innovative resource of stem cells for bone tissue regenerative applications. Summary This review recapitulates the current knowledge and recent progress regarding utilization of iPSCs for bone therapy. A review of current findings suggests that a combination of a three-dimensional scaffolding system with iPSC technology to mimic the physiological complexity of the native stem cell niche is highly favorable for bone tissue repair and regeneration.

RNA-seq in Skeletal Biology Abstract Purpose of Review The goal of this paper is to review state-of-the-art transcriptome profiling methods and their recent applications in the field of skeletal biology. Recent Findings Next-generation sequencing of mRNA (RNA-seq) methods have been established and routinely used in skeletal biology research. RNA-seq has led to the identification of novel genes and transcription factors involved in skeletal development and disease, through its application in small and large animal models, as well as human tissue and cells. With the availability of advanced techniques such as single-cell RNA-seq, novel cell types in skeletal tissues are being identified. Summary As the sequencing technologies are rapidly evolving, the exciting discoveries supported by transcriptomics will continue to emerge and improve our understanding of the biology of the skeleton.

Towards a Connectomic Description of the Osteocyte Lacunocanalicular Network in Bone Abstract Purpose of Review Osteocytes are the most abundant bone cells. They are completely encased in mineralized tissue, sitting inside lacunae that are connected by a multitude of canaliculi. In recent years, the osteocyte network has been shown to fulfill endocrine functions and to communicate with a number of other organs. This review addresses emerging knowledge on the connectome of the lacunocanalicular network in different types of bone tissue. Recent Findings Recent advances in three-dimensional imaging technology started to reveal parameters that are well known from general theory to characterize the function of networks, such as network density, degree of nodes, or shortest path length through the network. Summary The connectome of the lacunocanalicular network differs in some aspects between lamellar and woven bone and seems to change with age. More research is needed to relate network structure to function, such as intercellular transport or communication and its role in mechanosensation, as well as to understand the effect of diseases.

Falls and Fractures in Diabetes—More than Bone Fragility Abstract Purpose of Review Based on a systematic literature search, we performed a comprehensive review of risk factors for falls and fractures in patients with diabetes. Recent Findings Patients with diabetes have an increased risk of fractures partly explained by increased bone fragility. Several risk factors as altered body composition including sarcopenia and obesity, impaired postural control, gait deficits, neuropathy, cardiovascular disease, and other co-morbidities are considered to increase the risk of falling. Summary Diabetes and bone fragility is well studied, but new thresholds for fracture assessment should be considered. In general, the risk factors for falls in patients with diabetes are well documented in several studies. However, the fall mechanisms among diabetic patients have only been assessed in few studies. Thus, a gab of knowledge exits and may influence the current understanding and treatment, in order to reduce the risk of falling and thereby prevent fractures.

The Osteocyte as a Novel Key Player in Understanding Periodontitis Through its Expression of RANKL and Sclerostin: a Review Abstract Purpose of Review Periodontitis is the inflammation-associated bone loss disease of the alveolar bone that surrounds teeth. Classically, the emphasis on the etiology of periodontitis has been on the products of periodontal pathogens that lead to an inflammatory response of the soft tissues of the periodontium, eventually leading to activation of osteoclasts that degrade the alveolar bone. Until recently, the response of osteocytes that populate the alveolar bone, and that are known for their regulatory role in bone anabolism and catabolism, has not been addressed. Recent Findings This review demonstrates that osteocytes play a key contributing role in periodontitis progression in various experimental mouse and rat periodontitis models. Osteocytes are the key expressing cells of both osteoclast differentiation factor RANKL as well as osteoblast activity regulator sclerostin. Targeted deletion of RANKL in osteocytes prevents osteoclast formation, thereby impairing periodontitis, despite the pressure of periodontitis-associated bacteria. Antibodies against the osteocyte-derived protein sclerostin inhibit and partially revert periodontitis by stimulating bone formation. Summary Experimental mouse and rat periodontitis models strongly indicate a key role for the bone-encapsulated osteocyte in understanding periodontitis etiology.