The immune system is strongly linked to the maintenance of healthy bone. Inflammatory cytokines, specifically, are crucial to skeletal homeostasis and any dysregulation can result in detrimental health complications. Interleukins, such as interleukin 6 (IL-6), act as osteoclast differentiation modulators and as such, must be carefully monitored and regulated. IL-6 encourages osteoclastogenesis when bound to progenitors and can cause excessive osteoclastic activity and osteolysis when overly abundant. Numerous bone diseases are tied to IL-6 overexpression, including rheumatoid arthritis, osteoporosis, and bone-metastatic cancers. In the latter, IL-6 can be released with growth factors into the bone marrow microenvironment (BMM) during osteolysis from bone matrix or from cancer cells and osteoblasts in an inflammatory response to cancer cells. Thus, IL-6 helps create an ideal microenvironment for oncogenesis and metastasis. Multiple myeloma (MM) is a blood cancer that homes to the BMM and is strongly tied to overexpression of IL-6 and bone loss. The roles of IL-6 in the progression of MM are discussed in this review, including roles in bone homing, cancer-associated bone loss, disease progression and drug resistance. MM disease progression often includes the development of drug-resistant clones, and patients commonly struggle with reoccurrence. As such, therapeutics that specifically target the microenvironment, rather than the cancer itself, are ideal and IL-6, and its myriad of downstream signalling partners, are model targets. Lastly, current and potential therapeutic interventions involving IL-6 and connected signalling molecules are discussed in this review.

/pdf/interleukin-6-interweaves-the-bone-marrow-microenvironment-2wykxlx1ga.pdf

Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma.

Current approaches to fabrication of nSC composites for bone tissue engineering (BTE) have limited capacity to achieve uniform surface functionalization while replicating the complex architecture and bioactivity of native bone, compromising application of these nanocomposites for in situ bone regeneration. A robust biosilicification strategy is reported to impart a uniform and stable osteoinductive surface to porous collagen scaffolds. The resultant nSC composites possess a native-bone-like porous structure and a nanosilica coating. The osteoinductivity of the nSC scaffolds is strongly dependent on the surface roughness and silicon content in the silica coating. Notably, without the use of exogenous cells and growth factors (GFs), the nSC scaffolds induce successful repair of a critical-sized calvarium defect in a rabbit model. It is revealed that topographic and chemical cues presented by nSC scaffolds could synergistically activate multiple signaling pathways related to mesenchymal stem cell recruitment and bone regeneration. Thus, this facile surface biosilicification approach could be valuable by enabling production of BTE scaffolds with large sizes, complex porous structures, and varied osteoinductivity. The nanosilica-functionalized scaffolds can be implanted via a cell/GF-free, one-step surgery for in situ bone regeneration, thus demonstrating high potential for clinical translation in treatment of massive bone defects.

Biomimetic Nanosilica–Collagen Scaffolds for In Situ Bone Regeneration: Toward a Cell‐Free, One‐Step Surgery

Bone homeostasis is a complex process, wherein osteoclasts resorb bone and osteoblasts produce new bone tissue. For the maintenance of skeletal integrity, this sequence has to be tightly regulated and orchestrated. Iron overload as well as iron deficiency disrupt the delicate balance between bone destruction and production, via influencing osteoclast and osteoblast differentiation as well as activity. Iron overload as well as iron deficiency are accompanied by weakened bones, suggesting that balanced bone homeostasis requires optimal—not too low, not too high—iron levels. The goal of this review is to summarize our current knowledge about how imbalanced iron influence skeletal health. Better understanding of this complex process may help the development of novel therapeutic approaches to deal with the pathologic effects of altered iron levels on bone.

https://www.mdpi.com/1424-8247/11/4/107/pdf

Influence of Iron on Bone Homeostasis.

Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment. 

/pdf/the-role-of-the-immune-microenvironment-in-bone-cartilage-254udnqp.pdf

The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity

Calcium phosphate cements: Optimization toward biodegradability.

Bone regeneration is a well organized but complex physiological process, in which different cell types and their activated signaling pathways are involved In bone regeneration and remodeling processes, mesenchymal stem cells (MSCs) have a crucial role, and their differentiation during these processes is regulated by specific signaling molecules (growth factors/cytokines and hormones) and their activated intracellular networks Especially the utilization of the molecular machinery seems crucial to consider prior to developing bone implants, bone-substitute materials, and cell-based constructs for bone regeneration The aim of this review is to provide an overview of the signaling mechanisms involved in bone regeneration and remodeling and the osteogenic potential of MSCs to become a key cellular resource for such regeneration and remodeling processes Additionally, an overview of possibilities to beneficially exploit cell signaling processes to optimize bone regeneration is provided

Signaling pathways involved in osteogenesis and their application for bone regenerative medicine

Calcium phosphate cements (CPCs) are frequently used as synthetic bone graft materials in view of their excellent osteocompatibility and clinical handling behavior. Hydroxyapatite-forming CPCs, however, degrade at very low rates, thereby limiting complete bone regeneration. The current study has investigated whether degradation of apatite-forming cements can be tuned by incorporating acid-producing slow-resorbing poly(D,L-lactic-co-glycolic) acid (PLGA) porogens, fast-resorbing glucono-delta-lactone (GDL) porogens, or mixtures thereof. The physicochemical, mechanical, and degradation characteristics of these CPC formulations were systematically analyzed upon soaking in phosphate-buffered saline (PBS). In parallel, various CPC formulations were implanted intramuscularly and orthotopically on top of the transverse process of goats followed by analysis of the soft tissue response and bone ingrowth after 12 weeks. In vitro degradation of GDL was almost completed after 2 weeks, as evidenced by characterization of the release of gluconic acid, while PLGA-containing CPCs released glycolic acid throughout the entire study (12 weeks), resulting in a decrease in compression strength of CPC. Extensive in vitro degradation of the CPC matrix was observed upon simultaneous incorporation of 30% PLGA-10% GDL. Histomorphometrical evaluation of the intramuscularly implanted samples revealed that all CPCs exhibited degradation, accompanied by an increase in capsule thickness. In the in vivo goat transverse process model, incorporation of 43% PLGA, 30% PLGA-5% GDL, and 30% PLGA-10% GDL in CPC significantly increased bone formation and resulted in higher bone height compared with both 10% GDL and 20% GDL-containing CPC samples.

Tuning the Degradation Rate of Calcium Phosphate Cements by Incorporating Mixtures of Polylactic-co-Glycolic Acid Microspheres and Glucono-Delta-Lactone Microparticles

Osseointegration of dental and orthopedic bone implants is the important process that leads to mechanical fixation of implants and warrants implant functionality. In view of increasing numbers of osteoporotic patients, bone implant surface optimization strategies with instructive and drug-loading ability have been heavily explored. However, few animal models are available to study the effect of novel implant surface modifications in osteoporotic conditions. Since laboratory rats comply with a number of practical advantages, including the reliability of several methods for rapid induction of osteoporotic conditions, the present work aimed to define the use of the femoral condyle in osteoporotic female and male rats as a suitable implantation model to study osseointegration of bone implants. The method describes the procedures for induction (by hypogonadism) and assessment (by in vivo micro-computed tomography [CT]) of osteoporotic conditions in both female and male rats. The implantation site architecture (femoral condyle bone properties and dimensions) was comparatively evaluated for female and male rats, and the implant installation procedures are described. Finally, the possible analytical techniques to evaluate bone responses via mechanical tests, ex vivo micro-CT, and histological methods are provided.

Osteoporotic rat models for evaluation of osseointegration of bone implants.

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Signaling pathways involved in osteogenesis and their application for bone regenerative medicine

Tuning the Degradation Rate of Calcium Phosphate Cements by Incorporating Mixtures of Polylactic-co-Glycolic Acid Microspheres and Glucono-Delta-Lactone Microparticles

Osteoporotic rat models for evaluation of osseointegration of bone implants.