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Biodegradable Mg‐based metals may be promising orthopedic implants for treating challenging bone diseases, attributed to their desirable mechanical and osteopromotive properties. This Review summarizes the current status and future research trends for Mg‐based orthopedic implants. First, the properties between Mg‐based implants and traditional orthopedic implants are compared on the following aspects: in vitro and in vivo degradation mechanisms of Mg‐based implants, peri‐implant bone responses, the fate of the degradation products, and the cellular and molecular mechanisms underlying the beneficial effects of Mg ions on osteogenesis. Then, the preclinical studies conducted at the low weight bearing sites of animals are introduced. The innovative strategies (for example, via designing Mg‐containing hybrid systems) are discussed to address the limitations of Mg‐based metals prior to their clinical applications at weight‐bearing sites. Finally, the available clinical studies are summarized and the challenges and perspectives of Mg‐based orthopedic implants are discussed. Taken together, the progress made on the development of Mg‐based implants in basic, translational, and clinical research has laid down a foundation for developing a new era in the treatment of challenging and prevalent bone diseases. This Review summarizes the current status and future research trends for Mg‐based or containing orthopedic implants. The progress made on the development of Mg‐based or containing implants in basic, translational, and clinical research can lay down a foundation for opening a new era to improve clinical healing outcomes in the treatment of challenging bone diseases.

Epididymal white adipose tissue (eWAT) secretes an array of cytokines to regulate the metabolism of organs and tissues in high-fat diet (HFD)-induced obesity, but its effects on bone metabolism are not well understood. Here, we report that macrophages in eWAT are a main source of osteopontin, which selectively circulates to the bone marrow and promotes the degradation of the bone matrix by activating osteoclasts, as well as modulating bone marrow-derived macrophages (BMDMs) to engulf the lipid droplets released from adipocytes in the bone marrow of mice. However, the lactate accumulation induced by osteopontin regulation blocks both lipolysis and osteoclastogenesis in BMDMs by limiting the energy regeneration by ATP6V0d2 in lysosomes. Both surgical removal of eWAT and local injection of either clodronate liposomes (for depleting macrophages) or osteopontin-neutralizing antibody show comparable amelioration of HFD-induced bone loss in mice. These results provide an avenue for developing therapeutic strategies to mitigate obesity-related bone disorders. Visceral adipose tissue secretes cytokines to regulate the homeostasis of organs. Here, the authors show that epididymal white adipose tissue-secreted osteopontin induces lipophagocytic mobilization of macrophages and promotes bone matrix degradation via activating osteoclasts.

Fibrous dysplasia/McCune Albright syndrome (FD/MAS) is a rare genetic disease caused by postzygotic activating variants in the GNAS gene, encoding the α subunit of stimulatory G protein (Gα s ). Although multiple organs may be involved, skeletal lesions usually represent the most severe and least treatable expression of the disease, leading to bone deformities, spontaneous fractures, and chronic pain that severely reduce patients’ quality of life. The recognition of the causative Gα s variants and the consequent ligand-independent activation of the adenylyl cyclase/cAMP/PKA pathway has provided a clear molecular explanation to most extra-skeletal pathologies of FD/MAS, leading to the development of effective therapeutic approaches. In contrast, a detailed understanding of the cellular and molecular mechanisms that act downstream of the Gα s pathway to generate FD bone lesions and clinical expression thereof remain elusive. Multiple key issues remain to be addressed, including some questions that have recently emerged such as the interaction between mutated and non-mutated cells and the role of the latter in the development of the fibrotic tissue. In this review, we provide a summary of the proof-of-concept, preclinical data, and experimental tools that have emerged to date from basic and translational studies on FD and represent the background for future research on the pathogenesis and treatment of this rare disease.

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid-conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated PICK1 inhibitor, myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favorable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity as well as ongoing hypersensitivity and anxiodepressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks after spared nerve injury surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.

Cancer-induced bone pain (CIBP) due to metastatic breast cancer is common and debilitating. Effective, long-term treatment options have side-effects that reduce patients' quality of life. Preclinical models are valuable tools for testing novel analgesics, but new methods that are translationally and clinically relevant are necessary. This study aimed to assess spontaneous pain-like behavior of home cage activity and wheel running in Digital Ventilated Cages . Twenty BALB/cAnNHsd mice were housed in Digital Ventilated Cages from Tecniplast with GYM500 home cage running wheels. Ten mice underwent 4T1-Luc2 mammary gland adenocarcinoma cell inoculation into the right femur to establish CIBP and another ten mice underwent a sham procedure. Mice were assessed by limb use and static weight bearing to determine the development of CIBP and this was compared to the dark-phase home cage activity and wheel running in the Digital Ventilated Cages . The 4T1-Luc2-inoculated mice displayed pain-like behavior in limb-use and weight-bearing tests, demonstrating a preference for the contralateral limb. The limb-use scores were compared with home cage activity and wheel running. Reduced wheel running distance corresponded to reduced limb-use scores, with the shortest wheel running distances corresponding to the lowest scores. However, this behavioral pattern was not observed in home-cage activity, which remained consistent throughout the study. Wheel running behavior appears to be affected by the development of metastatic breast cancer. Wheel running in a Digital Ventilated Cage may be a useful behavioral assessment of spontaneous pain-like behavior of CIBP and may be useful to assess analgesic efficacy.

Background: The ways in which peripheral sensory nerves interact with osteosarcomas are important to understand because it could lead to development of new approaches to treat bone cancer pain. This study aimed to determine how cancer affects sensory nerve density and distribution in a murine model of osteosarcoma-induced bone pain. Methods: The femoral marrow cavities of male C3H/HeNHsd mice were injected with either NCTC 2472 primary osteosarcoma (cancer) cells or phosphate buffered saline (control). Pain behavior was assessed using limb use score and static weight bearing assays. At the experimental endpoint, femurs were collected, decalcified, immunolabeled, cleared and imaged using light sheet microscopy (Ultramicroscope Blaze, Miltenyi Biotec). The distribution of sensory nerves was traced through the marrow cavity of the proximal femur and the periosteum overlying the third trochanter (Imaris, Bitplane). Results: Weight bearing on the injected limb was decreased in osteosarcoma-injected but not saline-injected mice. Filament tracing revealed a reduced density of neurofilament 200 kDa-positive (NF200+; myelinated nerve marker) but not calcitonin gene-related peptide-positive (CGRP+; peptidergic nerve marker) sensory nerves in the marrow cavity of osteosarcoma-injected relative to saline-injected mice. There was increased density of CGRP+ but not NF200+ nerves in the periosteum of osteosarcoma-injected relative to saline-injected mice. Conclusions: Osteosarcoma differentially affects the density and distribution of different subtypes of peripheral sensory nerves in bone. Understanding how osteosarcomas affect different populations of sensory nerves could lead to more targeted mechanism-based treatments for bone cancer-induced pain.

Every year, as the collegiate basketball season comes to an end, many studentathletes are considering or have already decided to leave their current institution for another. Transferring has become popular in the collegiate realm of sports, as players search for playing time, a more suitable coach, or a program that will allow them to reach their highest potential on the court. Regardless of the reason, athletes are making moves hoping to find that the grass is greener on the other side. This is true amongst all National Collegiate Athletic Association athletes but probably most visible in Division I men's basketball. The national trend has taken over and greatly impacted collegiate programs across the country. Each university is expected to encourage student success in the classroom and provide a fair opportunity in their respective sports but at the same time, they want to give students the option to transfer when it makes sense for all parties. Rules are in place to discourage athletes from constantly switching schools and of course, the student must seek permission to leave their current institution but none of that seems to matter. The NCAA is seeing more movement amongst student-athletes than ever before and it is becoming increasingly more difficult to explain why. Are universities and institutions to blame for these inconsistencies? Maybe schools are failing to provide accurate information throughout the recruiting process or even making undeliverable promises to prospective student-athletes. Perhaps, the student didn't \"sign up\" for the time and effort commitment associated with representing an athletic program. Every situation is different and almost every student-athlete will encounter some sort of difficulty along the road to their degree but why are they are not willing to stick it out? Today, it seems much easier to go somewhere else than face whatever adversity lies ahead.

Cancer-induced bone pain (CIBP) due to metastatic breast cancer is common and debilitating. Effective, long-term treatment options have side effects that reduce patients’ quality of life. Preclinical models are a valuable tool to test novel analgesics, but new methods that are translationally and clinically relevant are necessary. This study aimed to assess spontaneous pain-like behaviour of home cage activity and wheel running in Digital Ventilated Cages®. Twenty BALB/cAnNHsd mice were housed in Digital Ventilated Cages® from Tecniplast® with GYM500 home cage running wheels. Mice were assessed by limb use analysis and static weight bearing to determine the development of CIBP and this was compared to the dark-phase home cage activity and wheel running in the Digital Ventilated Cages®. Ten mice underwent 4T1-Luc2 mammary gland adenocarcinoma cell inoculation into the right femur to establish CIBP and another ten mice underwent a sham surgical procedure. The 4T1-inoculated mice displayed pain-like behaviour in limb use and weight bearing tests, demonstrating a preference for the contralateral limb. The limb use scores were compared with home cage activity and wheel running. A reduced wheel running distance corresponded to reduced limb use scores, with the shortest wheel running distances corresponding to the lowest limb use scores. However, this behavioural pattern was not observed in home cage activity, which remained consistent over the study period. Reduced wheel running corresponded with reduced limb use scores. This suggests that wheel running behaviour is affected by the development of metastatic breast cancer. However, the home cage activity was not influenced by disease development. Digital Ventilated Cage® wheel running may be a useful behavioural assessment of spontaneous pain-like behaviour of CIBP and may be useful to assess analgesic efficacy.

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we develop and characterize a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assess its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2, (mPD5), self-assembles into core-shell micelles that provide favourable pharmacodynamic properties and relieves ongoing and evoked mechanical hypersensitivity, thermal hypersensitivity as well as anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt no side effects were associated with mPD5 administration, and it has no effect on acute nociception. Finally, neuropathic pain is relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceases after a few hours, repeated administration provides pain relief lasting up to 20 hours after the last injection.

Chronic pain is a complex, debilitating and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we develop and characterize a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assess its effects on chronic pain. The myristoylated myr-NPEG4-(HWLKV)2, (mPD5), self-assembles core-shell micelles that provide favourable pharmacodynamic properties and relieves ongoing and evoked mechanical hypersensitivity, thermal hypersensitivity as well as anxio-depressive symptoms in an inflammatory pain model following subcutaneous administration. Further, mPD5 dose-dependently relieves pain in two neuropathic pain models without affecting motor behaviour. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceased after a few hours repeated administration provided pain relief lasting up to 20 hrs after last injection.Competing Interest StatementThe lipidated dimeric peptides, their usage, and their extended utilization are disclosed in patent application WO2021/176094 currently being processed by patent authorities. KLM and ATS have ownership interest and are co-founders of Zyneyro, a company having exclusive license rights on the patent, which is owned by the University of Copenhagen, Denmark.