Life history theory predicts that when food intake and body reserves are insufficient to maintain all life processes, resource allocation trade-offs should occur. Lactation is costly and requires increased food intake. In spotted hyaenas, energy expenditure on lactation is high, particularly for mothers rearing twin litters, and foraging effort and food intake are influenced by social status. We investigated whether lactation in this species results in a reduction in resource allocation to immune processes sufficient to increase parasite infection. We expected higher parasite infection in lactating than non-lactating females, in mothers nursing twin than singleton litters, in females of lower than higher social status and in less than more experienced foragers. We quantified Ancylostoma egg load (AEL) and the presence of oocysts of Cystoisospora spp. as a proxy measure of immune function in 58 females. Lactating females were significantly more often infected with Ancylostoma, and their AEL was higher than in non-lactating females. Females nursing twins had significantly higher AELs than those nursing singletons. As social status increased, AELs significantly declined. This relationship was modulated by lactation status and litter size, being strongest in nonlactating females, moderate in females with twin litters and weakest in females with singleton litters. The decrease in AEL with increasing social status was greater for experienced than inexperienced females. Concurrent infection with Cystoisospora significantly increased with increasing AEL. Our results provide evidence for a resource allocation tradeoff in lactating spotted hyaenas.

Background Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. Method Bone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies. Findings WT mice with a femoral fracture display increased CGRP serum levels. αCGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, αCGRP-deficient mice display profoundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPARγ signaling plays a central role in fracture healing. Interpretation This study demonstrates an essential role of αCGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation. Funding This work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).

As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

Highlights CT levels are increased systemically during acute experimental RA CTR is primarily expressed in the superficial articular cartilage layer in CAIA In CAIA CTR-deficiency is associated with increased inflammation marker expression Bone architecture is impaired in experimental RA when CTR signaling is disrupted