Glucocorticoid (GC) induced osteoporosis (GIOP) and osteonecrosis remain a significant health issue with few approved therapies that can treat the bone loss and dysfunction of skeletal vasculature. Therefore, we aimed to investigate the cellular and molecular processes by which GCs affect osteogenesis and angiogenesis, as well as how treatment with parathyroid hormone (hPTH 1-34) modifies these effects in a mouse model of GIOP. GC treatment reduced bone mass through decreased bone formation by skeletal stem cells (SSCs) while also increasing osteoclast mediated resorption. Concomitantly, endothelial cells were increased in numbers but displayed distorted phenotypical features. However, hPTH treatment reversed GC induced changes in osteogenesis and angiogenesis to control levels. Transplantation studies of SSCs combined with molecular analysis by single cell RNA-sequencing and functional testing of primary human cells tied GC-induced skeletal changes to altered stem and progenitor cell differentiation dynamics. This in turn perpetuated reduced osteogenesis and vascular malformation through direct SSC-endothelial crosstalk mediated at least in part by Basigin. Intriguingly, antibody-mediated blockade of Basigin during GC treatment prevented detrimental bone loss. In addition, when administered to aged mice, anti-Basigin therapy reinstated bone remodeling to significantly improve bone mass independent of sex. These findings, while helping to explain the cellular and molecular basis of how hPTH treatment can mitigate GC induced bone loss, provide new therapeutic vantage points for GIOP and other conditions associated with bone loss.

The bone marrow (BM) niche is critical in regulating hematopoiesis, and sexual dimorphism and its underlying mechanism in the BM niche and its impact on hematopoiesis are not well understood. We show that male mice exhibited a higher abundance of leptin-receptor-expressing mesenchymal stromal cells (LepR-MSCs) compared with female mice. Sex-mismatched coculture and BM transplantation showed that the male BM niche provided superior support for in vitro colony formation and in vivo hematopoietic engraftment. The cotransplantation of male stromal cells significantly enhanced engraftment in female recipients. Single-cell RNA-seq revealed that the lower expression of the X-linked lysine H3K4 demethylase, Kdm5c, in male MSCs led to the increased expression of Cxcl12. In MSC-specific Kdm5c-KO mouse model, the reduction of KDM5C in female MSCs enhanced MSC quantity and function, ultimately improving engraftment to the male level. Kdm5c thus plays a role in driving sexual dimorphism in the BM niche and hematopoietic regeneration. Our study unveils a sex-dependent mechanism governing the BM niche regulation and its impact on hematopoietic engraftment. The finding offers potential implications for enhancing BM transplantation efficacy in clinical settings by harnessing the resource of male MSCs or targeting Kdm5c.

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.
© 2024. The Author(s).

Integrin affinity regulation, also termed integrin activation, is essential for metazoan life. Although talin and kindlin binding to the β-integrin cytoplasmic tail is indispensable for integrin activation, it is unknown how they achieve this function. By combining NMR, biochemistry and cell biology techniques, we found that talin and kindlin binding to the β-tail can induce a conformational change that increases talin affinity and decreases kindlin affinity toward it. We also discovered that this asymmetric affinity regulation is accompanied by a direct interaction between talin and kindlin, which promotes simultaneous binding of talin and kindlin to β-tails. Disrupting allosteric communication between the β-tail-binding sites of talin and kindlin or their direct interaction in cells severely compromised integrin functions. These data show how talin and kindlin cooperate to generate a small but critical population of ternary talin-β-integrin-kindlin complexes with high talin-integrin affinity and high dynamics.
© 2023. The Author(s).

The study of hip osteoarthritis (OA) was slowed due to a lack of a good definition of radiographic hip OA (RHOA). The radiographic changes that occur in hip OA include both joint space narrowing and femoral head osteophytes in the early stages of the disease. This differs from OA of the knee, in which radiographic OA changes initially include osteophytes and only much later is joint space narrowing considered. The modified Croft Score is a novel scoring method for the hip that includes an equal weighting of femoral osteophytes and joint space narrowing. It is used to evaluate the epidemiology of prevalent, incident, and progressive RHOA. Use of the Croft Score found that mild changes in the femoral head or acetabulum could increase the risk of incident RHOA. Pioneering research on active shape modeling was undertaken to provide a more comprehensive assessment of hip shape and define actual femoral head shapes that increased the risk of RHOA. After defining RHOA, investigators found several risk factors, which included higher total hip bone mineral density and polymorphisms of the wnt/β-catenin signaling pathway, to be significant predictors of RHOA in elderly white women. Recently, it was found that RHOA was a strong risk factor for both all-cause mortality and cardiovascular disease mortality in elderly women.
© The Author(s) 2023.