Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.

Irisin is a hormone-like myokine produced by the skeletal muscle in response to exercise. Upon its release into the circulation, it is involved in the browning process and thermogenesis, but recent evidence indicates that this myokine could also regulate the functions of osteoblasts, osteoclasts, and osteocytes. Most human studies have reported that serum irisin levels decrease with age and in conditions involving bone diseases, including both primary and secondary osteoporosis. However, it should be emphasized that recent findings have called into question the importance of circulating irisin, as well as the validity and reproducibility of current methods of irisin measurement. In this review, we summarize data pertaining to the role of irisin in the bone homeostasis of healthy children and adults, as well as in the context of primary and secondary osteoporosis. Additional research is required to address methodological issues, and functional studies are required to clarify whether muscle and bone damage per se affect circulating levels of irisin or whether the modulation of this myokine is caused by the inherent mechanisms of underlying diseases, such as genetic or inflammatory causes. These investigations would shed further light on the effects of irisin on bone homeostasis and bone disease.

Osteocytes are specialized bone cells that orchestrate skeletal remodeling. Senescent osteocytes are characterized by an activation of cyclin-dependent kinase inhibitor p16^Ink4a and have been implicated in the pathogenesis of several bone loss disorders. In this issue of the JCI, Farr et al. have now shown that systemic removal of senescent cells (termed senolysis) prevented age-related bone loss at the spine and femur and mitigated bone marrow adiposity through a robust effect on osteoblasts and osteoclasts, whereas cell-specific senolysis in osteocytes alone was only partially effective. Surprisingly, transplantation of senescent fibroblasts into the peritoneum of young mice caused host osteocyte senescence associated with bone loss. This refined concept of osteocyte senescence and the effects of remote senolysis may help to develop improved senolytic strategies against multisystem aging in bone and beyond.

Thyroid hormones (TH) are essential for skeletal development and adult bone homeostasis. Their bioavailability is determined by specific transporter proteins at the cell surface. The TH-specific transporter monocarboxylate transporter 8 (MCT8) was recently reported as a regulator of bone mass in mice. Given that high systemic triiodothyronine (T₃) levels in Mct8 knockout (KO) mice are still able to cause trabecular bone loss, alternative TH transporters must substitute for MCT8 function in bone. In this study, we analyzed the skeletal phenotypes of male Oatp1c1 KO and Mct10 KO mice, which are euthyroid, and male Mct8/Oatp1c1 and Mct8/Mct10 double KO mice, which have elevated circulating T₃ levels, to unravel the role of TH transport in bone. MicroCT analysis showed no significant trabecular bone changes in Oatp1c1 KO mice at 4 weeks and 16 weeks of age compared with wild-type littermate controls, whereas 16-week-old Mct8/Oatp1c1 double KO animals displayed trabecular bone loss. At 12 weeks, Mct10 KO mice, but not Mct8/Mct10 double KO mice, had decreased trabecular femoral bone volume with reduced osteoblast numbers. By contrast, lack of Mct10 in 24-week-old mice led to trabecular bone gain at the femur with increased osteoblast numbers and decreased osteoclast numbers whereas Mct8/Mct10 double KO did not alter bone mass. Neither Mct10 nor Mct8/Mct10 deletion affected vertebral bone structures at both ages. In vitro, osteoblast differentiation and activity were impaired by Mct10 and Mct8/Mct10-deficiency. These data demonstrate that MCT10, but not OATP1C1, is a site- and age-dependent regulator of bone mass and turnover in male mice.

Hyperthyroidism is a well-known trigger of high bone turnover that can lead to the development of secondary osteoporosis. Previously, we have shown that blocking bone morphogenetic protein (BMP) signaling systemically with BMPR1A-Fc can prevent bone loss in hyperthyroid mice. To distinguish between bone cell type-specific effects, conditional knockout mice lacking Bmpr1a in either osteoclast precursors (LysM-Cre) or osteoprogenitors (Osx-Cre) were rendered hyperthyroid and their bone microarchitecture, strength and turnover were analyzed. While hyperthyroidism in osteoclast precursor-specific Bmpr1a knockout mice accelerated bone resorption leading to bone loss just as in wildtype mice, osteoprogenitor-specific Bmpr1a deletion prevented an increase of bone resorption and thus osteoporosis with hyperthyroidism. In vitro, wildtype but not Bmpr1a-deficient osteoblasts responded to thyroid hormone (TH) treatment with increased differentiation and activity. Furthermore, we found an elevated Rankl/Opg ratio with TH excess in osteoblasts and bone tissue from wildtype mice, but not in Bmpr1a knockouts. In line, expression of osteoclast marker genes increased when osteoclasts were treated with supernatants from TH-stimulated wildtype osteoblasts, in contrast to Bmpr1a-deficient cells. In conclusion, we identified the osteoblastic BMP receptor BMPR1A as a main driver of osteoporosis in hyperthyroid mice promoting TH-induced osteoblast activity and potentially its coupling to high osteoclastic resorption.

Thyroid hormones (TH) are important modulators of bone remodeling and thus, thyroid diseases, in particular hyperthyroidism, are able to compromise bone quality and fracture resistance. TH actions on bone are mediated by the thyroid hormone receptors (TR) TRα1 and TRβ1, encoded by Thra and Thrb, respectively. Skeletal phenotypes of mice lacking Thra (Thra^0/0) and Thrb (Thrb^−/−) are well‐described and suggest that TRα1 is the predominant mediator of TH actions in bone. Considering that bone cells might be affected by systemic TH changes seen in these mutant mice, here we investigated the effects of TR knockout on osteoblasts exclusively at the cellular level. Primary osteoblasts obtained from Thra^0/0, Thrb^−/−, and respective wildtype (WT) mice were analyzed regarding their differentiation potential, activity and TH responsiveness in vitro. Thra, but not Thrb knockout promoted differentiation and activity of early, mature and late osteoblasts as compared to respective WT cells. Interestingly, while mineralization capacity and expression of osteoblast marker genes and TH target gene Klf9 was increased by TH in WT and Thra‐deficient osteoblasts, Thrb knockout mitigated the responsiveness of osteoblasts to short (48 h) and long term (10 d) TH treatment. Further, we found a low ratio of Rankl, a potent osteoclast stimulator, over osteoprotegerin, an osteoclast inhibitor, in Thrb‐deficient osteoblasts and in line, supernatants obtained from Thrb^−/− osteoblasts reduced numbers of primary osteoclasts in vitro. In accordance to the increased Rankl/Opg ratio in TH‐treated WT osteoblasts only, supernatants from these cells, but not from TH‐treated Thrb^−/− osteoblasts increased the expression of Trap and Ctsk in osteoclasts, suggesting that osteoclasts are indirectly stimulated by TH via TRβ1 in osteoblasts. In conclusion, our study shows that both Thra and Thrb differentially affect activity, differentiation and TH response of osteoblasts in vitro and emphasizes the importance of TRβ1 to mediate TH actions in bone.