Interpretation of “Kidneys Govern Bones” Theory Based on the αKlotho-FGF23-FGFRs Axis

INTRODUCTION In Western medicine, the kidneys are primarily understood as anatomical organs essential for maintaining the body’s balance of substances. However, in traditional Chinese medicine (TCM), the concept of the kidney is much broader. It encompasses not only the anatomical kidneys but also a range of functions related to tissues and organs, including reproduction, urination, the nervous system, and bones. In TCM, the kidneys are believed to store essence, govern water metabolism, support bone health, regulate breathing, influence hearing (opening into the ears), and control urination and defecation. As early as the Yellow Emperor’s Inner Classic, TCM established a connection between natural life processes, such as growth, development, reproduction, and aging, and skeletal health, all of which are believed to be governed by kidney essence. This connection is the basis for the theory that “the kidney stores essence and governs the bones”. Based on this theory, TCM practitioners have long focused on treating bone diseases, chronic conditions, and aging by tonifying the kidneys. Chronic kidney disease (CKD) is associated with a significantly high risk of cardiovascular mortality, partly due to vascular calcification (VC), which occurs in the context of CKD-related mineral and bone disorders (MBDs). As kidney function declines, patients experience severe disturbances in mineral balance, including phosphate retention, low calcium levels, and altered levels of αKlotho, fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and calcitriol.[1] Although many factors in the uremic state contribute to the development and progression of VC, dysregulated mineral and bone metabolism is believed to play a key role in the pathogenesis of VC in CKD patients. Longitudinal cohort studies have found an inverse correlation between bone mineral density (BMD) and VC, with VC progression often accompanied by greater bone loss.[2] However, the precise mechanistic link between these conditions remains poorly understood. MOLECULAR AXIS OF αKLOTHO-FGF23-FGFRS Kuro-o et al. serendipitously discovered that the homozygous progeny of a particular transgenic founder exhibited a complex ageing-like phenotype. They reasoned that the integration of the transgene into the founder mouse genome had disrupted a putative “ageing-suppressor” gene, which they named Klotho after the Greek goddess Clotho.[3] Several years later, they found that genetic variants in Klotho were associated with human aging, and the Klotho protein was identified as a circulating factor detectable in serum, with levels that decline with age.[3] There are three isoforms of Klotho: α, β, and γ. The αKlotho (Kl) isoform is predominantly expressed in the distal convoluted tubules of the kidneys. Structural biology studies revealed the crystal structure of the Kl protein, which includes both intracellular and extracellular domains, referred to as transmembrane Kl protein (mKl). Notably, mKl is cleaved by disintegrin and metalloprotease (ADAM10/17), releasing extracellular domains that enter the circulation as soluble Kl (sKl).[4] Research has shown that mKl binds to FGF receptor 1 (FGFR1) to form a Kl/FGFR1 binary complex, which binds to FGF23 to form the Kl/FGFR1/FGF23 ternary complex.[4] This complex regulates the production of 1,25(OH)2D3 and controls PTH release.[3,4] Additionally, sKl has wider biological effects on various organs and tissues throughout the body,[5] and it has been identified as a potent vascular protective factor in CKD animal models.[6] Structural biology studies have also found that sKl can act as a co-receptor, binding to FGF23/FGFR1 to form a ternary complex. Disruption of this crystal structure impairs FGF23 signaling, which leads to imbalances in calcium and phosphate homeostasis and various aging phenotypes such as VC.[4] In addition to the Kl-dependent role of FGF23, accumulating evidence suggests that it also has Kl-independent functions. FGF23 has been shown to induce left ventricular hypertrophy and uremic cardiomyopathy independently of Kl by activating calcineurin signaling and the FGFR4/PLCγ pathway.[7,8] Our recent study revealed that FGFR4 expression was abnormally increased in the thoracic aorta of mice with diabetic nephrology. In these mice, the absence of Kl was associated with increased expression of FGF23 and FGFR4, their binding, and the activation of PLCγ and calcineurin in the thoracic aorta. These findings suggest that the molecular axis of Kl-FGF23-FGFRs cooperatively regulates the fate of the kidney-bone-vasculature axis, influencing various interrelated systems. “Kidneys Govern Bones” and the αKlotho-FGF23-FGFRs Axis Clinical symptoms such as muscle weakness, osteoporosis, premature aging, and early death—resulting from kidney essence and kidney qi deficiency—closely mirror the phenotypic changes caused by defects in mKl and sKl, produced by the kidneys, as well as FGF23 secreted by the bones. This suggests that the kidneys’ role in regulating bones and controlling aging (including VC) is achieved through the reciprocal and synergistic signaling of the Kl-FGF23-FGFRs axis. In TCM, the vasculature can be viewed as an extension of the theory that “kidneys govern bones”. The concept of kidney essence aligns closely with the phenotypic expression of mKl in the kidneys, leading to the proposal that kidney essence may encompass the function of mKl. Similarly, kidney qi, which is derived from kidney essence and distributed throughout the body, resembles sKl, which is cleaved from the extracellular domain of mKl and circulates in the bloodstream. Thus, it can be hypothesized that kidney qi represents the function of sKl. In CKD, damage to the kidneys reduces kidney essence, which parallels the decreased expression of mKl. The decline in kidney function reduces Kl expression, which diminishes it response to bone-secreted FGF23. Additionally, the accumulation of turbid toxins can be understood as the failure of mKl to cooperate with FGFR1, preventing FGF23 from anchoring to renal tubular epithelial cells. Likewise, sKl is unable to interact with FGFR1 to bind FGF23 in the vasculature, resulting in off-target accumulation of FGF23 in the circulation [Figure 1].Figure 1.: The relationship between the TCM concept “kidneys govern bones”, the αKlotho-FGF23-FGFRs signaling pathway, and the role of Shen-Yuan granules in addressing the abnormal kidney-bone response in CKD. In CKD, insufficient kidney essence is analogous to reduced expression of mKl. This decline impairs the ability of the kidneys to regulate bone function, leading to. diminished Kl response to FGF23 secreted by the bones. mKl is unable to cooperate with FGFR1 to anchor FGF23 on renal tubular epithelial cells, and sKl cannot assist FGFR1 in binding FGF23 to the vasculature. This results in off-target accumulation of FGF23 in circulation. Shen-Yuan granules may provide a promising therapeutic strategy for addressing CKD-MBD and cardiovascular complications by upregulating renal Kl and serum sKl expression. CKD, chronic kidney disease; mKl, transmembrane Klotho; FGF23, fibroblast growth factor 23; Kl, αKlotho; sKl, soluble Klotho; FGFR1, fibroblast growth factor receptor 1; CKD-MBD, chronic kidney disease-mineral and bone disorders; TCM, traditional Chinese medicine. We used polymerase chain reaction (PCR) direct sequencing to detect the Kl-G-395A single nucleotide polymorphism (SNP) in 67 patients with diabetic kidney disease (DKD) . The results indicated that the GA and AA genotypes are susceptibility markers for DKD, and the A allele is significantly associated with spleen-kidney yang deficiency syndrome.[9] Furthermore, we found that spleen-kidney yang deficiency syndrome is an independent risk factor for secondary hyperparathyroidism in CKD patients undergoing maintenance hemodialysis. These studies suggest that the theory of kidneys governing bones is related to the phenotype of the Kl-FGF23-FGFRs Axis.[10] The TCM approach to treating CKD focuses on tonifying the kidneys and draining turbidity. The formulation of Shenyuan granules embodies this concept. This hospital preparation, which has been used for at least 20 years to treat CKD, includes Astragalus membranaceus (Huangqi), Epimedium brevicornum (Yinyanghuo), and wine-processed Rheum palmatum (Jiu Zhi Dahuang) . The formulation strengthens the spleen and kidneys while also dispelling stasis and resolving turbidity. Our studies confirmed that Shen-Yuan granules improve renal function, attenuate bone damage, and reduce VC in a mouse model of diabetic nephropathy. Mechanistically, Shen-Yuan granules may upregulate renal Kl and serum sKl expression, downregulate skeletal FGF23 secretion, and inhibit the vascular FGFR4 response to FGF23 [Figure 1].[11-14] These findings indicate that Chinese herbal medicine can effectively delay renal failure and improve calcium-phosphate metabolism, renal osteodystrophy, and VC. CONCLUSION The Kl-FGF23-FGFRs signaling pathway has provided valuable insights into the scientific foundation of the TCM theory that kidneys govern bones. This understanding has enhanced our knowledge of the prognosis for CKD patients. Chinese herbal medicines, such as Shen-Yuan granules, demonstrate therapeutic potential in treating kidney damage, renal osteodystrophy, and VC, partly through the regulation of the Kl-FGF23-FGFRs signaling pathway. However, despite this progress, cardiovascular disease (CVD) complications remain the leading causes of morbidity and mortality in CKD. Current strategies, such as blocking the renin-angiotensin system (RAS), using sodium-glucose transporter (SGLT) -2, or targeting the mineralocorticoid receptor (MR), can only delay the onset of ESRD and often cause serious side effects. Renewed exploration of TCM theories, herbal formulations, and their active ingredients may lead to innovative treatments for CKD. Integrative medicine not only has the potential to improve kidney function and alleviate CVD complications but also promises to combine Eastern and Western approaches, facilitating the discovery of novel approaches to prevent and treat aging-related diseases.