Calcified Tissue International

, Volume 100, Issue 5, pp 486–499 | Cite as

The Activity of Adiponectin in Bone

  • Dorit NaotEmail author
  • David S. Musson
  • Jillian Cornish
Original Research


The adipokine adiponectin affects multiple target tissues and plays important roles in glucose metabolism and whole-body energy homeostasis. Circulating adiponectin levels in obese people are lower than in non-obese, and increased serum adiponectin is associated with weight loss. Numerous clinical studies have established that fat mass is positively related to bone mass, a relationship that is maintained by communication between the two tissues through hormones and cytokines. Since adiponectin levels inversely correspond to fat mass, its bone effects and its potential contribution to the relationship between fat and bone have been investigated. In clinical observational studies, adiponectin was found to be negatively associated with bone mineral density, suggesting it might be a negative regulator of bone metabolism. In order to identify the mechanisms that underlie the activity of adiponectin in bone, a large number of laboratory studies in vitro and in animal models of mice over-expressing or deficient of adiponectin have been carried out. Results of these studies are not entirely congruent, partly due to variation among experimental systems and partly due to the complex nature of adiponectin signaling, which involves a combination of multiple direct and indirect mechanisms.


Adiponectin Adipokine Bone Fat 


Adiponectin was discovered two decades ago as a secreted protein produced almost exclusively by adipocytes [1]. In a cDNA library from human adipose tissue, adiponectin was the most abundant transcript [2] and later studies have shown that adiponectin levels in the circulation are in the range of µg/mL—much higher than the circulating levels of similar hormones and cytokines [3]. Concentrations of circulating adiponectin in obese people are significantly lower than in non-obese, and increase in serum adiponectin is associated with weight loss [4, 5]. This finding, which has since been reproduced and confirmed in numerous studies in rodents and humans, appears paradoxical, as the levels of this adipose tissue-secreted factor inversely relate to adipose tissue mass.

Human adiponectin is a protein of 244 amino acids, with an N-terminal signaling sequence, a hypervariable region, a collagenous domain and a globular domain, which has high level of similarity to complement factor C1q [1]. When initially characterized under reducing conditions, adiponectin was described as a 30 kDa protein, but later studies found circulating adiponectin in complex forms of either trimers, hexamers or high molecular weight complexes of 12–18 units [6, 7]. The specific complex and the ratio among the different multimeric forms affect the downstream activities of adiponectin [7].

Adiponectin binds to two seven-transmembrane domain receptors, AdipoR1 and AdipoR2, which share 67% identity at the protein level [8]. The high affinity receptor AdipoR1 is ubiquitously expressed, whereas AdipoR2 binds adiponectin with lower affinity and its expression is mainly restricted to the liver. An important mediator of the downstream intracellular effects of adiponectin following receptor-ligand binding is adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) [9]. APPL1 is a key mediator in adiponectin’s effects on energy homeostasis. A third adiponectin receptor is T-cadherin, which is highly expressed in endothelial and smooth muscle cells, and specifically binds the higher molecular weight complexes of adiponectin [10].

Numerous studies investigated the biological activities of adiponectin, and a large number of target tissues have been identified [11]. Metabolic regulation and maintenance of whole-body energy homeostasis are considered the main physiological roles of adiponectin, and it is generally accepted that the primary target organs of adiponectin are the liver and skeletal muscle [12]. Other major physiological activities of adiponectin include anti-inflammatory and anti-apoptotic effects [13, 14]. Early evidence for the activity of adiponectin to promote insulin sensitivity came from a study in genetically obese and diet-induced obese mice [15]. In these mice, which had reduced levels of circulating adiponectin compared to wild-type (WT) controls, administration of adiponectin improved insulin sensitivity by increasing β-oxidation in skeletal muscle and suppressing lipid accumulation in the liver. In another study, injection of adiponectin into diabetic mice decreased blood glucose and transiently eliminated hyperglycemia without changing insulin levels [16]. The main underlying mechanism in this model system was suppression of gluconeogenesis in the liver. There are conflicting reports about the effect of adiponectin on insulin secretion from β-islet cells, with some studies showing enhanced insulin secretion while others show no effect [17, 18].

In humans, circulating adiponectin levels are negatively related to insulin resistance, body weight, blood pressure and serum lipids [11, 18, 19]. Serum adiponectin is low in obese, insulin-resistant subjects, and its levels are elevated under calorie restriction [20] and in patients with anorexia nervosa [21, 22]. An interesting development in the understanding of adiponectin levels and energy homeostasis, and a possible solution to the apparent paradox of the inverse relationship between adiponectin levels and fat mass was presented in a recent study [23]. The study found that in states of leanness, when white adipose tissue is reduced while marrow adipose tissue expands, bone marrow adipocytes function as the major source of circulating adiponectin. Thus, a positive relationship exists between increased marrow fat and higher circulating levels of adiponectin [23].

Positive association exists between fat and bone mass, and low body weight is a major risk factor for low bone mineral density (BMD) and fracture [24]. The coupling between fat and bone mass results not only from the direct response of the skeleton to mechanical loading by soft tissue, but also from communication between fat and bone through hormones and cytokines. Several early observations suggested that adiponectin might be one of the mediators of the fat-bone relationship: an inverse correlation was determined between circulating adiponectin concentrations and BMD [25], and AdipoR1 and AdipoR2 were found to be expressed in primary human osteoblasts [26, 27] and in bone marrow macrophages stimulated to differentiate to osteoclasts [28]. The effect of adiponectin on bone metabolism has since been studied extensively in various experimental systems. The current review aims to highlight the main findings in the field and to examine how close we are to understanding the physiological role of adiponectin in bone.

Adiponectin Bone Activity: Clinical Observations

Clinical studies assessing the effects of adiponectin in bone are mostly cross-sectional, although a number of longitudinal studies have also been conducted. In many of these studies, the circulating levels of a multiple adipokines were measured, most commonly including leptin, and bone and fat parameters were determined. When interpreting clinical studies relating adiponectin circulating levels to bone, it is important to bear in mind that these only capture the endocrine effects of adiponectin, while results from in vitro and animal studies strongly indicate that adiponectin activity in bone also includes paracrine and perhaps even autocrine mechanisms. In addition, given the multifactorial nature of the relationship between fat and bone tissue, the studies of adiponectin levels association with bone phenotype require adjustments to a substantial number of potential confounders including age, body mass index, fat mass and others.

A large number of studies relating adiponectin circulating levels to bone parameters in different populations have been published [29]. Although there is variability in the specific details, in general, the studies suggest that adiponectin circulating levels are inversely related to BMD. Data from a number of large population studies used to analyze the relationship between adiponectin levels, BMD and fracture risk are discussed below.

In a total of 1735 women recruited from the population-based cohort TwinsUK adult twin registry, Richards et al. [30] found that each doubling of serum adiponectin was associated with a mean 2.7% decrease in BMD. The relationship persisted, although decreased in magnitude, after adjustment to a number of potential confounding factors including BMI, serum leptin and central fat mass. Since adiponectin levels were inversely related to BMD even in non-load bearing sites, the authors suggest that adiponectin affects bone metabolism independent of mechanical loading [30]. In another large study, the adiponectin levels and BMD were measured in the Uppsala Seniors cohort of 441 men and 457 women aged 70 years, and in participants of the Uppsala Longitudinal Study of Adult Men, who had 314 fractures documented during a 15-year follow-up [31]. The study found negative association between adiponectin levels and BMD in the two cohorts, but adiponectin was not associated with fracture risk [31]. Using data from a community-based longitudinal study (the Rancho Bernardo study), Araneta et al. [32] analyzed the prospective association between adiponectin and BMD, bone loss, and fractures. The study collected baseline measurements from 447 postmenopausal women and 484 men, and BMD was measured again 4 and 8 years later, with approximately half of the participants included at the last time point. The study found that baseline adiponectin was inversely associated with BMD in a number of the sites measured in both women and men and was inversely associated with vertebral fracture among men only. However, adiponectin was not associated with bone loss that occurred over the initial 4-year period in either sex [32]. In a study of 231 men and 170 post-menopausal women with type 2 diabetes, Kanazawa et al. [33] found that in men only, adiponectin levels were negatively correlated to BMD at several skeletal sites, while a positive correlation was found with the urinary marker of bone resorption, N-terminal telopeptide (NTX). In men, circulating adiponectin was also inversely associated with vertebral fractures. In the InCHIANTI study, conducted in Italy and designed to investigate factors contributing to the decline of mobility in older persons, peripheral quantitative computed tomography (pQCT) was used to determine BMD [34]. In this study population of 320 men and 271 postmenopausal women, adiponectin was not independently associated with BMD in men, but in postmenopausal women adiponectin was inversely associated with total, trabecular and cortical BMD. The largest prospective cohort study included 3075 women and men aged 70–79 years (the Health Aging and Body Composition study) and documented 406 fracture incidents [35]. Analysis of the association between baseline serum adiponectin and fracture risk in this cohort found that men with the highest adiponectin level (tertile 3) had a 94% increased risk of fracture compared with the lowest tertile. The increased risk was independent of potential confounders including BMI and BMD, and the authors conclude that adiponectin may be a risk factor for increased fracture risk in men, independent of body composition and BMD [35]. The association between adiponectin and fracture was not present in women. The association of baseline serum adiponectin with rates of BMD change was also assessed in the same study population, using data of hip and whole-body areal BMD that were measured five times over a 10-year period, and trabecular lumbar spine volumetric BMD measured in a subgroup of the cohort [36]. The study found that in women, higher adiponectin levels predicted a greater areal BMD loss at the hip only, whereas in men there was no association between adiponectin levels and rate of bone loss.

In 2011, a systemic review and meta-analysis was published of the influence of four adipokines: adiponectin, leptin, resistin and visfatin and the hormone ghrelin, on BMD and fracture risk in healthy men and women [37]. The 59 studies included in the meta-analysis had a combined sample size of 10,451 patients and were mostly cross-sectional with only three longitudinal studies. Inverse correlation was found consistently between circulating adiponectin and BMD at the lumbar spine, total hip and total body in postmenopausal women and in men. After adjusting adipokines for fat-related parameters, adiponectin was the only factor that was correlated to BMD. The authors conclude that ‘adiponectin is the most relevant adipokine negatively associated with BMD, independent of gender and menopausal status’ [37]. Leptin was positively correlated to BMD, particularly in postmenopausal women, but this finding was likely confounded with fat mass parameters. Resistin, visfatin and ghrelin were not associated with BMD or fracture.

Thus, as presented in the summary diagram in Fig. 1, clinical studies consistently find inverse association between serum adiponectin levels and BMD, an association that persists after adjusting for multiple potential confounding factors. Three out of the four studies that determined fracture risk found that circulating adiponectin is positively correlated with an increased risk of fracture in men only [32, 33, 35]. This finding suggests that the effect of adiponectin in bone is sex-dependent, and that in men, adiponectin could be a novel risk factor for increased fracture risk, independent of body composition and BMD.

Adiponectin Effects on Bone Phenotype in Animal Models

Studies in Mice Over-Expressing Adiponectin

In one of the early animal studies of the bone effect of adiponectin, mice were infected with an adenoviral adiponectin construct [38]. In this model, adiponectin over-expression was transient, lasting approximately 2 weeks, and had no effects on circulating insulin and glucose levels. Using microcomputed tomography (microCT), the authors found increased fractional volume in the trabecular bone of mice over-expressing adiponectin in comparison with controls, whereas no differences were found in the cortical bone. Decrease in the circulating level of NTX and in the number of osteoclasts identified by histology suggested that the increase in bone volume fraction in mice over-expressing adiponectin was mainly due the inhibition of bone resorption. Further studies in vitro supported this mechanism, as adiponectin inhibited osteoclast formation and activity in mouse bone marrow cultures and in mononuclear cultures from humans [38].

A number of studies examined the bone phenotype of transgenic mice over-expressing adiponectin (APN-Tg) in the liver. BMD measurements, bone histology and histomorphometry of 8-week-old male mice over-expressing mouse globular adiponectin found no differences between transgenic mice and controls [28]. The authors concluded that neither bone mass nor bone turnover is affected by increase in circulating adiponectin. In contrast, a study of 12-week-old males of two different lines of APN-Tg mice over-expressing human full-length adiponectin in the liver found a small increase in femoral BMD [39]. Circulating bone turnover markers and histomorphometric analysis of the tibia in this study found elevated osteocalcin, osteoblast surface and osteoid surface, whereas bone resorption parameters did not differ between APN-Tg mice and controls.

Another APN-Tg mouse was generated by introducing a dominant, gain-of-function mutant allele of the murine adiponectin gene carrying a deletion of the collagenous domain [40]. In this model system, adiponectin levels are chronically elevated, although they remain within the physiological range. Insulin sensitivity was greatly improved in this APN-Tg mouse model in comparison with control [40]. The bone phenotype of these APN-Tg mice was studied in females and males at 8 and 16 weeks of age [41]. Female APN-Tg mice had lower femur bone mineral content (BMC) and inferior mechanical properties in the femur and vertebra in comparison with controls, whereas the bone phenotype of males was less consistent [41]. The study demonstrated inverse relationship between adiponectin levels and femur BMC. Another, more recent study, investigated the bone phenotype of 12-week-old male and female mice of the same APN-Tg strain [42]. Similar to the previous study, changes in bone phenotype were found mostly in female mice. There were no major changes identified in the expression levels of osteoblastic marker genes in RNA extracted from tibia. However, microCT analysis determined reduced fractional bone volume and cortical thickness in the proximal tibia of the APN-Tg females, and dynamic histomorphometry showed that APN-Tg females had decreased mineral apposition rate and bone formation rate, and increased numbers of adipocytes were seen in the tibia marrow of the APN-Tg female mice. As all these changes were restricted to the tibia and not seen in the femur, the authors suggest a local, site-specific effect of adiponectin in bone [42]. Table 1 presents the main bone effects identified in studies of mice overexpressing adiponectin.
Table 1

Animal models

(a) Animal models of adiponectin over-expression


Experimental system

Bone phenotype—main observations

Main conclusions

Oshima et al. [38]

Mice were injected with an adenoviral adiponectin construct

Age 8 weeks

Bone phenotype was analyzed 14 days after the injection


Trabecular bone—increased fractional volume in mice over-expressing adiponectin

No differences were found in cortical bone


Decreased number of osteoclasts

Adiponectin has a positive effect on bone through the inhibition of resorption

Shinoda et al. [28]

Male APN-Tg mice over-expressing mouse globular adiponectin in the liver

Age 8 weeks


No differences in BMD between transgenic mice and controls


No differences between transgenic mice and controls

No bone abnormality, possibly due to opposing actions of local and systemic effects

Mitsui et al. [39]

Male APN-Tg over-expressing human full-length adiponectin in the liver

Age 12 weeks


BMC and BMD of femur were slightly higher in APN-Tg


Bone volume was significantly higher in tibiae in APN-Tg mice. Increase in bone formation, no effect on bone resorption

Adiponectin has a positive effect on bone formation, but no effect on bone resorption

Ealey et al. [41]

Female and male APN-Tg with a dominant mutation that results in increased levels of circulating adiponectin

Age 8 and 16 weeks


Females—Lower BMC/BMD in APN-Tg mice, only in some of the sites measured

Males—lower BMD in APN-Tg, less consistent

biomechanical testing

Lower peak load in some of the sites, most consistent in females, in femoral neck and LV3.

Inverse relationship between serum adiponectin and femur BMC

Adiponectin has a negative effect on bone

Abbott et al. [42]

Female and male APN-Tg with a dominant mutation that results in increased levels of circulating adiponectin

Age 12 weeks

Shorter tibia in APN-Tg mice


Decrease in fractional bone volume in APN-Tg in proximal tibia

No changes in distal femur


Decrease in bone formation in proximal tibia

Adiponectin has a local negative effect in the tibia due to inhibition of bone formation

(b) Animal models of adiponectin deficiency


Experimental system

Bone phenotype—main observations

Main conclusions

Shinoda et al. [28]

Male APN-KO mice

Age 8 weeks


No differences in BMD between APN-KO mice and controls


No differences between APN-KO mice and controls

No bone abnormality

Possibly due to opposing actions of local and systemic effects

Williams et al. [43]

Male APN-KO mice

Ages 8–22 weeks


Trabecular bone volume and trabecular number increased at 14 weeks in KO proximal tibia

Biomechanical testing

Lower bone fragility in femur of APN-KO at 14 weeks

Adiponectin deficiency has an age-specific positive effect in bone

Naot et al. [45]

Female APN-KO mice

Ages 8–37 weeks


Decreased whole-skeleton BMD in APN-KO mice


Reduced cortical area fraction and thickness in femur of APN-KO mice in all the age groups

Reduced trabecular bone volume fraction only in young APN-KO mice

Biomechanical testing

No major differences in bone fragility and material properties

Adiponectin deficiency has a mild negative effect in bone

Kajimura et al. [46]

Male and female APN-KO mice and several other genetically modified strains

Ages 6–36 weeks

microCT and histomorphometry

At 6 and 12 weeks—high bone mass in axial and appendicular skeleton in trabecular and cortical bone, due to an increase in bone formation

At 36 weeks—severe low bone mass affecting all skeletal elements, due to decrease in bone formation and increase in bone resorption

The bone effects of adiponectin are age-dependent

At a young age, local positive bone effects of adiponectin are dominant. At an older age, central negative bone effects of adiponectin are dominant

Wang et al. [47]

Male APN-KO mice

Ages 12 weeks


Higher bone volume fraction, BMD, trabecular thickness and number in APN-KO mice


Fewer osteoclasts in APN-KO

Adiponectin has a negative effect in bone, acting through the OPG/RANKL pathway

Wu et al. [44]


Age 4–8 weeks


Decreased trabecular bone in distal femur of APN-KO

Adiponectin has positive bone effects—decreases bone resorption through central and peripheral mechanisms, and increases osteoblast commitment through a central mechanism


Intracerebroventricular administration of adiponectin

microCT and immunohistochemistry

Centrally administered adiponectin increased the fractional volume of trabecular bone in KO and WT

Central and peripheral adiponectin reduced osteoclasts numbers. Central administration increased osteoblast commitment of BMSC and bone trabecular mass and volume


Tu et al. [48]

Femur explants from 3-day-old mice were transplanted into WT and APN-KO mice, and analyzed 4 weeks later

In vivo imaging

The bone explants had a much slower growth rate in the APN-KO mice


Bones explanted in APN-KO mice had reduced trabecular bone volume and cortical bone thickness


Increased number of osteoclasts in bone explanted in APN-KO mice

Adiponectin has a positive effect in bone through the inhibition of osteoclast formation and bone resorption

Wang et al. [49]

Female WT and APN-KO mice 6-8 weeks of age underwent OVX or sham operations. Bone properties were analyzed 10 weeks after surgery


No difference in BMD between WT and APN-KO mice

After surgery—in WT, OVX mice had reduced BMD in comparison with WT sham, while APN-KO had no differences in BMD between OVX and sham


APN-KO had increased osteoclast numbers in comparison with WT

WT—decrease in bone area and increase in osteoclasts in OVX versus sham, in APN-KO there were no differences between OVX and sham

Biomechanical testing

No difference between WT and APN-KO

In WT, bone strength was reduced in OVX compared to sham, while in APN-KO there was no difference between OVX and sham

Adiponectin reduces osteoclast numbers but has no effect on BMD

Adiponectin deficiency protects against OVX-induced bone loss

Yu et al. [50]

Calvarial bone defect surgeries were performed on 12- to 14-week-old WT, APN-KO, and DIO mice. A micro-osmotic pump was inserted subcutaneously for daily delivery of adiponectin or vehicle control

Bone regeneration in the calvarial defect region was analyzed by histomorphometry

No differences were found in bone healing between WT and APN-KO, but systemic infusion of adiponectin increased the percentage of newly formed bone, through facilitating cell migration from BMSC

Adiponectin has a positive effect on bone healing by increasing BMSC migration in response to bone injury

APN-KO adiponectin-knockout, APN-Tg adiponectin transgenic, BMC, bone mineral content, BMD bone mineral density, BMSC bone marrow stem cells, DIO diet-induced obese, DXA dual-energy X-ray absorptiometry, LV3 lumbar vertebra 3, microCT microcomputed tomography, OVX ovariectomized, WT wild-type

Studies in Adiponectin-Knockout Mice

Adiponectin deficiency had no effect or only mild effects on bone phenotype in a number of studies. Comparison of long bones and vertebrae between 8-week-old APN-KO mice and littermate controls found no significant differences in BMD and other bone indices [28], while another study found mild positive effect of adiponectin deficiency on bone phenotype of male mice at 14-weeks of age [43]. Mild negative effects of adiponectin deficiency have been identified by a number of groups. In one such study, APN-KO mice had decreased fractional volume of trabecular bone, lower mineralization and increased bone marrow adiposity compared to the control mice [44]. In a recent study, microCT analysis of mice of different ages between 8 and 37 weeks identified reduced cortical area fraction and average cortical thickness in female APN-KO mice in comparison with age-matched controls in all the age groups, and reduced trabecular bone volume fraction only in young APN-KO mice [45]. No significant differences were found in bone strength and material properties between APN-KO mice and their controls.

A number of studies of APN-KO mice specifically focused on the differentiation between the local bone effects of adiponectin and its central effects through the nervous system. Previously, the adipokine leptin, which had been studied extensively for its bone effects, was found to affect bone through a combination of local and central mechanisms of action [24]. Thus, leptin acts directly on osteoblasts and osteoclasts with a combined effect of increasing skeletal mass, whereas through the central nervous system leptin has the opposite effect of inhibiting bone formation and stimulating resorption. Similar to leptin, adiponectin appears to be playing a dual role in the regulation of bone mass [46]. In contrast to the majority of the in vitro studies that have previously shown a positive effect of adiponectin on osteoblast proliferation, in this study adiponectin directly inhibited osteoblast proliferation, induced osteoblast apoptosis and promoted bone resorption through increased expression of receptor activator of nuclear factor kappa-B ligand (RANKL). The direct osteoblast activities identified here were not mediated by the AdipoR1/R2 receptors and involved the inhibitions of FoxO1 signaling. Acting centrally in the brain, adiponectin reduced energy expenditure through decrease in the sympathetic tone. In agreement with previous studies, which demonstrated that the sympathetic nervous system inhibits bone formation and favors bone resorption, the decrease in sympathetic tone by adiponectin produced an increase in bone mass. The study by Kajimura et al. [46] found that while the local effects are dominant in young mice, in the older animals the systemic effects become more prominent and thus APN-KO mice have higher bone mass in young age and lower bone mass in older age compared to controls. The analysis of the bone of 12-week-old males by a different group found similar phenotype to the one described by Kajimura et al. for the young animals [47]. In this study microCT analysis found that APN-KO mice had higher BMD, greater bone volume fraction and greater trabecular thickness in the femur in comparison with control mice [47]. Osteoblasts cultured from the APN-KO mice expressed lower levels of RANKL and higher levels of osteoprotegerin (OPG) than WT mice, a change that might explain the lower numbers of osteoclasts and the lower levels of circulating bone resorption markers found in the APN-KO mice. Intracerebroventricular infusion of adiponectin in APN-KO and WT mice was also used to differentiate between the local effect of adiponectin on bone and its centrally mediated activity, as in this model system only negligible amounts of the infused adiponectin reach the circulation [44]. Similar to the previously described study, centrally administered adiponectin decreased sympathetic tone and produced increase in fractional volume of trabecular bone in both WT and APN-KO mice. Adiponectin infusion increased the expression of osteoblast markers and decreased the number of osteoclasts [44]. In contrast to the previous study [46], this study suggested that while the local effect of adiponectin on osteoblasts may oppose its central effect, adiponectin’s effects on osteoclasts and bone resorption are similar regardless of the site of action. Central adiponectin decreased osteoclasts and bone resorption through inhibition of RANKL expression, while peripheral adiponectin directly inhibited osteoclast differentiation using a mechanism that involved binding of the receptors expressed on osteoclast precursors [44].

One of the challenges of knockout animal studies is the adaption and compensation mechanisms that can sometimes mask the initial effect of the deficiency and lead to mistaken conclusions about the physiological role of the absent protein. An interesting approach aimed to overcome these challenges was used by Tu et al. [48] who used femur explants from 3-day-old mice that were transplanted into APN-KO and WT controls and studied the effect of a transient exposure to adiponectin deficiency on bone growth and metabolism. The growth of bone explants was significantly retarded in the APN-KO mice in comparison with WT controls. MicroCT and histological analyses of the explants showed that in the APN-KO mice trabecular bone volume and cortical bone indices were reduced, while osteoclast numbers were increased, suggesting that adiponectin inhibits osteoclast formation and bone resorption. Further in vitro analysis using RAW264.7 cells confirmed that adiponectin inhibits RANKL-induced osteoclastogenesis.

The possible involvement of adiponectin in estrogen deficiency-induced bone loss was studied by comparing the phenotype of ovariectomized (OVX) APN-KO and WT mice [49]. In contrast to WT mice, which had significant bone loss in femurs and vertebrae and an increase in the number of osteoclasts as a result of the estrogen deficiency, OVX APN-KO mice had similar bone properties to the sham controls, suggesting that in this model adiponectin deficiency protects against bone loss.

As mentioned above, Yu et al. [50] studied the effect of adiponectin deficiency on the bone marrow niche and on cell mobilizations from the bone marrow in response to bone injury. Bone marrow of APN-KO mice contained a higher number of adipocytes, although the number of mesenchymal stem cells appeared similar to WT controls. Adiponectin facilitated mesenchymal stem cells migration into the circulation, through regulation of the expression of SDF-1. Although SDF-1-mediated chemotaxis is well established and has been implicated in recruitment of cells into fracture sites, the activation of Smad1/5/8 signaling downstream of adiponectin binding to AdipoR1 is novel. In a calvaria defect model, there were no differences in bone healing between WT and APN-KO mice, but systemic infusion of adiponectin increased the percentage of newly formed bone [50]. Table 1 presents the main bone effects identified in studies of adiponectin-deficient mice.

Inconsistency of Adiponectin Bone Effects in Pre-clinical Studies

Animal studies of the effects of adiponectin in bone produced inconsistent results (summary diagram, Fig. 1). Clearly, the inconsistency can be explained by the use of different mouse strains, gender, age, skeletal sites analyzed and other variables (Table 1). However, if the activity of adiponectin depends on these parameters, the generalizability of the models comes into question, and with it the ability to make meaningful inference from the animal studies to human physiology. Alternatively, it is possible that not all the observations are reliable, and the potential influence of publication bias should also be taken into account.

Although it seems logical to consider animal models that produced results consistent with those observed in humans as ‘good models,’ it appears wrong to ignore scientifically sound studies that produced conflicting results. As discussed above, clinical studies find an inverse relationship between circulating adiponectin and BMD. However, some of the mechanisms determined in animal models that seem inconsistent with this observation might be contributing to the local activities of adiponectin, or operating within complex, multifactorial physiological networks that are either not reflected in the clinical association studies or masked by confounders. Furthermore, not all findings that are consistent with the clinical observations are necessarily relevant to humans. Since causal relationship between adiponectin and bone properties cannot be easily established in humans, results from all scientifically sound studies in different experimental systems might be necessary to understand the true effects of adiponectin in bone.

Adiponectin Activity in Bone Cells

Primary cells and cell lines of osteoblastic and osteoclastic lineages have been used to study the effects of adiponectin in bone and to investigate the signaling pathways that mediate these effects. Low levels of adiponectin were found to be expressed in both osteoblastic and osteoclastic cells, suggesting a contribution of autocrine/paracrine mechanisms of action in addition to the endocrine activity of adipocyte-secreted adiponectin in bone [26, 28]. It is important to note that adiponectin binds lipopolysaccharide (LPS) [51] and that most commercially available preparations of adiponectin appear to be contaminated with LPS [52, 53]. Thus, studies of adiponectin that do not include appropriate controls for the specificity of the effects could be measuring the combined activity of adiponectin and LPS in the experimental system. Most of the studies referred to below included controls for the specificity of the measured effects to adiponectin.

The Activity of Adiponectin in Osteoblast-Like Cells

The Effect of Adiponectin on Proliferation and Induction of Signaling Pathways in Osteoblasts

Stimulation of osteoblast proliferation by adiponectin was determined in MC3T3-E1 cells and in primary rat and human osteoblasts [26, 27, 43, 54]. The proliferative effect in osteoblasts is mediated via AdipoR1 and requires the activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) [27, 54]. Activation of p38-MAPK and JNK by adiponectin has been determined in numerous other cell types and tissues, although the effect of these signaling molecules on cell proliferation depends on cellular context [55]. Suppression of AdipoR1 with small-interfering RNA (siRNA) abolished the activation of these signaling pathways and the stimulation of osteoblast proliferation [27, 54]. The loss of adiponectin proliferative effect by suppression of AdipoR1 indicates that the activity measured was that of adiponectin itself and not of contaminating LPS. An additional signaling pathway activated by adiponectin was identified in MC3T3-E1 cells, where binding of adiponectin to AdipoR1 induced the phosphorylation and nuclear localization of Smad1/5/8 and increased the expression of stromal cell-derived factor-1 (SDF-1) [50]. The specificity of the effect to adiponectin is suggested by co-immunoprecipitation experiments that showed direct interactions between AdipoR1 and Smad1/5/8 in untreated cells and a decreased interaction in adiponectin-treated cells, with the nuclear translocation of Smad1/5/8. In contrast to the studies described above, adiponectin was found to inhibit proliferation of osteoblast progenitor cells and induce their apoptosis [46]. Although the reasons for these conflicting results are not clear, it is interesting to note that the authors found that the inhibitory effect was independent of all known adiponectin receptors (AdipoR1, AdipoR2 and T-cadherin) and was dependent on FoxO1 activity. The fact that these results were in agreement with the authors’ observations in their in vivo models, as discussed above, indicates that the effect was likely to be specific to adiponectin.

The Effect of Adiponectin on Mesenchymal Progenitor Cell Mobilization and Commitment to the Osteoblastic Lineage

In mouse bone marrow mesenchymal cells and in the C3H10T1/2 mesenchymal progenitor cell line, adiponectin increased commitment and differentiation of cells toward the osteoblastic linage, as shown by alkaline phosphatase staining and the increase in expression of several osteogenic marker genes [56]. Adiponectin binding to AdipoR1 activated cyclooxygenase-2 (COX2), and bone morphogenetic protein 2 (BMP2) expression was stimulated in a COX2-dependent manner. Although adiponectin had no effect on the expression of the key osteoblastic transcription factor Runx2, it greatly augmented its activity and the expression of genes regulated by Runx2. AdipoR1 expression increased during differentiation of the mesenchymal progenitor cells, and suppression of its expression by siRNA substantially reduced the adiponectin-dependent activation of gene expression. A study by Wu et al. [44] found that adiponectin-knockout (APN-KO) mice have increased sympathetic tone and bone marrow adiposity. Using pharmacological induction of sympathetic activity in bone marrow cell cultures to model the effect of adiponectin deficiency, the authors found that the cells were induced to differentiate to adipocytes rather than osteoblasts. This result indicates that adiponectin promotes osteoblastic commitment through a central effect on the sympathetic nervous system. Yu et al. [50] used a mouse bone defect model to study the effect of adiponectin on progenitor cell migration from the bone marrow into sites of bone regeneration. The hypothesis tested in this experimental system originated from the observation that patients with type-2 diabetes have impaired mobilization of cells from bone marrow and reduced serum adiponectin levels [57, 58]. The study found that adiponectin stimulates progenitor cell migration from bone marrow through the regulation of SDF-1 and that infusion of adiponectin in mice with diet-induced obesity ameliorates the impaired cell migration from the bone marrow [50].

The Effect of Adiponectin on Late Differentiation Stages and the Formation of Mineralized Nodules

In MC3T3-E1 osteoblast-like cells, binding of adiponectin to AdipoR1 activated the adenosine monophosphate-activated protein kinase (AMPK) pathway and enhanced alkaline phosphatase expression and mineralization [38, 54]. AMPK is a key molecule in adiponectin signaling and is activated downstream of the adaptor protein APPL1 in many cell types. Knockdown of AdipoR1 by siRNA decreased the expression of type I collagen and osteocalcin and reduced alkaline phosphatase activity and mineralization [54]. Similar to other osteoblastic cells, MC3T3-E1 cells have been shown to express adiponectin and therefore the authors suggest that knocking down AdipoR1 inhibited the autocrine effect of adiponectin in these cells. In human osteoblasts, adiponectin increased alkaline phosphatase activity, expression of collagen type I and osteocalcin, and mineralized matrix production [27]. In these cells, the effects of adiponectin on differentiation were mediated via AdipoR1 and the p38 MAPK pathway. In the human osteoblast-like cell lines MG-63 and hFOB, Huang et al. [59] have shown that adiponectin stimulates the expression of BMP-2. Analysis of the signaling pathways involved demonstrated that BMP-2 activation depends on adiponectin binding to AdipoR1 and downstream stimulation of AMPK, p38 and nuclear factor-kappaB (NF-kappaB) signaling.

In summary, in vitro studies of adiponectin effect on osteoblast proliferation produced conflicting results, whereas a positive effect on osteoblast differentiation was found more consistently. The evidence for positive effects of adiponectin in osteoblasts appears contradictory to the inverse relations between adiponectin levels and BMD determined in clinical studies.

The Activity of Adiponectin in Osteoclast-Like Cells

The Effects of Adiponectin on Osteoclast Formation and Activity

Adiponectin has predominantly been shown to strongly inhibit osteoclast formation, as has been demonstrated in human CD14+ peripheral blood mononuclear cells (PBMC), mouse primary bone marrow cultures and in RAW264.7 cells [38, 43, 48, 60, 61]. Only some of these studies mention the use of columns to remove LPS contamination or show that the effects were dependent on AdipoR1 [59, 60]. The inhibitory effect of adiponectin appears to be specific to the early differentiation stage of the osteoclasts. Thus, the inhibition of TNF-α and RANKL-induced osteoclast formation in RAW264.7 cells was only observed when adiponectin was added during the early stages of osteoclastogenesis, with no effect seen when treatment was delayed [61]. In addition, in a study of primary mouse bone marrow cultures adiponectin, in concentrations of 10 μg/mL or above, completely abolished osteoclast formation, but had no effect on osteoclast activity or pit formation in an isolated mature osteoclast assay [43].

In contrast, there is evidence that adiponectin induces osteoclastogenesis by osteoblast-mediated pathways. In primary human osteoblasts, adiponectin produced a dose- and time-dependent increase in the mRNA expression and protein synthesis of RANKL and decrease in OPG mRNA and protein secretion [62]. Suppression of AdipoR1 with siRNA abolished the effects of adiponectin on RANKL and OPG expression. When adiponectin was added to co-cultures of osteoblasts and isolated CD14+ PBMCs, there was an increase in the number of positively stained tartrate-resistant acid phosphatase (TRAP) multinucleated cells, suggesting that adiponectin stimulates osteoclast formation in an indirect manner by modulating the RANKL/OPG pathway. In this experimental system, the differentiation of osteoclasts from purified CD14+ PBMCs was not affected by adiponectin, suggesting that adiponectin has no direct effect in osteoclasts [62]. The latter observation is in contrast to Oshima et al. [38] who used the same experimental system and found that adiponectin dose-dependently suppressed differentiation of human CD14+ PBMCs into osteoclasts.

Signaling Pathways Induced by Adiponectin in Cells of the Osteoclast-Lineage

Adiponectin’s mechanisms of action and the signaling pathways involved in its inhibition of osteoclast formation have largely been studied in RAW264.7 cells. Adiponectin was shown to inhibit the expression of RANKL-stimulated nuclear factor of activated T cells c1 (Nfatc1), cathepsin K (Cstk) and tartrate-resistant acid phosphatase 5 (Acp5) mRNA, and decrease the activity of the Cstk promotor [48]. Similarly, adiponectin inhibited TNF-α/RANKL-induced Nfatc1 and Traf6 mRNA expression in RAW264.7 cells [61]. A study that tested the activity of adiponectin as a negative regulator of osteoclastogenesis induced by activation of Toll-like receptor 4 (TLR4) found that adiponectin inhibited TLR-mediated activation of NF-kappaB, as well as TLR-mediated increase in nitric oxide synthase expression and production of nitric oxide [60]. Using siRNA to knockdown APPL1 in RAW264.7 cells, Tu et al. [48] have shown that the inhibitory effect of adiponectin on osteoclasts was induced by APPL1-mediated down-regulation of Akt1 activity. Moreover, in this study overexpression of Akt1 successfully reversed adiponectin-induced inhibition in RANKL-stimulated osteoclast differentiation [48]. Adiponectin has also been shown to stimulate FoxO1 expression in RAW264.7 cells and induce the phosphorylation of JNK. Furthermore, over-expression of FOXO1 inhibited osteoclast formation and inhibited NFATc1 and cathepsin K production. This suggests that adiponectin may exert its anti-osteoclastogenic effects through the JNK/FOXO1 pathway [63].


The large number of studies that investigated the activity of adiponectin in bone substantially increased our understanding of the mechanisms of action of adiponectin in this tissue. As summarized in Fig. 1, adiponectin’s bone activity has been studied in vitro, in vivo and in clinical studies, and the strengths and weaknesses of each of these approaches should be considered when trying to draw overall conclusions about the role of adiponectin in bone physiology. The majority of in vitro studies found that adiponectin promotes osteoblast proliferation and differentiation while inhibiting osteoclastogenesis, activities that predict a positive effect in bone. However, clinical studies consistently show an inverse relationship between circulating adiponectin levels and BMD, and moreover, adiponectin has been identified as an independent risk factor for fracture in men. Studies of the bone properties of mice over-expressing adiponectin and adiponectin-deficient mice have been largely inconsistent, and results vary greatly among the different experimental models. Clearly, there is no simple unifying model that accounts for all the different experimental and observational results. This is perhaps unsurprising, given the multiple mechanisms that potentially underlie adiponectin’s activity in bone: local paracrine effects of adiponectin secreted from bone marrow adipocytes, endocrine effects of adiponectin secreted from white adipose tissue into the circulation, and indirect effects through modulation of the sympathetic tone and the regulation of insulin sensitivity and energy homeostasis. Future studies will hopefully discover the missing parts of the complex puzzle and further our understanding of the physiological role of adiponectin in bone biology.
Fig. 1

Summary of the key findings of adiponectin effects in bone in different experimental systems. Note: The diagram summarizes the main findings in vitro, in vivo and in clinical studies, and some of the strengths and weaknesses of each of these experimental approaches. The reference numbers of studies quoted in the manuscript are indicated. In the ‘Clinical studies’ panel the arrows indicate the direction of changes in BMD and fracture incidence with increased levels of adiponectin; in the ‘In vivo’ panel the arrows pointing upwards indicate increase in bone indices (including bone volume fraction, BMD, bone strength and others); and  in the ‘In vitro’ panel, the arrows pointing upwards indicate increase in proliferation and/or differentiation induced by adiponectin, and the arrows pointing down indicate inhibition. A small number of studies that found that adiponectin does not affect bone have not been included in the diagram



The authors thank Mr Greg Gamble for the valuable discussion. The work was supported by the Health Research Council of New Zealand and the Auckland Medical Research Foundation.

Compliance with Ethical Standards

Conflict of interest

Dorit Naot, David S. Musson, Jillian Cornish declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

For this type of study formal consent is not required.


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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of MedicineUniversity of AucklandAucklandNew Zealand

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